ANTI-FOLATE RECEPTOR CONJUGATE COMBINATION THERAPY WITH BEVACIZUMAB

Abstract

The present disclosure relates to combination therapies with antibody conjugates with binding specificity for folate receptor alpha (FOLR1) and its isoforms and homologs. Also provided are methods of using the combinations with antibody conjugates and compositions thereof, such as in therapeutic and diagnostic methods.

Claims

1. A method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject: (a) an effective amount of an antibody conjugate comprising an antibody that specifically binds to folate receptor alpha (FOLR1) linked site-specifically to at least one payload moiety, wherein the antibody comprises one or more non-natural amino acids at sites selected from the group consisting of: HC F404, HC-K121, HC-Y180, HC-F241, HC-221, LC-T22, LC-S7, LC-N152, LC-K42, LC-E161, LC-D170, HC-S136, HC S25, HC-A40, HC-S119, HC-S190, HC-K222, HC-R19, HC-Y52, or HC-S70, according to the Kabat, Chothia, or EU numbering scheme; and (b) an effective amount of one or more VEGF-A inhibitors.

2. The method of claim 1, wherein the administering is by intravenous (IV) administration.

3. The method of claim 1 or 2, wherein the antibody conjugate and the one or more VEGF-A inhibitors are administered separately on the same day.

4. The method of claim 1 or 2, wherein the antibody conjugate and the one or more VEGF-A inhibitors are administered simultaneously on the same day.

5. The method of any one of the previous claims, wherein the antibody conjugate and the one or more VEGF-A inhibitors are administered about once every 3 weeks or longer for the remainder of the treating.

6. The method of any one of the previous claims, wherein the antibody conjugate and the one or more VEGF-A inhibitors are administered about once every 3 weeks.

7. The method of any one of the previous claims, wherein the antibody conjugate and the one or more VEGF-A inhibitors are administered about once every 4 weeks.

8. The method of any one of the previous claims, wherein the amount of the antibody conjugate is about 3.5 mg/kg or more.

9. The method of any one of the previous claims, wherein the amount of the antibody conjugate is about 4.3 mg/kg.

10. The method of any one of the previous claims, wherein the amount of the antibody conjugate is about 5.2 mg/kg.

11. The method of any of the previous claims, further comprising administering to the subject the antibody conjugate at a reduced dose.

12. The method of claim 11, wherein the reduced dose is about 4.3 mg/kg or less.

13. The method of claim 11 or 12, wherein the reduced dose is about 4.3 mg/kg.

14. The method of claim 11 or 12, wherein the reduced dose is about 3.5 mg/kg.

15. The method of claim 11 or 12, wherein the reduced dose is about 2.9 mg/kg.

16. The method of any one of claims 11-15, wherein prior to the reduced dose, the antibody conjugate is administered to the subject at a first dose for one to five cycles, wherein each cycle is about 3 weeks or longer.

17. The method of claim 16, wherein prior to the reduced dose, the antibody conjugate is administered to the subject at a first dose for one to three cycles, wherein each cycle is about 3 weeks or longer.

18. The method of claim 16, wherein prior to the reduced dose, the antibody conjugate is administered to the subject at a first dose for two to four cycles, wherein each cycle is about 3 weeks or longer.

19. The method of any one of of the previous claims, wherein the one or more VEGF-A inhibitors comprise bevacizumab or a bevacizumab biosimilar.

20. The method of claim 19, wherein the bevacizumab biosimilar is selected from the group consisting of: MVASI, Zirabev, Bevax, Lumiere, Apotex, Equidacent, Avegra, BP 01, BCD500, Krabeva, BAT1706, BXT-2316, Bevaro, BI 695502, CT-P16, CHS-5217, DRZ_BZ, Cizumab, Byvasda, MIL60, MYL 14020, ONS-1045, HD204, Ankeda, Bevacirel, Aybintio, Onbevzi, HLX04, TX16, MB02, BI 695502, and Oyavas.

21. The method of claim 19, wherein the one or more VEGF-A inhibitors is bevacizumab.

22. The method of any one of the previous claims, wherein the amount of the one or more VEGF-A inhibitors is about 15 mg/kg.

23. The method of any one of the previous claims, wherein the one or more non-natural amino acids is selected from the group consisting of p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, an -3-(2-naphthyl) alanine, 3-methyl-phenylalanine, 0-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, a tri-O-acetyl-GlcNAcP-serine, L-Dopa, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-azido-methyl-L-phenylalanine, compound 56, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-iodo-phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, and -propargyloxy-phenylalanine.

24. The method of any one of the previous claims, wherein the one or more non-natural amino acids is compound (30) or compound (56).

25. The method of any one of the previous claims, wherein a residue of the one or more non-natural amino acids is linked to the payload moiety via a linker that is hydrolytically stable.

26. The method of any one of the previous claims, wherein a residue of the one or more non-natural amino acids is linked to the payload moiety via a linker that is cleavable.

27. The method of any one of the previous claims, wherein the payload moiety is selected from the group consisting of maytansines, hemiasterlins, amanitins, and auristatins.

28. The method of any one of the previous claims, wherein the payload moiety is selected from the group consisting of DM1, hemiasterlin, amanitin, MMAF, and MMAE.

29. The method of any one of the previous claims, wherein the payload moiety is a hemiasterlin derivative.

30. The method of any one of the previous claims, wherein the payload moiety is ##STR00026## wherein Ar is optionally substituted aryl or optionally substituted heteroaryl, L is a linker, and the wiggly line indicates a bond to the antibody.

31. The method of any one of the previous claims, wherein the antibody comprises: (i) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 362, and the V.sub.L region SEQ ID NO: 367; (ii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 323, and the V.sub.L region SEQ ID NO: 367; (iii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 308, and the V.sub.L region SEQ ID NO: 367; (iv) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 309, and the V.sub.L region SEQ ID NO: 367; (v) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 310, and the V.sub.L region SEQ ID NO: 367; (vi) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 311, and the V.sub.L region SEQ ID NO: 367; (vii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 312, and the V.sub.L region SEQ ID NO: 367; (viii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 313, and the V.sub.L region SEQ ID NO: 367; (ix) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 314, and the V.sub.L region SEQ ID NO: 367; (x) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 315, and the V.sub.L region SEQ ID NO: 367; (xi) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 316, and the V.sub.L region SEQ ID NO: 367; (xii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 317, and the V.sub.L region SEQ ID NO: 367; (xiii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 318, and the V.sub.L region SEQ ID NO: 367; (xiv) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 319, and the V.sub.L region SEQ ID NO: 367; (xv) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 320, and the V.sub.L region SEQ ID NO: 367; (xvi) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 321, and the V.sub.L region SEQ ID NO: 367; (xvii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 322, and the V.sub.L region SEQ ID NO: 367; (xviii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 324, and the V.sub.L region SEQ ID NO: 367; (xix) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 325, and the V.sub.L region SEQ ID NO: 367; (xx) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 326, and the V.sub.L region SEQ ID NO: 367; or (xxi) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 327, and the V.sub.L region SEQ ID NO: 367; (xxii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 328, and the V.sub.L region SEQ ID NO: 367; (xxiii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 329, and the V.sub.L region SEQ ID NO: 367; (xxiv) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 330, and the V.sub.L region SEQ ID NO: 367; (xxv) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 331, and the V.sub.L region SEQ ID NO: 367; (xxvi) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 332, and the V.sub.L region SEQ ID NO: 367; (xxvii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 333, and the V.sub.L region SEQ ID NO: 367; (xxviii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 334, and the V.sub.L region SEQ ID NO: 367; (xxix) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 335, and the V.sub.L region SEQ ID NO: 367; (xxx) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 336, and the V.sub.L region SEQ ID NO: 367; (xxxi) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 337, and the V.sub.L region SEQ ID NO: 367; (xxxii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 338, and the V.sub.L region SEQ ID NO: 367; (xxxiii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 339, and the V.sub.L region SEQ ID NO: 367; (xxxiv) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 340, and the V.sub.L region SEQ ID NO: 367; (xxxv) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 341, and the V.sub.L region SEQ ID NO: 367; (xxxvi) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 342, and the V.sub.L region SEQ ID NO: 367; (xxxvii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 343, and the V.sub.L region SEQ ID NO: 367; (xxxviii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 344, and the V.sub.L region SEQ ID NO: 367; (xxxix) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 345, and the V.sub.L region SEQ ID NO: 367; (xl) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 346, and the V.sub.L region SEQ ID NO: 367; (xli) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 347, and the V.sub.L region SEQ ID NO: 367; (xlii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 348, and the V.sub.L region SEQ ID NO: 367; (xliii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 349, and the V.sub.L region SEQ ID NO: 367; (xliv) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 350, and the V.sub.L region SEQ ID NO: 367; (xlv) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 351, and the V.sub.L region SEQ ID NO: 367; (xlvi) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 352, and the V.sub.L region SEQ ID NO: 367; (xlvii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 353, and the V.sub.L region SEQ ID NO: 367; (xlviii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 354, and the V.sub.L region SEQ ID NO: 367; (xlix) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 355, and the V.sub.L region SEQ ID NO: 367; (1) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 356, and the V.sub.L region SEQ ID NO: 367; (li) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 357, and the V.sub.L region SEQ ID NO: 367; (lii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 358, and the V.sub.L region SEQ ID NO: 367; (liii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 359, and the V.sub.L region SEQ ID NO: 367; (liv) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 360, and the V.sub.L region SEQ ID NO: 367; (lv) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 361, and the V.sub.L region SEQ ID NO: 367; (lvi) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 363, and the V.sub.L region SEQ ID NO: 368; (lvii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 364, and the V.sub.L region SEQ ID NO: 368; (lviii) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 365, and the V.sub.L region SEQ ID NO: 369; or (lix) three heavy chain CDRs and three light chain CDRs of the V.sub.H region SEQ ID NO: 366, and the V.sub.L region SEQ ID NO: 369.

32. The method of any one of the previous claims, wherein the antibody comprises: (i) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 58 and 117; a CDR-H2 comprising one of SEQ ID NOs: 176 and 235; and a CDR-H3 comprising SEQ ID NO: 294; (ii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 19 and 78; a CDR-H2 comprising one of SEQ ID NOs: 137 and 196; and a CDR-H3 comprising SEQ ID NO: 255; (iii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 4 and 63; a CDR-H2 comprising one of SEQ ID NOs: 122 and 181; and a CDR-H3 comprising SEQ ID NO: 240; (iv) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 5 and 64; a CDR-H2 comprising one of SEQ ID NOs: 123 and 182; and a CDR-H3 comprising SEQ ID NO: 241; (v) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 6 and 65; a CDR-H2 comprising one of SEQ ID NOs: 124 and 183; and a CDR-H3 comprising SEQ ID NO: 242; (vi) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 7 and 66; a CDR-H2 comprising one of SEQ ID NOs: 125 and 184; and a CDR-H3 comprising SEQ ID NO: 243; (vii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 8 and 67; a CDR-H2 comprising one of SEQ ID NOs: 126 and 185; and a CDR-H3 comprising SEQ ID NO: 244; (viii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 9 and 68; a CDR-H2 comprising one of SEQ ID NOs: 127 and 186; and a CDR-H3 comprising SEQ ID NO: 245; (ix) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 10 and 69; a CDR-H2 comprising one of SEQ ID NOs: 128 and 187; and a CDR-H3 comprising SEQ ID NO: 246; (x) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 11 and 70; a CDR-H2 comprising one of SEQ ID NOs: 129 and 188; and a CDR-H3 comprising SEQ ID NO: 247; (xi) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 12 and 71; a CDR-H2 comprising one of SEQ ID NOs: 130 and 189; and a CDR-H3 comprising SEQ ID NO: 248; (xii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 13 and 72; a CDR-H2 comprising one of SEQ ID NOs: 131 and 190; and a CDR-H3 comprising SEQ ID NO: 249; (xiii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 14 and 73; a CDR-H2 comprising one of SEQ ID NOs: 132 and 191; and a CDR-H3 comprising SEQ ID NO: 250; (xiv) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 15 and 74; a CDR-H2 comprising one of SEQ ID NOs: 133 and 192; and a CDR-H3 comprising SEQ ID NO: 251; (xv) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 16 and 75; a CDR-H2 comprising one of SEQ ID NOs: 134 and 193; and a CDR-H3 comprising SEQ ID NO: 252; (xvi) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 17 and 76; a CDR-H2 comprising one of SEQ ID NOs: 135 and 194; and a CDR-H3 comprising SEQ ID NO: 253; (xvii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 18 and 77; a CDR-H2 comprising one of SEQ ID NOs: 136 and 195; and a CDR-H3 comprising SEQ ID NO: 254; (xviii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 20 and 79; a CDR-H2 comprising one of SEQ ID NOs: 138 and 197; and a CDR-H3 comprising SEQ ID NO: 256; (xix) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 21 and 80; a CDR-H2 comprising one of SEQ ID NOs: 139 and 198; and a CDR-H3 comprising SEQ ID NO: 257; (xx) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 22 and 81; a CDR-H2 comprising one of SEQ ID NOs: 140 and 199; and a CDR-H3 comprising SEQ ID NO: 258; (xxi) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 23 and 82; a CDR-H2 comprising one of SEQ ID NOs: 141 and 200; and a CDR-H3 comprising SEQ ID NO: 259; (xxii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 24 and 83; a CDR-H2 comprising one of SEQ ID NOs: 142 and 201; and a CDR-H3 comprising SEQ ID NO: 260; (xxiii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 25 and 84; a CDR-H2 comprising one of SEQ ID NOs: 143 and 202; and a CDR-H3 comprising SEQ ID NO: 261; (xxiv) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 26 and 85; a CDR-H2 comprising one of SEQ ID NOs: 144 and 203; and a CDR-H3 comprising SEQ ID NO: 262; (xxv) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 27 and 86; a CDR-H2 comprising one of SEQ ID NOs: 145 and 204; and a CDR-H3 comprising SEQ ID NO: 263; (xxvi) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 28 and 87; a CDR-H2 comprising one of SEQ ID NOs: 146 and 205; and a CDR-H3 comprising SEQ ID NO: 264; (xxvii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 29 and 88; a CDR-H2 comprising one of SEQ ID NOs: 147 and 206; and a CDR-H3 comprising SEQ ID NO: 265; (xxviii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 30 and 89; a CDR-H2 comprising one of SEQ ID NOs: 148 and 207; and a CDR-H3 comprising SEQ ID NO: 266; (xxix) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 31 and 90; a CDR-H2 comprising one of SEQ ID NOs: 149 and 208; and a CDR-H3 comprising SEQ ID NO: 267; (xxx) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 32 and 91; a CDR-H2 comprising one of SEQ ID NOs: 150 and 209; and a CDR-H3 comprising SEQ ID NO: 268; (xxxi) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 33 and 92; a CDR-H2 comprising one of SEQ ID NOs: 151 and 210; and a CDR-H3 comprising SEQ ID NO: 269; (xxxii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 34 and 93; a CDR-H2 comprising one of SEQ ID NOs: 152 and 211; and a CDR-H3 comprising SEQ ID NO: 270; (xxxiii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 35 and 94; a CDR-H2 comprising one of SEQ ID NOs: 153 and 212; and a CDR-H3 comprising SEQ ID NO: 271; (xxxiv) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 36 and 95; a CDR-H2 comprising one of SEQ ID NOs: 154 and 213; and a CDR-H3 comprising SEQ ID NO: 272; (xxxv) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 37 and 96; a CDR-H2 comprising one of SEQ ID NOs: 155 and 214; and a CDR-H3 comprising SEQ ID NO: 273; (xxxvi) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 38 and 97; a CDR-H2 comprising one of SEQ ID NOs: 156 and 215; and a CDR-H3 comprising SEQ ID NO: 274; (xxxvii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 39 and 98; a CDR-H2 comprising one of SEQ ID NOs: 157 and 216; and a CDR-H3 comprising SEQ ID NO: 275; (xxxviii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 40 and 99; a CDR-H2 comprising one of SEQ ID NOs: 158 and 217; and a CDR-H3 comprising SEQ ID NO: 276; (xxxix) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 41 and 100; a CDR-H2 comprising one of SEQ ID NOs: 159 and 218; and a CDR-H3 comprising SEQ ID NO: 277; (xl) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 42 and 101; a CDR-H2 comprising one of SEQ ID NOs: 160 and 219; and a CDR-H3 comprising SEQ ID NO: 278; (xli) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 43 and 102; a CDR-H2 comprising one of SEQ ID NOs: 161 and 220; and a CDR-H3 comprising SEQ ID NO: 279; (xlii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 44 and 103; a CDR-H2 comprising one of SEQ ID NOs: 162 and 221; and a CDR-H3 comprising SEQ ID NO: 280; (xliii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 45 and 10.sup.4; a CDR-H2 comprising one of SEQ ID NOs: 163 and 222; and a CDR-H3 comprising SEQ ID NO: 281; (xliv) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 46 and 10.sup.5; a CDR-H2 comprising one of SEQ ID NOs: 164 and 223; and a CDR-H3 comprising SEQ ID NO: 282; (xlv) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 47 and 106; a CDR-H2 comprising one of SEQ ID NOs: 165 and 224; and a CDR-H3 comprising SEQ ID NO: 283; (xlvi) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 48 and 10.sup.7; a CDR-H2 comprising one of SEQ ID NOs: 166 and 225; and a CDR-H3 comprising SEQ ID NO: 284; (xlvii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 49 and 10.sup.8; a CDR-H2 comprising one of SEQ ID NOs: 167 and 226; and a CDR-H3 comprising SEQ ID NO: 285; (xlviii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 50 and 10.sup.9; a CDR-H2 comprising one of SEQ ID NOs: 168 and 227; and a CDR-H3 comprising SEQ ID NO: 286; (xlix) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 51 and 110; a CDR-H2 comprising one of SEQ ID NOs: 169 and 228; and a CDR-H3 comprising SEQ ID NO: 287; (1) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 52 and 111; a CDR-H2 comprising one of SEQ ID NOs: 170 and 229; and a CDR-H3 comprising SEQ ID NO: 288; (li) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 53 and 112; a CDR-H2 comprising one of SEQ ID NOs: 171 and 230; and a CDR-H3 comprising SEQ ID NO: 289; (lii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 54 and 113; a CDR-H2 comprising one of SEQ ID NOs: 172 and 231; and a CDR-H3 comprising SEQ ID NO: 290; (liii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 55 and 114; a CDR-H2 comprising one of SEQ ID NOs: 173 and 232; and a CDR-H3 comprising SEQ ID NO: 291; (liv) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 56 and 115; a CDR-H2 comprising one of SEQ ID NOs: 174 and 233; and a CDR-H3 comprising SEQ ID NO: 292; (lv) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 57 and 116; a CDR-H2 comprising one of SEQ ID NOs: 175 and 234; and a CDR-H3 comprising SEQ ID NO: 293; (lvi) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 59 and 118; a CDR-H2 comprising one of SEQ ID NOs: 177 and 236; and a CDR-H3 comprising SEQ ID NO: 295; (lvii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 60 and 119; a CDR-H2 comprising one of SEQ ID NOs: 178 and 237; and a CDR-H3 comprising SEQ ID NO: 296; (lviii) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 61 and 120; a CDR-H2 comprising one of SEQ ID NOs: 179 and 238; and a CDR-H3 comprising SEQ ID NO: 297; or (lix) a V.sub.H comprising: a CDR-H1 comprising one of SEQ ID NOs: 62 and 121; a CDR-H2 comprising one of SEQ ID NOs: 180 and 239; and a CDR-H3 comprising SEQ ID NO: 298.

33. The method of any one of the previous claims, wherein the antibody comprises: (a) a V.sub.L comprising: a CDR-L1 comprising SEQ ID NO: 300; a CDR-L2 comprising SEQ ID NO: 303; and a CDR-L3 comprising SEQ ID NO: 306; or (b) a V.sub.L comprising: a CDR-L1 comprising SEQ ID NO: 301; a CDR-L2 comprising SEQ ID NO: 304; and a CDR-L3 comprising SEQ ID NO: 307.

34. The method of any one of the previous claims, wherein the antibody comprises: (i) the V.sub.H region is SEQ ID NO: 362, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (ii) the V.sub.H region is SEQ ID NO: 323, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (iii) the V.sub.H region is SEQ ID NO: 308, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (iv) the V.sub.H region is SEQ ID NO: 309, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (v) the V.sub.H region is SEQ ID NO: 310, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (vi) the V.sub.H region is SEQ ID NO: 311, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (vii) the V.sub.H region is SEQ ID NO: 312, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (viii) the V.sub.H region is SEQ ID NO: 313, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (ix) the V.sub.H region is SEQ ID NO: 314, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (x) the V.sub.H region is SEQ ID NO: 315, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xi) the V.sub.H region is SEQ ID NO: 316, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xii) the V.sub.H region is SEQ ID NO: 317, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xiii) the V.sub.H region is SEQ ID NO: 318, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xiv) the V.sub.H region is SEQ ID NO: 319, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xv) the V.sub.H region is SEQ ID NO: 320, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xvi) the V.sub.H region is SEQ ID NO: 321, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xvii) the V.sub.H region is SEQ ID NO: 322, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xviii) the V.sub.H region is SEQ ID NO: 324, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xix) the V.sub.H region is SEQ ID NO: 325, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xx) the V.sub.H region is SEQ ID NO: 326, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; or (xxi) the V.sub.H region is SEQ ID NO: 327, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxii) the V.sub.H region is SEQ ID NO: 328, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxiii) the V.sub.H region is SEQ ID NO: 329, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxiv) the V.sub.H region is SEQ ID NO: 330, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxv) the V.sub.H region is SEQ ID NO: 331, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxvi) the V.sub.H region is SEQ ID NO: 332, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxvii) the V.sub.H region is SEQ ID NO: 333, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxviii) the V.sub.H region is SEQ ID NO: 334, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxix) the V.sub.H region is SEQ ID NO: 335, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxx) the V.sub.H region is SEQ ID NO: 336, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxxi) the V.sub.H region is SEQ ID NO: 337, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxxii) the V.sub.H region is SEQ ID NO: 338, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxxiii) the V.sub.H region is SEQ ID NO: 339, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxxiv) the V.sub.H region is SEQ ID NO: 340, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxxv) the V.sub.H region is SEQ ID NO: 341, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxxvi) the V.sub.H region is SEQ ID NO: 342, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxxvii) the V.sub.H region is SEQ ID NO: 343, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxxviii) the V.sub.H region is SEQ ID NO: 344, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xxxix) the V.sub.H region is SEQ ID NO: 345, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xl) the V.sub.H region is SEQ ID NO: 346, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xli) the V.sub.H region is SEQ ID NO: 347, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xlii) the V.sub.H region is SEQ ID NO: 348, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xliii) the V.sub.H region is SEQ ID NO: 349, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xliv) the V.sub.H region is SEQ ID NO: 350, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xlv) the V.sub.H region is SEQ ID NO: 351, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xlvi) the V.sub.H region is SEQ ID NO: 352, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xlvii) the V.sub.H region is SEQ ID NO: 353, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xlviii) the V.sub.H region is SEQ ID NO: 354, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (xlix) the V.sub.H region is SEQ ID NO: 355, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (1) the V.sub.H region is SEQ ID NO: 356, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (li) the V.sub.H region is SEQ ID NO: 357, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (lii) the V.sub.H region is SEQ ID NO: 358, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (liii) the V.sub.H region is SEQ ID NO: 359, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (liv) the V.sub.H region is SEQ ID NO: 360, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (lv) the V.sub.H region is SEQ ID NO: 361, or a variant thereof, and the V.sub.L region is SEQ ID NO: 367, or a variant thereof; (lvi) the V.sub.H region is SEQ ID NO: 363, or a variant thereof, and the V.sub.L region is SEQ ID NO: 368, or a variant thereof; (lvii) the V.sub.H region is SEQ ID NO: 364, or a variant thereof, and the V.sub.L region is SEQ ID NO: 368, or a variant thereof; (lviii) the V.sub.H region is SEQ ID NO: 365, or a variant thereof, and the V.sub.L region is SEQ ID NO: 369, or a variant thereof; or (lix) the V.sub.H region is SEQ ID NO: 366, or a variant thereof, and the V.sub.L region is SEQ ID NO: 369, or a variant thereof.

35. The method of any one of the previous claims, wherein the antibody comprises one or more non-natural amino acids at sites selected from the group of: HC-F404, HC-Y180, and LC-K42 according to the Kabat or EU numbering scheme of Kabat.

36. The method of any one of the previous claims, wherein the antibody comprises a non-natural amino acid at site HC-F404.

37. The method any one of the previous claims, wherein the antibody comprises non-natural amino acids at sites HC-F404 and HC-Y180.

38. The method of any one of the previous claims, wherein the antibody comprises non-natural amino acids at sites HC-F404 and LC-K42.

39. The method of any one of the previous claims, wherein the antibody comprises non-natural amino acids at sites HC-Y180 and LC-K42.

40. The method of any one of claims 36 to 39, wherein one or both non-natural amino acids is selected from the group consisting of para-azidomethylphenylalanine and -azido-methyl-L-phenylalanine.

41. The method of any one of the previous claims, wherein the antibody conjugate has the structure of Conjugate P: ##STR00027## wherein n is an integer from 1 to 6.

42. The method of any one of claims 1 to 40, wherein the antibody conjugate has the structure of Conjugate M: ##STR00028## wherein n is an integer from 1 to 6.

43. The method of any one of claims 1 to 40, wherein the antibody conjugate has the structure of Conjugate Q: ##STR00029## wherein n is an integer from 1 to 6.

44. The method of any one of the previous claims, wherein the antibody comprises a V.sub.H region of SEQ ID NO: 362, or a variant thereof 7 or fewer amino acid substitutions, and a V.sub.L region of SEQ ID NO: 367, or a variant thereof having 7 or fewer amino acid substitutions.

45. The method of any one of the previous claims, wherein the antibody comprises a V.sub.H region of SEQ ID NO: 323, or a variant thereof 7 or fewer amino acid substitutions, and a V.sub.L region of SEQ ID NO: 367, or a variant thereof having 7 or fewer amino acid substitutions.

46. The method of claim 44 or 45, wherein the amino acid substitutions are conservative amino acid substitutions.

47. The method of any one of the previous claims, wherein the antibody further comprises at least one constant region domain.

48. The method of claim 47, wherein the constant region comprises a sequence selected from SEQ ID NOs: 370, 371, and 372.

49. The method of any one of the previous claims, wherein the antibody is a monoclonal antibody.

50. The method of any one of the previous claims, wherein the antibody is an IgA, an IgD, an IgE, an IgG, or an IgM.

51. The method of any one of the previous claims, wherein the antibody is humanized or human.

52. The method of any one of the previous claims, wherein the antibody is aglycosylated.

53. The method of any one of the previous claims, wherein the antibody is an antibody fragment.

54. The method of claim 53, wherein the antibody fragment is selected from an Fv fragment, a Fab fragment, a F(ab).sub.2 fragment, a Fab fragment, an scFv (sFv) fragment, and an scFv-Fc fragment.

55. The method of claim 54, wherein the antibody fragment is an scFv fragment.

56. The method of claim 55, wherein the antibody fragment is an scFv-Fc fragment.

57. The method of any one of the previous claims, wherein the subject previously received cancer treatment.

58. The method of any one of the previous claims, wherein the subject did not previously receive cancer treatment.

59. The method of any one of the previous claims, wherein the subject was diagnosed with cancer.

60. The method of any one of the previous claims, wherein the cancer is ovarian cancer.

61. The method of claim 35, wherein the cancer is epithelial ovarian cancer.

62. The method of any one of the previous claims, wherein the cancer is endometrial cancer.

63. The method of any of the previous claims wherein the VEGF inhibitor is bevacizumab and the antibody conjugate has the structure of Conjugate P: ##STR00030## wherein n is 4; the antibody is an IgG antibody comprising V.sub.H regions according to SEQ ID NO: 362, and V.sub.L regions according SEQ ID NO: 367; the antibody further comprises para-azidomethylphenylaline residues substituting for Y180 and F404 of each V.sub.H region; and each bond in the structure to the antibody is to the side chain of one of the para-azidomethylphenylaline residues.

64. The method of claim 63, wherein the antibody constant regions are according to SEQ ID NO:370.

65. The method of claim 63, wherein the antibody constant regions are according to SEQ ID NO:371.

66. The method of claim 63, wherein the antibody constant regions are according to SEQ ID NO:372.

67. A kit comprising: (a) an effective amount of an antibody conjugate according to any one of the previous claims; (b) an effective amount of one or more VEGF-A inhibitors, and (c) instructions for use of the antibody conjugate and the VEGF-A inhibitor.

68. A pharmaceutical package or kit, comprising: a container; a folate receptor alpha (FOLR1) antibody conjugate; a VEGF-A inhibitor; and a package insert comprising instructions to administer the FOLR1 antibody conjugate and the VEGF-A inhibitor according the method of any of the previous claims.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0015] FIG. 1 provides tumor size over time and body weight change over time for OV-90 mouse tumor models following administration of 2.5 mg/kg Conjugate A, 5.0 mg/kg VEGF trap, and a combination of 2.5 mg/kg Conjugate A and 5.0 mg/kg bevacizumab.

[0016] FIG. 2A provides in vivo efficacy of Conjugate A as 5 mg/kg monotherapy and combined with 5 mg/kg bevacizumab in OV-90 tumor models. FIG. 2B provides percent body weight change calculated relative to animal weight at the start of the study.

DETAILED DESCRIPTION OF THE EMBODIMENTS

1. Definitions

[0017] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0018] It is understood that aspects and embodiments described herein as comprising include consisting of and consisting essentially of embodiments.

[0019] As used herein, the singular forms a, an, and the include the plural referents unless the context clearly indicates otherwise.

[0020] The term about indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term about indicates the designated value10%, 5%, or 1%. In certain embodiments, the term about indicates the designated valueone standard deviation of that value.

[0021] The term combinations thereof includes every possible combination of elements to which the term refers to. For example, a sentence stating that if .sub.2 is A, then .sub.3 is not D; Us is not S; or .sub.6 is not S; or combinations thereof includes the following combinations when .sub.2 is A: (1) .sub.3 is not D; (2) .sub.5 is not S; (3) .sub.6 is not S; (4) .sub.3 is not D; .sub.6 is not S; and .sub.6 is not S; (5) .sub.3 is not D and .sub.5 is not S; (6) .sub.3 is not D and .sub.6 is not S; and (7) .sub.5 is not S and .sub.6 is not S.

[0022] The terms folate receptor alpha and folate receptor 1 are used interchangeably herein. Folate receptor alpha is also known by synonyms, including FOLR1, Fo1R, folate binding protein, FBP, adult folate binding protein, Fo1bp1, FR-alpha, FR, KB cells FBP, and ovarian tumor-associated antigen MOv18, among others. Unless specified otherwise, the terms include any variants, isoforms and species homologs of human folate receptor alpha that are naturally expressed by cells, or that are expressed by cells transfected with a folate receptor alpha or FOLR1 gene. Folate receptor alpha proteins include, for example, human folate receptor alpha (SEQ ID NO: 1). In some embodiments, folate receptor alpha proteins include cynomolgus monkey folate receptor alpha (SEQ ID NO: 2). In some embodiments, folate receptor alpha proteins include murine folate receptor alpha (SEQ ID NO: 3).

[0023] The term angiogenesis inhibitor as used herein refers to a substance that inhibits the formation of new blood vessels.

[0024] VEGF refers to vascular endothelial growth factor. VEGF is a signaling protein produced by many cells that stimulates the formation of blood vessels. VEGF is known in the art (see e.g., Shibuya, M. (2013) J Biochem 153(1):13-19). Normally, VEGF functions to facilitate the creation of new blood vessels during embryonic development, new blood vessels after injury, muscle following exercise, and new vessels (collateral circulation) to bypass blocked vessels. The VEGF family comprises five members: VEGF-A, placenta growth factor (PGF), VEGF-B, VEGF-C, VEGF-D, VEGF-E, and endocrine gland-derived vascular endothelial growth factor (EG-VEGF). The latter members were discovered after VEGF-A; before their discovery, VEGF-A was known as VEGF. Accordingly, as used herein, the term VEGF and VEGF-A and synonymous.

[0025] Bevacizumab is a humanized monoclonal antibody that produces angiogenesis inhibition by inhibiting the activity of vascular endothelial growth factor A (VEGF-A). Bevacizumab binds VEGF, thus preventing the binding of VEGF to the VEGF receptor (VEGFR). Bevacizumab is known in the art (see e.g., Ignoffo, R. J. (2004) American Journal of Health-System Pharmacy 61, Issue suppl 5: S21-S26).

[0026] The term biologic as used herein, refers to a drug substance is made by a living organism or derived from a living organism or made through recombinant DNA or controlled gene expression methodologies.

[0027] The term biosimilar or follow-on-biologic as used herein, refers to products that have similar structures and properties to existing biologic products. Thus, the term biosimilar is generally used to describe subsequent versions (generally from a different source) of innovator biopharmaceutical products that have previously been approved and officially granted marketing authorization. Because biologics have a high degree of molecular complexity, and are generally sensitive to changes in manufacturing processes (e.g. if different cell lines are used in their production), and since subsequent follow-on manufacturers generally do not have access to the originators molecular clone, cell bank, know-how regarding the production process, nor to the active drug substance itself (only the innovator's commercialized drug product), a biosimilar may not be exactly the same as the innovator drug product. However, biosimilars must demonstrate that they have no clinically meaningful differences from their reference products in terms of safety and effectiveness. Therefore, because biosimilars are subsequent versions of a known product and must demonstrate that they have no clinically meaningful differences from their reference products, the term biosimilar as used herein includes currently known and approved biosimilars as well as any biosimilars developed in the future.

[0028] The term immunoglobulin refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an intact immunoglobulin, all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (V.sub.H) and a heavy chain constant region (C.sub.H). The heavy chain constant region typically comprises three domains, abbreviated C.sub.H1, C.sub.H2, and C.sub.H3. Each light chain typically comprises a light chain variable region (V.sub.L) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated C.sub.L.

[0029] The term antibody describes a type of immunoglobulin molecule and is used herein in its broadest sense. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), and antibody fragments. Antibodies comprise at least one antigen-binding domain. One example of an antigen-binding domain is an antigen binding domain formed by a V.sub.H-V.sub.L dimer. A folate receptor alpha antibody, anti-folate receptor alpha antibody, folate receptor alpha Ab, folate receptor alpha-specific antibody, anti-folate receptor alpha Ab, FOLR1 antibody, Fo1R antibody, anti-FOLR1 antibody, anti-Fo1R antibody, FOLR1 Ab, Fo1R Ab, FOLR1-specific antibody, Fo1R-specific antibody, anti-Fo1R Ab, or anti-FOLR1 Ab is an antibody, as described herein, which binds specifically to folate receptor alpha or FOLR1. In some embodiments, the antibody binds the extracellular domain of folate receptor alpha (FOLR1).

[0030] The V.sub.H and V.sub.L regions may be further subdivided into regions of hypervariability (hypervariable regions (HVRs); also called complementarity determining regions (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs). Each V.sub.H and V.sub.L generally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The CDRs are involved in antigen binding, and influence antigen specificity and binding affinity of the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, incorporated by reference in its entirety.

[0031] The light chain from any vertebrate species can be assigned to one of two types, called kappa and lambda, based on the sequence of the constant domain.

[0032] The heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated , , , , and , respectively. The IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0033] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (Kabat numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (Chothia numbering scheme); MacCallum et al., 1996, J. Mol. Biol. 262:732-745 (Contact numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (IMGT numbering scheme); and Honegge and Pluckthun, J. Mol. Biol., 2001, 309:657-70 (AHo numbering scheme), each of which is incorporated by reference in its entirety.

[0034] Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

TABLE-US-00001 TABLE 1 Residues in CDRs according to Kabat and Chothia numbering schemes. CDR Kabat Chothia L1 L24-L34 L24-L34 L2 L50-L56 L50-L56 L3 L89-L97 L89-L97 H1 (Kabat Numbering) H31-H35B H26-H32 or H34* H1 (Chothia Numbering) H31-H35 H26-H32 H2 H50-H65 H52-H56 H3 H95-H102 H95-H102 *The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.

[0035] Unless otherwise specified, the numbering scheme used for identification of a particular CDR herein is the Kabat/Chothia numbering scheme. Where the residues encompassed by these two numbering schemes diverge (e.g., CDR-H1 and/or CDR-H2), the numbering scheme is specified as either Kabat or Chothia. For convenience, CDR-H3 is sometimes referred to herein as either Kabat or Chothia. However, this is not intended to imply differences in sequence where they do not exist, and one of skill in the art can readily confirm whether the sequences are the same or different by examining the sequences.

[0036] CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at www.bioinf.org.uk/abs/abnum/, and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, incorporated by reference in its entirety.

[0037] The EU numbering scheme is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0038] An antibody fragment comprises a portion of an intact antibody, such as the antigen binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab).sub.2 fragments, Fab fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0039] Fv fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0040] Fab fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (C.sub.H1) of the heavy chain.

[0041] Fab fragments may be generated, for example, by recombinant methods or by papain digestion of a full-length antibody.

[0042] F(ab).sub.2 fragments contain two Fab fragments joined, near the hinge region, by disulfide bonds. F(ab).sub.2 fragments may be generated, for example, by recombinant methods or by pepsin digestion of an intact antibody. The F(ab) fragments can be dissociated, for example, by treatment with -mercaptoethanol.

[0043] Single-chain Fv or sFv or scFv antibody fragments comprise a V.sub.H domain and a V.sub.L domain in a single polypeptide chain. The V.sub.H and V.sub.L are generally linked by a peptide linker. See Plckthun A. (1994). In some embodiments, the linker is SEQ ID NO: 377. In some embodiments, the linker is SEQ ID NO: 378. Antibodies from Escherichia coli. In Rosenberg M. & Moore G. P. (Eds.), The Pharmacology of Monoclonal Antibodies vol. 113 (pp. 269-315). Springer-Verlag, New York, incorporated by reference in its entirety.

[0044] scFv-Fc fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminus of the scFv. The Fc domain may follow the V.sub.H or V.sub.L, depending on the orientation of the variable domains in the scFv (i.e., V.sub.H-V.sub.L or V.sub.L-V.sub.H). Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises an IgG1 Fc domain. In some embodiments, the IgG1 Fc domain comprises SEQ ID NO: 370, or a portion thereof. SEQ ID NO: 370 provides the sequence of C.sub.HI, C.sub.H2, and C.sub.H3 of the human IgG1 constant region.

[0045] The term monoclonal antibody refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (affinity maturation), to humanize the antibody, to improve its production in cell culture, and/or to reduce its immunogenicity in a subject.

[0046] The term chimeric antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.

[0047] Humanized forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. A humanized antibody is generally a human immunoglobulin (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs of a non-human antibody (donor antibody). The donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biological effect. In some instances, selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues from the donor antibody. Humanized antibodies may also comprise residues that are not found in either the recipient antibody or the donor antibody. Such modifications may be made to further refine antibody function. For further details, see Jones et al., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety.

[0048] A human antibody is one which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0049] An isolated antibody is one that has been separated and/or recovered from a component of its natural environment. Components of the natural environment may include enzymes, hormones, and other proteinaceous or nonproteinaceous materials. In some embodiments, an isolated antibody is purified to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, for example by use of a spinning cup sequenator. In some embodiments, an isolated antibody is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or nonreducing conditions, with detection by Coomassie blue or silver stain. An isolated antibody includes an antibody in situ within recombinant cells, since at least one component of the antibody's natural environment is not present. In some aspects, an isolated antibody is prepared by at least one purification step.

[0050] In some embodiments, an isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by weight. In some embodiments, an isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by volume. In some embodiments, an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by weight. In some embodiments, an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by volume.

[0051] Affinity refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, binding affinity refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can be represented by the dissociation constant (K.sub.D). Affinity can be measured by common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology, such as a Biacore instrument. In some embodiments, the affinity is determined at 25 C.

[0052] With regard to the binding of an antibody to a target molecule, the terms specific binding, specifically binds to, specific for, selectively binds, and selective for a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. Specific binding can also be determined by competition with a control molecule that mimics the antibody binding site on the target. In that case, specific binding is indicated if the binding of the antibody to the target is competitively inhibited by the control molecule.

[0053] The term k.sub.d (sec.sup.1), as used herein, refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the k.sub.off value.

[0054] The term k.sub.a (M.sup.1sec.sup.1), as used herein, refers to the association rate constant of a particular antibody-antigen interaction. This value is also referred to as the k.sub.on value.

[0055] The term K.sub.D (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. K.sub.D=k.sub.d/k.sub.a.

[0056] The term K.sub.A (M.sup.1), as used herein, refers to the association equilibrium constant of a particular antibody-antigen interaction. K.sub.A=k.sub.a/k.sub.d.

[0057] An affinity matured antibody is one with one or more alterations in one or more CDRs or FRs that result in an improvement in the affinity of the antibody for its antigen, compared to a parent antibody which does not possess the alteration(s). In one embodiment, an affinity matured antibody has nanomolar or picomolar affinity for the target antigen. Affinity matured antibodies may be produced using a variety of methods known in the art. For example, Marks et al. (Bio Technology, 1992, 10:779-783, incorporated by reference in its entirety) describes affinity maturation by V.sub.H and V.sub.L domain shuffling. Random mutagenesis of CDR and/or framework residues is described by, for example, Barbas et al. (Proc. Nat. Acad. Sci. U.S.A., 1994, 91:3809-3813); Schier et al., Gene, 1995, 169:147-155; Yelton et al., J. Immunol., 1995, 155:1994-2004; Jackson et al., J. Immunol., 1995, 154:3310.sup.33199; and Hawkins et al, J. Mol. Biol., 1992, 226:889-896, each of which is incorporated by reference in its entirety.

[0058] When used herein in the context of two or more antibodies, the term competes with or cross-competes with indicates that the two or more antibodies compete for binding to an antigen (e.g., folate receptor alpha, or FOLR1). In one exemplary assay, FOLR1 is coated on a plate and allowed to bind a first antibody, after which a second, labeled antibody is added. If the presence of the first antibody reduces binding of the second antibody, then the antibodies compete. In another exemplary assay, a first antibody is coated on a plate and allowed to bind the antigen, and then the second antibody is added. The term competes with also includes combinations of antibodies where one antibody reduces binding of another antibody, but where no competition is observed when the antibodies are added in the reverse order. However, in some embodiments, the first and second antibodies inhibit binding of each other, regardless of the order in which they are added. In some embodiments, one antibody reduces binding of another antibody to its antigen by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0059] The term epitope means a portion of an antigen capable of specific binding to an antibody. Epitopes frequently consist of surface-accessible amino acid residues and/or sugar side chains and may have specific three dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to variants of folate receptor alpha (FOLR1) with different point-mutations.

[0060] Percent identity between a polypeptide sequence and a reference sequence, is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0061] A conservative substitution or a conservative amino acid substitution, refers to the substitution of an amino acid with a chemically or functionally similar amino acid. Conservative substitution tables providing similar amino acids are well known in the art. Polypeptide sequences having such substitutions are known as conservatively modified variants. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles. By way of example, the groups of amino acids provided in Tables 2-4 are, in some embodiments, considered conservative substitutions for one another.

TABLE-US-00002 TABLE 2 Selected groups of amino acids that are considered conservative substitutions for one another, in certain embodiments. Acidic Residues D and E Basic Residues K, R, and H Hydrophilic Uncharged Residues S, T, N, and Q Aliphatic Uncharged Residues G, A, V, L, and I Non-polar Uncharged Residues C, M, and P Aromatic Residues F, Y, and W Alcohol Group-Containing Residues S and T Aliphatic Residues I, L, V, and M Cycloalkenyl-associated Residues F, H, W, and Y Hydrophobic Residues A, C, F, G, H, I, L, M, R, T, V, W, and Y Negatively Charged Residues D and E Polar Residues C, D, E, H, K, N, Q, R, S, and T Positively Charged Residues H, K, and R Small Residues A, C, D, G, N, P, S, T, and V Very Small Residues A, G, and S Residues Involved in Turn A, C, D, E, G, H, K, N, Q, R, S, Formation P, and T Flexible Residues Q, T, K, S, G, P, D, E, and R

TABLE-US-00003 TABLE 3 Additional selected groups of amino acids that are considered conservative substitutions for one another, in certain embodiments. Group 1 A, S, and T Group 2 D and E Group 3 N and Q Group 4 R and K Group 5 I, L, and M Group 6 F, Y, and W

TABLE-US-00004 TABLE 4 Further selected groups of amino acids that are considered conservative substitutions for one another, in certain embodiments. Group A A and G Group B D and E Group C N and Q Group D R, K, and H Group E I, L, M, V Group F F, Y, and W Group G S and T Group H C and M

[0062] Additional conservative substitutions may be found, for example, in Creighton, Proteins: Structures and Molecular Properties 2nd ed. (1993) W. H. Freeman & Co., New York, NY. An antibody generated by making one or more conservative substitutions of amino acid residues in a parent antibody is referred to as a conservatively modified variant.

[0063] The term amino acid refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), Glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

[0064] Naturally encoded amino acids are the proteinogenic amino acids known to those of skill in the art. They include the 20 common amino acids (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine) and the less common pyrrolysine and selenocysteine. Naturally encoded amino acids include post-translational variants of the 22 naturally occurring amino acids such as prenylated amino acids, isoprenylated amino acids, myrisoylated amino acids, palmitoylated amino acids, N-linked glycosylated amino acids, O-linked glycosylated amino acids, phosphorylated amino acids and acylated amino acids.

[0065] The term non-natural amino acid refers to an amino acid that is not a proteinogenic amino acid, or a post-translationally modified variant thereof. In particular, the term refers to an amino acid that is not one of the 20 common amino acids or pyrrolysine or selenocysteine, or post-translationally modified variants thereof.

[0066] The term conjugate or antibody conjugate refers to an antibody linked to one or more payload moieties. The antibody can be any antibody described herein. The payload can be any payload described herein. The antibody can be directly linked to the payload via a covalent bond, or the antibody can be linked to the payload indirectly via a linker. Typically, the linker is covalently bonded to the antibody and also covalently bonded to the payload. The term antibody drug conjugate or ADC refers to a conjugate wherein at least one payload is a therapeutic moiety such as a drug.

[0067] The term payload refers to a molecular moiety that can be conjugated to an antibody. In particular embodiments, payloads are selected from the group consisting of therapeutic moieties and labelling moieties.

[0068] The term linker refers to a molecular moiety that is capable of forming at least two covalent bonds. Typically, a linker is capable of forming at least one covalent bond to an antibody and at least another covalent bond to a payload. In certain embodiments, a linker can form more than one covalent bond to an antibody. In certain embodiments, a linker can form more than one covalent bond to a payload or can form covalent bonds to more than one payload. After a linker forms a bond to an antibody, or a payload, or both, the remaining structure, i.e. the residue of the linker after one or more covalent bonds are formed, may still be referred to as a linker herein. The term linker precursor refers to a linker having one or more reactive groups capable of forming a covalent bond with an antibody or payload, or both. In some embodiments, the linker is a cleavable linker. For example, a cleavable linker can be one that is released by an bio-labile function, which may or may not be engineered. In some embodiments, the linker is a non-cleavable linker. For example, a non-cleavable linker can be one that is released upon degradation of the antibody.

[0069] The terms pharmaceutical formulation and pharmaceutical composition refer to preparations that are in such form as to permit the biological activity of the active ingredient to be effective, and that contain no additional components that are unacceptably toxic to an individual to which the formulation or composition would be administered. Such formulations or compositions may be sterile.

[0070] Excipients as used herein include pharmaceutically acceptable excipients, carriers, vehicles, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. In some embodiments, the physiologically acceptable excipient is an aqueous pH buffered solution.

[0071] Treating or treatment of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject. In another embodiment, treating or treatment includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, treating or treatment includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, treating or treatment includes delaying or preventing the onset of the disease or disorder.

[0072] As used herein, the term therapeutically effective amount or effective amount refers to an amount of an antibody or composition that when administered to a subject is effective to treat a disease or disorder. In some embodiments, a therapeutically effective amount or effective amount refers to an amount of an antibody or composition that when administered to a subject is effective to prevent or ameliorate a disease or the progression of the disease, or result in amelioration of symptoms.

[0073] As used herein, the term inhibits growth (e.g. referring to cells, such as tumor cells) is intended to include any measurable decrease in cell growth (e.g., tumor cell growth) when contacted with a folate receptor alpha (FOLRT) antibody, as compared to the growth of the same cells not in contact with a FOLR1 antibody. In some embodiments, growth may be inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100%. The decrease in cell growth can occur by a variety of mechanisms, including but not limited to antibody internalization, apoptosis, necrosis, and/or effector function-mediated activity.

[0074] As used herein, the term subject means a mammalian subject. Exemplary subjects include, but are not limited to humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, avians, goats, and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has a disease that can be treated or diagnosed with an antibody provided herein. In some embodiments, a subject has a disease that can be treated or diagnosed with an antibody provided herein in combination with an angiogenesis inhibitor (e.g., bevacizumab or a bevacizumab biosimilar). In some embodiments, the disease is epithelial ovarian, fallopian tube, or primary peritoneal cancer. In some embodiments, the disease is gastric carcinoma, colorectal carcinoma, renal cell carcinoma, cervical carcinoma, non-small cell lung carcinoma, ovarian cancer, breast cancer, triple-negative breast cancer, endometrial cancer, prostate cancer, and/or a cancer of epithelial origin.

[0075] In some chemical structures illustrated herein, certain substituents, chemical groups, and atoms are depicted with a curvy/wavy line (e.g.

##STR00001##

) that intersects a bond or bonds to indicate the atom through which the substituents, chemical groups, and atoms are bonded. For example, in some structures, such as but not limited to

##STR00002##

this curvy/wavy line indicates the atoms in the backbone of a conjugate or linker-payload structure to which the illustrated chemical entity is bonded. In some structures, such as but not limited to

##STR00003##

this curvy/wavy line indicates the atoms in the antibody or antibody fragment as well as the atoms in the backbone of a conjugate or linker-payload structure to which the illustrated chemical entity is bonded.

[0076] The term site-specific refers to a modification of a polypeptide at a predetermined sequence location in the polypeptide. The modification is at a single, predictable residue of the polypeptide with little or no variation. In particular embodiments, a modified amino acid is introduced at that sequence location, for instance recombinantly or synthetically. Similarly, a moiety can be site-specifically linked to a residue at a particular sequence location in the polypeptide. In certain embodiments, a polypeptide can comprise more than one site-specific modification.

1. Combinations

[0077] Provided herein are anti-FOLR1 antibody conjugates for use in combination with a second therapeutic agent that modulates angiogenesis. In certain embodiments, combination of the anti-FOLR1 antibody conjugate with the second therapeutic agent yields substantially increased efficacy against solid tumors in vivo. In certain embodiments, combination of anti-FOLR1 antibody conjugate with the second therapeutic agent yields substantially increased efficacy against hematologic cancers in vivo. The anti-FOLR1 antibody conjugate can be any anti-FOLR1 antibody conjugate described herein. In particular embodiments, the second therapeutic agent is a VEGF inhibitor. Useful VEGF inhibitors are described herein.

[0078] Generally, the anti-FOLR1 antibody conjugate and the VEGF inhibitor are administered according to their own doses and schedules. Thus, in certain embodiments, the anti-FOLR1 antibody conjugate is administered at a dose and schedule deemed useful by the practitioner of skill. In certain embodiments, the VEGF inhibitor is administered at a dose and schedule deemed useful by the practitioner of skill. In particular embodiments, the VEGF inhibitor is administered according to its labelled instruction.

[0079] The combinations can be used for the treatment or prevention of any disease or disorder deemed suitable by the practitioner of skill. In certain embodiments, the patient has cancer. In certain embodiments, the patient has endometrial cancer. In certain embodiments, the patient has ovarian cancer. In certain embodiments, the subject previously received cancer treatment. In certain embodiments, the subject did not previously receive cancer treatment. In certain embodiments, the anti-FOLR1 antibody conjugate enhances a therapy provided by the VEGF inhibitor. In certain embodiments, the VEGF inhibitor enhances a therapy provided by the anti-FOLR1 antibody conjugate. In certain embodiments, the enhancement is synergistic. In certain embodiments, the disease or disorder is any disease or disorder suitable for treatment with the anti-FOLR1 antibody conjugate. In certain embodiments, the disease or disorder is any disease or disorder suitable for treatment with the VEGF inhibitor. In certain embodiments, the combination is for the treatment of a cancer. In certain embodiments, the combination is for the treatment of a solid tumor. In certain embodiments, the combination is for the treatment of ovarian cancer. In certain embodiments, the combination is for the treatment of relapsed ovarian cancer. In certain embodiments, the combination is for the treatment of refractory ovarian cancer. In certain embodiments, the combination is for the treatment of relapsed/refractory ovarian cancer. Useful diseases and disorders are described herein.

[0080] In certain embodiments, the amount of the anti-FOLR1 antibody conjugate is therapeutically effective. In certain embodiments, the amount of the VEGF inhibitor is therapeutically effective. In certain embodiments, the amount of the anti-FOLR1 antibody conjugate is therapeutically effective, and the amount of the VEGF inhibitor is therapeutically effective. In certain embodiments, the amount of the anti-FOLR1 antibody conjugate is sub-therapeutic. In certain embodiments, the amount of the VEGF inhibitor is sub-therapeutic. In certain embodiments, the amount of the anti-FOLR1 antibody conjugate is sub-therapeutic, and the amount of the VEGF inhibitor is sub-therapeutic. In certain sub-therapeutic embodiments, the combination is therapeutic while one or both components are at sub-therapeutic doses.

[0081] In some embodiments, the amount of the one or more VEGF-A inhibitors is about 15 mg/kg. In some embodiments, the amount of the one or more VEGF-A inhibitors is 15 mg/kg.

[0082] In some embodiments, the amount of the antibody conjugate is about 3.5 mg/kg or more. In some embodiments, the amount of the antibody conjugate is 3.5 mg/kg or more. In some embodiments, the amount of the antibody conjugate is about 4.3 mg/kg. In some embodiments, the amount of the antibody conjugate is 4.3 mg/kg. In some embodiments, the amount of the antibody conjugate is about 5.2 mg/kg. In some embodiments, the amount of the antibody conjugate is 5.2 mg/kg.

[0083] In some embodiments, further comprising administering to the subject the antibody conjugate at a reduced dose. In some embodiments, the reduced dose is about 4.3 mg/kg or less. In some embodiments, the reduced dose is 4.3 mg/kg or less. In some embodiments, the reduced dose is about 4.3 mg/kg. In some embodiments, the reduced dose is 4.3 mg/kg. In some embodiments, the reduced dose is about 3.5 mg/kg. In some embodiments, the reduced dose is 3.5 mg/kg. In some embodiments, the reduced dose is about 2.9 mg/kg. In some embodiments, the reduced dose is 2.9 mg/kg. In some embodiments, the initial dose of the antibody conjugate is 5.3 mg/kg and then subsequently reduced to 4.3 mg/kg. The antibody conjugate may be further dose reduced to 3.5 mg/kg. In some embodiments, the initial dose of the antibody conjugate is 4.3 mg/kg and then subsequently reduced to 3.5 mg/kg. The antibody conjugate may be further dose reduced to 2.9 mg/kg.

[0084] In some embodiments, prior to the reduced dose, the antibody conjugate is administered to the subject at a first dose for one to five cycles, wherein each cycle is about 3 weeks or longer. For example, the antibody conjugate may be administered for one, two, three, four or five cycles. Each cycle may be 3, 4, 5, or 6 weeks. The cycle length may be 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 days. The duration of each cycle may be the same or different from cycle to cycle. In some embodiments, each cycle is about 3-5 weeks. In some embodiments, each cycle is 3-5 weeks. In some embodiments, each cycle is about 3-4 weeks. In some embodiments, each cycle is 3-4 weeks. In some embodiments, prior to the reduced dose, the antibody conjugate is administered to the subject at a first dose for one to five cycles, wherein each cycle is 3 weeks or longer. In some embodiments, prior to the reduced dose, the antibody conjugate is administered to the subject at a first dose for one to five cycles, wherein each cycle is 3 weeks to 5 weeks. In some embodiments, prior to the reduced dose, the antibody conjugate is administered to the subject at a first dose for one to three cycles, wherein each cycle is about 3 weeks or longer. In some embodiments, prior to the reduced dose, the antibody conjugate is administered to the subject at a first dose for one to three cycles, wherein each cycle is 3 weeks to 4 weeks. In some embodiments, prior to the reduced dose, the antibody conjugate is administered to the subject at a first dose for two to four cycles, wherein each cycle is about 3 weeks or longer. In some embodiments, prior to the reduced dose, the antibody conjugate is administered to the subject at a first dose for two to four cycles, wherein each cycle is 3 weeks to 4 weeks. In certain embodiments, the clinician or practicing physician will adjust the cycle length. In certain embodiments, the clinician or treating physician will switch from the first dose to the reduced dose as described herein. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response. For example, the clinician or treating physician may further adjust dose level in conjunction with subject side effects from treatment or underlying disease for which the subject is receiving treatment.

[0085] In certain embodiments, the anti-FOLR1 antibody conjugate and the additional therapeutic agent are administered consecutively in either order. As used herein, the terms consecutively, serially, and sequentially refer to administration of an anti-FOLRT antibody conjugate after an additional therapeutic agent, or administration of the additional therapeutic agent after the anti-FOLR1 antibody conjugate. For instance, consecutive administration may involve administration of the anti-FOLR1 antibody conjugate in the absence of the additional therapeutic agent during an induction phase (primary therapy), which is followed by a post-induction treatment phase comprising administration of the additional therapeutic agent. The methods may further comprise a maintenance phase comprising administration of the anti-FOLR1 antibody conjugate or the additional therapeutic agent, or both. Alternatively, consecutive administration may involve administration of the additional therapeutic agent in the absence of the anti-FOLR1 antibody conjugate during an induction phase (primary therapy), which is followed by a post-induction treatment phase comprising administration of the anti-FOLR1 antibody conjugate. The methods may further comprise a maintenance phase comprising administration of the anti-FOLR1 antibody conjugate or the additional therapeutic agent, or both.

[0086] In some embodiments, the administering is by intravenous (IV) administration. In some embodiments, the antibody conjugate and the one or more VEGF-A inhibitors are administered separately on the same day. In some embodiments, the antibody conjugate and the one or more VEGF-A inhibitors are administered simultaneously on the same day. In some embodiments, the antibody conjugate and the one or more VEGF-A inhibitors are administered about once every 3 weeks or longer for the remainder of the treating. In some embodiments, the antibody conjugate and the one or more VEGF-A inhibitors are administered about once every 3 weeks. In some embodiments, the antibody conjugate and the one or more VEGF-A inhibitors are administered about once every 4 weeks.

[0087] In certain embodiments, the anti-FOLR1 antibody conjugate and the additional therapeutic agent are administered concurrently. As used herein, the terms concurrently, simultaneously, and in parallel refer to administration of an anti-FOLR1 antibody conjugate and an additional therapeutic agent during the same doctor visit or during the same phase of treatment. For instance, both the anti-FOLR1 antibody conjugate and the additional therapeutic agent may be administered during one or more of an induction phase, a treatment phase, and a maintenance phase. However, concurrent administration does not require that the anti-FOLR1 antibody conjugate and the additional therapeutic agent be present together in a single formulation or pharmaceutical composition, or that the anti-FOLR1 antibody conjugate and the additional therapeutic agent be administered at precisely the same time.

[0088] In certain embodiments, a combination provided herein can be administered directly to an individual to modulate an immune response, treat a disease or condition (e.g., cancer and/or abnormal cell proliferation) and/or inhibit FOLR1 activity and/or VEGF activity in the individual.

[0089] In certain embodiments, provided herein is a method of treating cancer responsive to inhibition of FOLR1 activity, the method comprising administering an effective amount of a combination provided herein to an individual to treat the cancer responsive to inhibition of FOLR1 activity. In certain embodiments, the cancer is an ovarian cancer such as one described herein.

[0090] In certain embodiments, provided herein is a method of treating cancer that is nonresponsive to the inhibition of FOLR1 activity alone, the method comprising administering an effective amount of a combination provided herein to such an individual to treat the cancer nonresponsive to inhibition of FOLR1 activity alone. In certain embodiments, the cancer is an ovarian cancer such as one described herein.

[0091] In certain embodiments, provided herein is a method of treating cancer responsive to inhibition of VEGF activity, the method comprising administering an effective amount of a combination provided herein to an individual to treat the cancer responsive to inhibition of VEGF activity. In certain embodiments, the cancer is an ovarian cancer such as one described herein.

[0092] In certain embodiments, provided herein is a method of treating cancer that is nonresponsive to the inhibition of VEGF activity alone, the method comprising administering an effective amount of a combination provided herein to such an individual to treat the cancer nonresponsive to inhibition of VEGF activity alone. In certain embodiments, the cancer is an ovarian cancer such as one described herein.

[0093] In certain embodiments, provided herein is a method of inhibiting abnormal cell proliferation (e.g., hyperplasia), the method comprising administering an effective amount of a combination provided herein to an individual to inhibit abnormal cell proliferation in the individual.

[0094] In certain embodiments, provided herein is a method of inhibiting FOLR1 activity, the method comprising administering an effective amount of a combination provided herein to an individual to inhibit FOLR1 activity in the individual.

[0095] In certain embodiments, provided herein is a method of inhibiting VEGF activity, the method comprising administering an effective amount of a combination provided herein to an individual to inhibit VEGF activity in the individual.

[0096] In certain embodiments, provided herein is a method of inhibiting FOLR1 activity and VEGF activity, the method comprising administering an effective amount of a combination provided herein to an individual to inhibit FOLR1 activity and VEGF activity in the individual.

[0097] In certain embodiments, such as in the modulation of an immune response in an individual in need thereof (e.g., an individual with a T-cell dysfunction disorder), treatment of a disease or condition in an individual (e.g., an individual cancer and/or abnormal cell proliferation) and/or inhibition of FOLR1 or VEGF activity in an individual, the appropriate dosage of an active agent, will depend on the type of condition, disease, or disorder to be treated, as defined above, the severity and course of the condition, disease, or disorder, whether the agent is administered for preventive or therapeutic purposes, previous therapy, the subject's clinical history and response to the anti-FOLR1 antibody conjugate or VEGF inhibitor, and the discretion of the attending physician.

[0098] The anti-FOLR1 antibody conjugate or composition thereof is suitably administered to the individual at one time or over a series of treatments. In certain embodiments, the treatment includes multiple administrations of the anti-FOLR1 antibody conjugate or composition, wherein the interval between administrations may vary. For example, the interval between the first administration and the second administration is about one month, and the intervals between the subsequent administrations are about three months. In certain embodiments, an anti-FOLR1 antibody conjugate is administered at a flat dose. In certain embodiments, an anti-FOLR1 antibody conjugate described herein is administered to an individual at a fixed dose based on the individual's weight (e.g., mg/kg).

[0099] The VEGF inhibitor or composition thereof is suitably administered to the individual at one time or over a series of treatments. In certain embodiments, the treatment includes multiple administrations of the VEGF inhibitor or composition, wherein the interval between administrations may vary. For example, the interval between the first administration and the second administration is about one month, and the intervals between the subsequent administrations are about three months. In certain embodiments, a VEGF inhibitor is administered at a flat dose. In certain embodiments, a VEGF inhibitor is administered to an individual at a fixed dose based on the individual's weight (e.g., mg/kg).

[0100] In certain embodiments of this disclosure, the cancer is a solid tumor. For example, the cancer may be ovarian cancer, ovarian carcinoma, ovary cancer, endometrial cancer, endometrioid adenocarcinoma, fallopian tube cancer, or primary peritoneal carcinoma. In certain embodiments, the cancer is relapsed ovarian cancer. In certain embodiments, the cancer is refractory ovarian cancer. In certain embodiments, the cancer is relapsed/refractory ovarian cancer

[0101] In certain embodiments, the effectiveness of the combination in the methods herein (e.g., method of modulating an immune response in an individual) can be assessed by measuring the biological activity of cancer cells present in a sample isolated from the treated individual.

[0102] In certain embodiments, provided are compositions and therapeutic formulations comprising any of the antibody conjugates provided herein in combination with one or more VEGF inhibitors, and methods of treatment comprising administering such combinations to subjects in need thereof. In some embodiments, the one or more VEGF inhibitors comprise a an antibody that inhibits VEGF activity. In some embodiments, the one or more VEGF inhibitors are selected from bevacizumab (AVASTIN) and bevacizumab biosimilars. In some embodiments, the bevacizumab biosimilar is selected from the group consisting of. MVASI (ABP 215, Amgen), Zirabev (Pfizer), Bevax (BEVZ92, mAbxience), Lumiere (Elea), Apotex (Apobiologix), Equidacent (FKB238, AstraZeneca/Centus Biotherapeutics), Avegra (BCD-021, Biocad), BP 01 (Aurobindo Pharma), BCD500 (BIOCND), Krabeva (Biocon), BAT1706 (Bio-Thera Solutions), BXT-2316 (BioXpress Therapeutics), Bevaro (Cadila Pharmaceuticals), BI 695502 (Boehringer Ingelheim), CT-P16 (Celltrion), CHS-5217 (Coherus), DRZ_BZ (Dr Reddy's Laboratories), Cizumab (Hetero/Lupin), Byvasda (1B1305, Innovent Biologics), MIL60 (Mabworks), MYL 14020 (Mylan), ONS-1045 (Oncobiologics/Viropro), HD204 (Prestige Biopharma), Ankeda (QL1101, Qilu Pharmaceutical), Bevacirel (Reliance Life Sciences), Aybintio (SB8, Samsung Bioepis), Onbevzi (Samsung Bioepis), HLX04 (Shanghai Henlius Biotech), TX16 (Tanvex BioPharma), MB02(mAbxience), BI 695502 (Boehringer Ingelheim), and Oyavas (STADA).

2. Conjugates

[0103] In the combinations, anti-FOLR1 antibody conjugate can be any anti-FOLR1 antibody conjugate provided herein. The conjugates comprise an antibody to FOLR1 covalently linked directly or indirectly, via a linker, to a payload. In certain embodiments, the antibody is linked to one payload. In further embodiments, the antibody is linked to more than one payload. In certain embodiments, the antibody is linked to two, three, four, five, six, seven, eight, or more payloads. In certain embodiments, the anti-FOLR1 antibody conjugate is an anti-FOLR1 antibody conjugate described in U.S. Pat. No. 10,596,270, the content of which is hereby incorporated by reference.

[0104] In certain embodiments, the anti-FOLR1 antibody conjugate is according to the formula of Conjugate P, described herein, wherein the antibody is 1848-HO1 conjugated through p-azidomethylphenylalanine residues at heavy chain positions Y180 and F404. In certain embodiments, the antibody of the anti-FOLR1 antibody conjugate comprises three heavy chain CDRs of heavy chain SEQ ID NO:362 and three light chain CDRs of light chain SEQ ID NO:367. In certain embodiments, the antibody of the anti-FOLR1 antibody conjugate comprises the three heavy chain CDRs of SEQ ID NOS: 58, 176, and 294 and three light chain CDRs of light chain SEQ ID NO:367. the antibody of the anti-FOLR1 antibody conjugate comprises the three heavy chain CDRs of SEQ ID NOS: 117, 235, and 294 and three light chain CDRs of light chain SEQ ID NO:367. In certain embodiments, the antibody of the anti-FOLR1 antibody conjugate comprises the VH region of heavy chain SEQ ID NO:362 and the VL region of light chain SEQ ID NO:367. In certain embodiments, the antibody of the anti-FOLR1 antibody conjugate comprises heavy chain SEQ ID NO:362 and light chain SEQ ID NO:367. In each of these embodiments, the antibody may comprise Y180 and F404 mutations to p-azidomethylphenylalanine.

[0105] The payload can be any payload deemed useful by the practitioner of skill. In certain embodiments, the payload is a therapeutic moiety. In certain embodiments, the payload is a diagnostic moiety, e.g. a label. Useful payloads are described in the sections and examples below.

[0106] The linker can be any linker capable of forming at least one bond to the antibody and at least one bond to a payload. Useful linkers are described the sections and examples below.

[0107] In the conjugates provided herein, the antibody can be any antibody with binding specificity for folate receptor alpha (FOLR1 or Fo1Ru). The FOLR1 can be from any species. In certain embodiments, the FOLR1 is a vertebrate FOLR1. In certain embodiments, the FOLR1 is a mammalian FOLR1. In certain embodiments, the FOLR1 is human FOLR1. In certain embodiments, the FOLR1 is mouse FOLR1. In certain embodiments, the FOLR1 is cynomolgus FOLR1.

[0108] In certain embodiments, the antibody to folate receptor alpha (FOLR1 or Fo1Ru) competes with an antibody described herein for binding. In certain embodiments, the antibody to FOLR1 binds to the same epitope as an antibody described herein.

[0109] The antibody is typically a protein comprising multiple polypeptide chains. In certain embodiments, the antibody is a heterotetramer comprising two identical light (L) chains and two identical heavy (H) chains. Each light chain can be linked to a heavy chain by one covalent disulfide bond. Each heavy chain can be linked to the other heavy chain by one or more covalent disulfide bonds. Each heavy chain and each light chain can also have one or more intrachain disulfide bonds. As is known to those of skill in the art, each heavy chain typically comprises a variable domain (V.sub.H) followed by a number of constant domains. Each light chain typically comprises a variable domain at one end (V.sub.L) and a constant domain. As is known to those of skill in the art, antibodies typically have selective affinity for their target molecules, i.e. antigens.

[0110] The antibodies provided herein can have any antibody form known to those of skill in the art. They can be full-length, or fragments. Exemplary full length antibodies include IgA, IgA1, IgA2, IgD, IgE, IgG, IgG1, IgG2, IgG3, IgG4, IgM, etc. Exemplary fragments include Fv, Fab, Fc, scFv, scFv-Fc, etc.

[0111] In certain embodiments, the antibody of the conjugate comprises one, two, three, four, five, or six of the CDR sequences described herein. In certain embodiments, the antibody of the conjugate comprises a heavy chain variable domain (V.sub.H) described herein. In certain embodiments, the antibody of the conjugate comprises a light chain variable domain (V.sub.L) described herein. In certain embodiments, the antibody of the conjugate comprises a heavy chain variable domain (V.sub.H) described herein and a light chain variable domain (V.sub.L) described herein. In certain embodiments, the antibody of the conjugate comprises a paired heavy chain variable domain and a light chain variable domain described herein (V.sub.H-V.sub.L pair).

[0112] In certain embodiments, the antibody of the conjugate comprises any of the amino acid sequences of the antibodies described above. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 10 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 9 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 8 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 7 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 6 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 5 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 4 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 3 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 2 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 1 conservative amino acid substitution. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. For example, in certain embodiments, the antibody comprises any of the amino acid sequences above with up to 10 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 9 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 8 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 7 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 6 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 5 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 4 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 3 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 2 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 1 conservative amino acid substitution.

[0113] In certain embodiments, the antibody conjugate can be formed from an antibody that comprises one or more reactive groups. In certain embodiments, the antibody conjugate can be formed from an antibody comprising all naturally encoded amino acids. Those of skill in the art will recognize that several naturally encoded amino acids include reactive groups capable of conjugation to a payload or to a linker. These reactive groups include cysteine side chains, lysine side chains, and amino-terminal groups. In these embodiments, the antibody conjugate can comprise a payload or linker linked to the residue of an antibody reactive group. In these embodiments, the payload precursor or linker precursor comprises a reactive group capable of forming a bond with an antibody reactive group. Typical reactive groups include maleimide groups, activated carbonates (including but not limited to, p-nitrophenyl ester), activated esters (including but not limited to, N-hydroxysuccinimide, p-nitrophenyl ester, and aldehydes). Particularly useful reactive groups include maleimide and succinimide, for instance N-hydroxysuccinimide, for forming bonds to cysteine and lysine side chains. Further reactive groups are described in the sections and examples below.

[0114] In further embodiments, the antibody comprises one or more modified amino acids having a reactive group, as described herein. Typically, the modified amino acid is not a naturally encoded amino acid. These modified amino acids can comprise a reactive group useful for forming a covalent bond to a linker precursor or to a payload precursor. One of skill in the art can use the reactive group to link the polypeptide to any molecular entity capable of forming a covalent bond to the modified amino acid. Thus, provided herein are conjugates comprising an antibody comprising a modified amino acid residue linked to a payload directly or indirectly via a linker. Exemplary modified amino acids are described in the sections below. Generally, the modified amino acids have reactive groups capable of forming bonds to linkers or payloads with complementary reactive groups.

[0115] The non-natural amino acids are positioned at select locations in a polypeptide chain of the antibody. These locations were identified as providing optimum sites for substitution with the non-natural amino acids. Each site is capable of bearing a non-natural amino acid with optimum structure, function and/or methods for producing the antibody.

[0116] In certain embodiments, a site-specific position for substitution provides an antibody that is stable. Stability can be measured by any technique apparent to those of skill in the art.

[0117] In certain embodiments, a site-specific position for substitution provides an antibody that has optimal functional properties. For instance, the antibody can show little or no loss of binding affinity for its target antigen compared to an antibody without the site-specific non-natural amino acid. In certain embodiments, the antibody can show enhanced binding compared to an antibody without the site-specific non-natural amino acid.

[0118] In certain embodiments, a site-specific position for substitution provides an antibody that can be made advantageously. For instance, in certain embodiments, the antibody shows advantageous properties in its methods of synthesis, discussed below. In certain embodiments, the antibody can show little or no loss in yield in production compared to an antibody without the site-specific non-natural amino acid. In certain embodiments, the antibody can show enhanced yield in production compared to an antibody without the site-specific non-natural amino acid. In certain embodiments, the antibody can show little or no loss of tRNA suppression compared to an antibody without the site-specific non-natural amino acid. In certain embodiments, the antibody can show enhanced tRNA suppression in production compared to an antibody without the site-specific non-natural amino acid.

[0119] In certain embodiments, a site-specific position for substitution provides an antibody that has advantageous solubility. In certain embodiments, the antibody can show little or no loss in solubility compared to an antibody without the site-specific non-natural amino acid. In certain embodiments, the antibody can show enhanced solubility compared to an antibody without the site-specific non-natural amino acid.

[0120] In certain embodiments, a site-specific position for substitution provides an antibody that has advantageous expression. In certain embodiments, the antibody can show little or no loss in expression compared to an antibody without the site-specific non-natural amino acid. In certain embodiments, the antibody can show enhanced expression compared to an antibody without the site-specific non-natural amino acid.

[0121] In certain embodiments, a site-specific position for substitution provides an antibody that has advantageous folding. In certain embodiments, the antibody can show little or no loss in proper folding compared to an antibody without the site-specific non-natural amino acid. In certain embodiments, the antibody can show enhanced folding compared to an antibody without the site-specific non-natural amino acid.

[0122] In certain embodiments, a site-specific position for substitution provides an antibody that is capable of advantageous conjugation. As described below, several non-natural amino acids have side chains or functional groups that facilitate conjugation of the antibody to a second agent, either directly or via a linker. In certain embodiments, the antibody can show enhanced conjugation efficiency compared to an antibody without the same or other non-natural amino acids at other positions. In certain embodiments, the antibody can show enhanced conjugation yield compared to an antibody without the same or other non-natural amino acids at other positions. In certain embodiments, the antibody can show enhanced conjugation specificity compared to an antibody without the same or other non-natural amino acids at other positions.

[0123] The one or more non-natural amino acids are located at selected site-specific positions in at least one polypeptide chain of the antibody. The polypeptide chain can be any polypeptide chain of the antibody without limitation, including either light chain or either heavy chain. The site-specific position can be in any domain of the antibody, including any variable domain and any constant domain.

[0124] In certain embodiments, the antibodies provided herein comprise one non-natural amino acid at a site-specific position. In certain embodiments, the antibodies provided herein comprise two non-natural amino acids at site-specific positions. In certain embodiments, the antibodies provided herein comprise three non-natural amino acids at site-specific positions. In certain embodiments, the antibodies provided herein comprise more than three non-natural amino acids at site-specific positions.

[0125] In certain embodiments, the antibodies provided herein comprise one or more non-natural amino acids each at a position selected from the group consisting of heavy chain or light chain residues HC-F404, HC-K121, HC-Y180, HC-F241, HC-221, LC-T22, LC-S7, LC-N152, LC-K42, LC-E161, LC-D170, HC-S136, HC-S25, HC-A40, HC-S119, HC-S190, HC-K222, HC-R19, HC-Y52, or HC-S70 according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In these designations, HC indicates a heavy chain residue, and LC indicates a light chain residue. In certain embodiments, the antibody comprises one or more non-natural amino acids at sites selected from the group consisting of. HC F404, HC-Y180, and LC-K42, according to the Kabat, Chothia, or EU numbering scheme. In certain embodiments, the antibody comprises a non-natural amino acid at site HC-F404. In certain embodiments, the antibody comprises a non-natural amino acid at site HC-F404. In certain embodiments, the antibody comprises non-natural amino acids at sites HC-F404 and HC-Y180.

[0126] In certain embodiments, a residue of the one or more non-natural amino acids is linked to the payload moiety via a linker that is hydrolytically stable. In certain embodiments, a residue of the one or more non-natural amino acids is linked to the payload moiety via a linker that is cleavable.

[0127] In certain embodiments, the one or more non-natural amino acids is selected from the group consisting of p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, an -3-(2-naphthyl) alanine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, a tri-O-acetyl-GlcNAcP-serine, L-Dopa, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-azido-methyl-L-phenylalanine, compound 56, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-iodo-phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, and p-propargyloxy-phenylalanine. In certain embodiments, the non-natural amino acid residue is a residue of compound (30) or compound (56).

[0128] In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (30), below. In particular embodiments, provided herein are anti-FOLRT conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (30), below, at heavy chain position 404 according to the EU numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (30), below, at heavy chain position 180 according to the EU numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (30), below, at heavy chain position 241 according to the EU numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (30), below, at heavy chain position 222 according to the EU numbering system. In particular embodiments, provided herein are anti-FOLRT conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (30), below, at light chain position 7 according to the Kabat or Chothia numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (30), below, at light chain position 42 according to the Kabat or Chothia numbering system. In certain embodiments, PAY is selected from the group consisting of maytansine, hemiasterlin, amanitin, monomethyl auristatin F (MMAF), and monomethyl auristatin E (MMAE). In certain embodiments, the PAY is maytansine. In certain embodiments, PAY is hemiasterlin. In certain embodiments, PAY is amanitin. In certain embodiments, PAY is MMAF. In certain embodiments, PAY is MMAE.

##STR00004##

[0129] In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (56), below. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (56), below, at heavy chain position 404 according to the EU numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (56), below, at heavy chain position 180 according to the EU numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (56), below, at heavy chain position 241 according to the EU numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (56), below, at heavy chain position 222 according to the EU numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (56), below, at light chain position 7 according to the Kabat or Chothia numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a residue of the non-natural amino acid according to Formula (56), below, at light chain position 42 according to the Kabat or Chothia numbering system. In certain embodiments, PAY is selected from the group consisting of maytansine, hemiasterlin, amanitin, MMAF, and MMAE. In certain embodiments, the PAY is maytansine. In certain embodiments, PAY is hemiasterlin. In certain embodiments, PAY is amanitin. In certain embodiments, PAY is MMAF. In certain embodiments, PAY is MMAE.

##STR00005##

[0130] In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a non-natural amino acid residue of para-azido-L-phenylalanine. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates the non-natural amino acid residue para-azido-phenylalanine at heavy chain position 404 according to the EU numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a non-natural amino acid residue of para-azido-L-phenylalanine at heavy chain position 180 according to the EU numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a non-natural amino acid residue para-azido-L-phenylalanine at heavy chain position 241 according to the EU numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a non-natural amino acid residue para-azido-L-phenylalanine at heavy chain position 222 according to the EU numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a non-natural amino acid residue para-azido-L-phenylalanine at light chain position 7 according to the Kabat or Chothia numbering system. In particular embodiments, provided herein are anti-FOLR1 conjugates according to any of Formulas 101a-104b wherein COMP indicates a non-natural amino acid residue para-azido-L-phenylalanine at light chain position 42 according to the Kabat or Chothia numbering system. In certain embodiments, PAY is selected from the group consisting of maytansine, hemiasterlin, amanitin, MMAF, and MMAE. In certain embodiments, the PAY is maytansine. In certain embodiments, PAY is hemiasterlin. In certain embodiments, PAY is amanitin. In certain embodiments, PAY is MMAF. In certain embodiments, PAY is MMAE.

[0131] In certain embodiments, the at least one payload moiety is selected from the group consisting of maytansines, hemiasterlins, amanitins, and auristatins. In certain embodiments, the at least one payload moiety is selected from the group consisting of DM1, hemiasterlin, amanitin, MMAF, and MMAE. In certain embodiments, the at least one payload moiety is a hemiasterlin derivative. In certain embodiments, the at least one payload moiety is:

##STR00006##

wherein Ar is optionally substituted aryl or optionally substituted heteroaryl, L is a linker, and the wiggly line indicates a bond to the antibody. In certain embodiments, the at least one payload moiety is:

##STR00007##

wherein L is a linker, and the wiggly line indicates a bond to the antibody.

[0132] In some embodiments, provided herein are anti-FOLR1 conjugates comprising a modified hemiasterlin and linker as described, for example, in PCT Publication No. WO 2016/123582. For example, the conjugate can have a structure comprising any of Formulas 1000-1000b, 1001-1001b, 1002-1002b, and I-XIXb-2, 101-111b, or 1-8b as described in PCT Publication No. WO 2016/2016/123582. Examples of conjugates comprising a modified hemiasterlin and linker are provided below.

[0133] In some embodiments, provided herein are anti-FOLR1 conjugates having the structure of Conjugate M:

##STR00008##

where n is an integer from 1 to 6. In some embodiments, n is an integer from 1 to 4. In some embodiments, n is 2. For example, in some embodiments, the anti-FOLR1 conjugate has the structure:

##STR00009##

In some embodiments, n is 4. For example, in some embodiments, the anti-FOLR1 conjugate has the structure:

##STR00010##

[0134] In some embodiments, provided herein are anti-FOLR1 conjugates having the structure of Conjugate P:

##STR00011##

where n is an integer from 1 to 6. In some embodiments, n is an integer from 1 to 4. In some embodiments, n is 2. For example, in some embodiments, the anti-FOLR1 conjugate has the structure:

##STR00012##

In some embodiments, n is 4. For example, in some embodiments, the anti-FOLR1 conjugate has the structure:

##STR00013##

[0135] In some embodiments, provided herein are anti-FOLR1 conjugates having the structure of Conjugate Q:

##STR00014##

where n is an integer from 1 to 6, In some embodiments, n is an integer from 1 to 4. In some embodiments, n is 2. For example, in some embodiments, the anti-FOLR1 conjugate has the structure:

##STR00015##

In some embodiments, n is 4. For example, in some embodiments, the anti-FOLR1 conjugate has the structure:

##STR00016##

[0136] In any of the foregoing embodiments wherein the anti-FOLR1 conjugate has a structure according to Conjugate M, Conjugate P, or Conjugate Q, the bracketed structure can be covalently bonded to one or more non-natural amino acids of the antibody, wherein the one or more non-natural amino acids are located at sites selected from the group consisting of: HC-F404, HC-Y180, and LC-K42 according to the Kabat or EU cumbering scheme of Kabat. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural amino acids at site LC-F424 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural amino acids at sites HC-F404 and HC-Y180 of the antibody. In some embodiments, at least one bracketed structure is covalently bonded to a non-natural amino acid at site HC-F404 of the antibody, and at least one bracketed structure is covalently bonded a non-natural amino acid at site HC-Y180 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural amino acids at sites HC-Y180 and LC-K42 of the antibody. In some embodiments, at least one bracketed structure is covalently bonded to a non-natural amino acid at site HC-Y180 of the antibody, and at least one bracketed structure is covalently bonded a non-natural amino acid at site LC-K32 of the antibody.

5. Antibody Specificity

[0137] The conjugates comprise antibodies that selectively bind human folate receptor alpha. In some aspects, the antibody selectively binds to the extracellular domain of human folate receptor alpha (human FOLR1).

[0138] In some embodiments, the antibody binds to a homolog of human FOLR1. In some aspects, the antibody binds to a homolog of human FOLR1 from a species selected from monkeys, mice, dogs, cats, rats, cows, horses, goats and sheep. In some aspects, the homolog is a cynomolgus monkey homolog. In some aspects, the homolog is a mouse or murine analog.

[0139] In some embodiments, the antibodies comprise at least one CDR sequence defined by a consensus sequence provided in this disclosure. In some embodiments, the antibodies comprise an illustrative CDR, V.sub.H, or V.sub.L sequence provided in this disclosure, or a variant thereof. In some aspects, the variant is a variant with a conservative amino acid substitution.

[0140] In some embodiments, the antibody has one or more CDRs having particular lengths, in terms of the number of amino acid residues. In some embodiments, the Chothia CDR-H1 of the antibody is 6, 7, or 8 residues in length. In some embodiments, the Kabat CDR-H1 of the antibody is 4, 5, or 6 residues in length. In some embodiments, the Chothia CDR-H2 of the antibody is 5, 6, or 7 residues in length. In some embodiments, the Kabat CDR-H2 of the antibody is 16, 17, or 18 residues in length. In some embodiments, the Kabat/Chothia CDR-H3 of the antibody is 13, 14, 15, 16, or 17 residues in length.

[0141] In some aspects, the Kabat/Chothia CDR-L1 of the antibody is 11, 12, 13, 14, 15, 16, 17, or 18 residues in length. In some aspects, the Kabat/Chothia CDR-L2 of the antibody is 6, 7, or 8 residues in length. In some aspects, the Kabat/Chothia CDR-L3 of the antibody is 8, 9, or 10 residues in length.

[0142] In some embodiments, the antibody comprises a light chain. In some aspects, the light chain is a kappa light chain. In some aspects, the light chain is a lambda light chain.

[0143] In some embodiments, the antibody comprises a heavy chain. In some aspects, the heavy chain is an IgA. In some aspects, the heavy chain is an IgD. In some aspects, the heavy chain is an IgE. In some aspects, the heavy chain is an IgG. In some aspects, the heavy chain is an IgM. In some aspects, the heavy chain is an IgG1. In some aspects, the heavy chain is an IgG2. In some aspects, the heavy chain is an IgG3. In some aspects, the heavy chain is an IgG4. In some aspects, the heavy chain is an IgA1. In some aspects, the heavy chain is an IgA2.

[0144] In some embodiments, the antibody is an antibody fragment. In some aspects, the antibody fragment is an Fv fragment. In some aspects, the antibody fragment is a Fab fragment.

[0145] In some aspects, the antibody fragment is a F(ab).sub.2 fragment. In some aspects, the antibody fragment is a Fab fragment. In some aspects, the antibody fragment is an scFv (sFv) fragment. In some aspects, the antibody fragment is an scFv-Fc fragment.

[0146] In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody.

[0147] In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody.

[0148] In some embodiments, the antibody is an affinity matured antibody. In some aspects, the antibody is an affinity matured antibody derived from an illustrative sequence provided in this disclosure.

[0149] The antibodies provided herein may be useful for the treatment of a variety of diseases and conditions including cancers. In some embodiments, the antibodies provided herein may be useful for the treatment of cancers of solid tumors. For example, the antibodies provided herein can be useful for the treatment of colorectal cancer.

[0150] In certain embodiments, the antibody comprises: three heavy chain CDRs and three light chain CDRs of a V.sub.H region provided herein, and a V.sub.L region provided herein. In certain embodiments, the V.sub.H region is selected from SEQ ID NOs:308-366. In certain embodiments, the V.sub.L region is selected from SEQ ID NOs: 367-369. In particular embodiments, the V.sub.H region is according to SEQ ID NO:362, and a V.sub.L region is according to SEQ ID NO:367. CDR sequences can be identified by routine techniques well known to those of skill in the art. In certain embodiments, the CDRs are identified according to Kabat numbering. In certain embodiments, the CDRs are identified according to Chothia numbering. In certain embodiments, the CDRs are identified according to Martin numbering. In certain embodiments, the CDRs identified according to AHo numbering. In certain embodiments, the CDRs identified according to IMGT numbering. Tools for identifying CDR sequences are available, for example, at abYsis.org, Swindells et al. 2017, J. Mol. Biol. 429:356-364.

5.1 CDR-H3 Sequences

[0151] In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of an illustrative antibody or V.sub.H sequence provided herein. In some aspects, the CDR-H3 sequence is a CDR-H3 sequence of a V.sub.H sequence provided in SEQ ID NOs.: 308-366.

[0152] In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs.: 240-298. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 240. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 241. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 242. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 243. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 244. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 245. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 246. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 247. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 248. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 249. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 250. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 251. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 252. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 253. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 254. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 255. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 256. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 257. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 258. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 259. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 260. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 261. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 262. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 263. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 264. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 265. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 266. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 267. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 268. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 269. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 270. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 271. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 272. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 273. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 274. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 275. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 276. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 277. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 278. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 279. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 280. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 281. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 282. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 283. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 284. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 285. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 286. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 287. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 288. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 289. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 290. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 291. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 292. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 293. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 294. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 295. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 296. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 297. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 298.

[0153] In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

5.2 V.SUB.H .Sequences Comprising Illustrative CDRs

[0154] In some embodiments, the antibody comprises a V.sub.H sequence comprising one or more CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-H sequences provided in this disclosure, and variants thereof. In some embodiments, the CDR-H sequences comprise, consist of, or consist essentially of one or more CDR-H sequences provided in a V.sub.H sequence selected from SEQ ID NOs: 308-366.

5.2.1. V.SUB.H .Sequences Comprising Illustrative Kabat CDRs

[0155] In some embodiments, the antibody comprises a V.sub.H sequence comprising one or more Kabat CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Kabat CDR-H sequences provided in this disclosure, and variants thereof.

5.2.1.1. Kabat CDR-H3

[0156] In some embodiments, the antibody comprises a V.sub.H sequence comprising a CDR-H3 sequence, wherein the CDR-H3 sequence comprises, consists of, or consists essentially of a Kabat CDR-H3 sequence of an illustrative antibody or V.sub.H sequence provided herein. In some aspects, the Kabat CDR-H3 sequence is a Kabat CDR-H3 sequence of a V.sub.H sequence provided in SEQ ID NOs: 308-366.

[0157] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs.: 240-298. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 240. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 241. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 242. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 243. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 244. In some aspects, the antibody comprises a V.sub.Hsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 245. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 246. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 247. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 248. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 249. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 250. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 251. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 252. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 253. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 254. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 255. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 256. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 257. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 258. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 259. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 260. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 261. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 262. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 263. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 264. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 265. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 266. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 267. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 268. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 269. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 270. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 271. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 272. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 273. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 274. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 275. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 276. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 277. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 278. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 279. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 280. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 281. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 282. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 283. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 284. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 285. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 286. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 287. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 288. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 289. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 290. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 291. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 292. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 293. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 294. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 295. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 296. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 297. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 298.

5.2.1.2. Kabat CDR-H2

[0158] In some embodiments, the antibody comprises a V.sub.H sequence comprising a CDR-H2 sequence, wherein the CDR-H2 sequence comprises, consists of, or consists essentially of a Kabat CDR-H2 sequence of an illustrative antibody or V.sub.H sequence provided herein. In some aspects, the Kabat CDR-H2 sequence is a Kabat CDR-H2 sequence of a V.sub.H sequence provided in SEQ ID NOs: 308-366.

[0159] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 181-239. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 181. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 182. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 183. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 184. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 185. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 186. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 187. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 188. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 189. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 190. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 191. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 192. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 193. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 194. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 195. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 196. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 197. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 198. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 199. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 200. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 201. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 202. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 203. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 204. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 205. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 206. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 207. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 208. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 209. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 210. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 211. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 212. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 213. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 214. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 215. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 216. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 217. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 218. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 219. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 220. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 221. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 222. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 223. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 224. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 225. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 226. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 227. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 228. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 229. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 230. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 231. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 232. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 233. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 234. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 235. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 236. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 237. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 238. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 239.

5.2.1.3. Kabat CDR-H1

[0160] In some embodiments, the antibody comprises a V.sub.H sequence comprising a CDR-H1 sequence, wherein the CDR-H1 sequence comprises, consists of, or consists essentially of a Kabat CDR-H1 sequence of an illustrative antibody or V.sub.H sequence provided herein. In some aspects, the Kabat CDR-H1 sequence is a Kabat CDR-H1 sequence of a V.sub.H sequence provided in SEQ ID NOs: 308-366.

[0161] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 63-121. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 63. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 64. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 65. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 66. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 67. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 68. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 69. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 70. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 71. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 72. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 73. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 74. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 75. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 76. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 77. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 78. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 79. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 80. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 81. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 82. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 83. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 84. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 85. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 86. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 87. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 88. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 89. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 90. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 91. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 92. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 93. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 94. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 95. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 96. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 97. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 98. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 99. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 100. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 101. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 102. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 103. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 104. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 105. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 106. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 107. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 108. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 109. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 110. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 111. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 112. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 113. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 114. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 115. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 116. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 117. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 118. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 119. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 120. In some aspects, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 121.

5.2.1.4. Kabat CDR-H3+Kabat CDR-H2

[0162] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 240-298, and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 181-239. In some aspects, the Kabat CDR-H3 sequence and the Kabat CDR-H2 sequence are both from a single illustrative V.sub.H sequence provided in this disclosure. For example, in some aspects, the Kabat CDR-H3 and Kabat CDR-H2 are both from a single illustrative V.sub.H sequence selected from SEQ ID NOs: 308-366.

5.2.1.5. Kabat CDR-H3+Kabat CDR-H1

[0163] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 240-298, and a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 63-121. In some aspects, the Kabat CDR-H3 sequence and the Kabat CDR-H1 sequence are both from a single illustrative V.sub.H sequence provided in this disclosure. For example, in some aspects, the Kabat CDR-H3 and Kabat CDR-H1 are both from a single illustrative V.sub.H sequence selected from SEQ ID NOs: 308-366.

5.2.1.6 Kabat CDR-H1+Kabat CDR-H2

[0164] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 63-121 and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 181-239. In some aspects, the Kabat CDR-H1 sequence and the Kabat CDR-H2 sequence are both from a single illustrative V.sub.H sequence provided in this disclosure. For example, in some aspects, the Kabat CDR-H1 and Kabat CDR-H2 are both from a single illustrative V.sub.H sequence selected from SEQ ID NOs: 308-366.

5.2.1.7. Kabat CDR-H1+Kabat CDR-H2+Kabat CDR-H3

[0165] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 63-121, a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 181-239, and a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 240-298. In some aspects, the Kabat CDR-H1 sequence, Kabat CDR-H2 sequence, and Kabat CDR-H3 sequence are all from a single illustrative V.sub.H sequence provided in this disclosure. For example, in some aspects, the Kabat CDR-H1, Kabat CDR-H2, and Kabat CDR-H3 are all from a single illustrative V.sub.H sequence selected from SEQ ID NOs: 308-366.

5.2.1.8. Variants of V.SUB.H .Sequences Comprising Illustrative Kabat CDRs

[0166] In some embodiments, the V.sub.H sequences provided herein comprise a variant of an illustrative Kabat CDR-H3, CDR-H2, and/or CDR-H1 sequence provided in this disclosure.

[0167] In some aspects, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H3 sequence provided in this disclosure. In some aspects, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H3 sequences provided in this disclosure. In some aspects, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0168] In some aspects, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H2 sequence provided in this disclosure. In some aspects, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H2 sequences provided in this disclosure. In some aspects, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0169] In some aspects, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H1 sequence provided in this disclosure. In some aspects, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H1 sequences provided in this disclosure. In some aspects, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

5.2.2. V.SUB.H .Sequences Comprising Illustrative Chothia CDRs

[0170] In some embodiments, the antibody comprises a V.sub.H sequence comprising one or more Chothia CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Chothia CDR-H sequences provided in this disclosure, and variants thereof.

5.2.2.1. Chothia CDR-H3

[0171] In some embodiments, the antibody comprises a V.sub.H sequence comprising a CDR-H3 sequence, wherein the CDR-H3 sequence comprises, consists of, or consists essentially of a Chothia CDR-H3 sequence of an illustrative antibody or V.sub.H sequence provided herein. In some aspects, the Chothia CDR-H3 sequence is a Chothia CDR-H3 sequence of a V.sub.H sequence provided in SEQ ID NOs: 308-366.

[0172] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 240-298. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 240. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 241. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 242. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 243. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 244. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 245. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 246. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 247. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 248. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 249. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 250. In some aspects, the antibody comprises a V.sub.Hsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 251. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 252. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 253. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 254. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 255. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 256. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 257. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 258. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 259. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 260. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 261. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 262. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 263. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 264. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 265. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 266. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 267. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 268. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 269. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 270. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 271. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 272. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 273. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 274. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 275. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 276. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 277. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 278. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 279. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 280. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 281. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 282. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 283. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 284. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 285. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 286. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 287. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 288. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 289. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 290. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 291. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 292. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 293. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 294. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 295. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 296. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 297. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 298.

5.2.2.2. Chothia CDR-H2

[0173] In some embodiments, the antibody comprises a V.sub.H sequence comprising a CDR-H2 sequence, wherein the CDR-H2 sequence comprises, consists of, or consists essentially of a Chothia CDR-H2 sequence of an illustrative antibody or V.sub.H sequence provided herein. In some aspects, the Chothia CDR-H2 sequence is a Chothia CDR-H2 sequence of a V.sub.H sequence provided in SEQ ID NOs: 308-366.

[0174] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 122-180. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 122. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 123. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 124. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 125. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 126. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 127. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 128. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 129. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 130. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 131. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 132. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 133. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 134. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 135. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 136. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 137. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 138. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 139. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 140. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 141. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 142. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 143. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 144. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 145. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 146. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 147. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 148. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 149. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 150. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 151. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 152. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 153. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 154. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 155. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 156. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 157. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 158. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 159. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 160. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 161. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 162. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 163. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 164. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 165. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 166. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 167. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 168. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 169. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 170. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 171. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 172. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 173. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 174. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 175. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 176. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 177. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 178. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 179. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 180.

5.2.2.3. Chothia CDR-H1

[0175] In some embodiments, the antibody comprises a V.sub.H sequence comprising a CDR-H1 sequence, wherein the CDR-H1 sequence comprises, consists of, or consists essentially of a Chothia CDR-H1 sequence of an illustrative antibody or V.sub.H sequence provided herein. In some aspects, the Chothia CDR-H1 sequence is a Chothia CDR-H1 sequence of a V.sub.H sequence provided in SEQ ID NOs: 308-366.

[0176] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 4-62. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 4. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 5. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 6. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 7. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 8. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 9. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 10. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 11. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 12. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 13. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 14. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 15. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 16. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 17. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 18. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 19. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 20. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 21. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 22. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 23. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 24. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 25. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 26. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 27. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 28. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 29. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 30. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 31. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 32. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 33. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 34. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 35. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 36. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 37. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 38. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 39. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 40. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 41. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 42. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 43. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 44. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 45. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 46. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 47. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 48. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 49. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 50. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 51. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 52. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 53. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 54. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 55. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 56. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 57. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 58. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 59. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 60. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 61. In some aspects, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 62.

5.2.2.4. Chothia CDR-H3+Chothia CDR-H2

[0177] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 240-298, and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 122-180. In some aspects, the Chothia CDR-H3 sequence and the Chothia CDR-H2 sequence are both from a single illustrative V.sub.H sequence provided in this disclosure. For example, in some aspects, the Chothia CDR-H3 and Chothia CDR-H2 are both from a single illustrative V.sub.H sequence selected from SEQ ID NOs: 308-366.

5.2.2.5. Chothia CDR-H3+Chothia CDR-H1

[0178] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 240-298, and a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 4-62. In some aspects, the Chothia CDR-H3 sequence and the Chothia CDR-H1 sequence are both from a single illustrative V.sub.H sequence provided in this disclosure. For example, in some aspects, the Chothia CDR-H3 and Chothia CDR-H1 are both from a single illustrative V.sub.H sequence selected from SEQ ID NOs: 308-366.

5.2.2.6 Chothia CDR-H1+Chothia CDR-H2

[0179] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 4-62 and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 122-180. In some aspects, the Chothia CDR-H1 sequence and the Chothia CDR-H2 sequence are both from a single illustrative V.sub.H sequence provided in this disclosure. For example, in some aspects, the Chothia CDR-H1 and Chothia CDR-H2 are both from a single illustrative V.sub.H sequence selected from SEQ ID NOs: 308-366.

5.2.2.7. Chothia CDR-H1+Chothia CDR-H2+Chothia CDR-H3

[0180] In some embodiments, the antibody comprises a V.sub.H sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 4-62, a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 122-180, and a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 240-298. In some aspects, the Chothia CDR-H1 sequence, Chothia CDR-H2 sequence, and Chothia CDR-H3 sequence are all from a single illustrative V.sub.H sequence provided in this disclosure. For example, in some aspects, the Chothia CDR-H1, Chothia CDR-H2, and Chothia CDR-H3 are all from a single illustrative V.sub.H sequence selected from SEQ ID NOs: 308-366.

5.2.2.8. Variants of V.SUB.H .Sequences Comprising Illustrative Chothia CDRs

[0181] In some embodiments, the V.sub.H sequences provided herein comprise a variant of an illustrative Chothia CDR-H3, CDR-H2, and/or CDR-H1 sequence provided in this disclosure.

[0182] In some aspects, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H3 sequence provided in this disclosure. In some aspects, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H3 sequences provided in this disclosure. In some aspects, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0183] In some aspects, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H2 sequence provided in this disclosure. In some aspects, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H2 sequences provided in this disclosure. In some aspects, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0184] In some aspects, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H1 sequence provided in this disclosure.

[0185] In some aspects, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H1 sequences provided in this disclosure. In some aspects, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

5.3. V.SUB.H .Sequences

[0186] In some embodiments, the antibody comprises, consists of, or consists essentially of a V.sub.H sequence provided in SEQ ID NOs: 308-366.

[0187] In some embodiments, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 308-366. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 308. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 309. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 310. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 311. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 312. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 313. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 314. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 315. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 316. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 317. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 318. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 319. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 320. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 321. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 322. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 323. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 324. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 325. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 326. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 327. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 328. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 329. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 330. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 331. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 332. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 333. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 334. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 335. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 336. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 337. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 338. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 339. In some aspects, the antibody comprises a V.sub.Hsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 340. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 341. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 342. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 343. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 344. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 345. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 346. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 347. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 348. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 349. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 350. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 351. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 352. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 353. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 354. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 355. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 356. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 357. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 358. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 359. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 360. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 361. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 362. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 363. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 364. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 365. In some aspects, the antibody comprises a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 366.

5.3.1. Variants of V.SUB.H .Sequences

[0188] In some embodiments, the V.sub.H sequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative V.sub.H sequence provided in this disclosure.

[0189] In some aspects, the V.sub.H sequence comprises, consists of, or consists essentially of a variant of an illustrative V.sub.H sequence provided in this disclosure. In some aspects, the V.sub.H sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative V.sub.H sequences provided in this disclosure.

[0190] In some embodiments, the V.sub.H sequence comprises, consists of, or consists essentially of any of the illustrative V.sub.H sequences provided in this disclosure having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

5.4. CDR-L3 Sequences

[0191] In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of an illustrative antibody or V.sub.L sequence provided herein. In some aspects, the CDR-L3 sequence is a CDR-L3 sequence of a V.sub.L sequence provided in SEQ ID NOs.: 367-369.

[0192] In some embodiments, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 305-307. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 305. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 306. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 307.

[0193] In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

5.5. V.SUB.L .Sequences Comprising Illustrative CDRs

[0194] In some embodiments, the antibody comprises a V.sub.L sequence comprising one or more CDR-L sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-L sequences provided in this disclosure, and variants thereof.

5.5.1. CDR-L3

[0195] In some embodiments, the antibody comprises a V.sub.L sequence comprising a CDR-L3 sequence, wherein the CDR-L3 sequence comprises, consists of, or consists essentially of a CDR-L3 sequence of an illustrative antibody or V.sub.L sequence provided herein. In some aspects, the CDR-L3 sequence is a CDR-L3 sequence of a V.sub.L sequence provided in SEQ ID NOs.: 367-369.

[0196] In some embodiments, the antibody comprises a V.sub.L sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 305-307. In some aspects, the antibody comprises a V.sub.L sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 305. In some aspects, the antibody comprises a V.sub.L sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 306. In some aspects, the antibody comprises a V.sub.L sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 307.

5.5.2. CDR-L2

[0197] In some embodiments, the antibody comprises a V.sub.L sequence comprising a CDR-L2 sequence, wherein the CDR-L2 sequence comprises, consists of, or consists essentially of a CDR-L2 sequence of an illustrative antibody or V.sub.L sequence provided herein. In some aspects, the CDR-L2 sequence is a CDR-L2 sequence of a V.sub.L sequence provided in SEQ ID NOs.: 367-369.

[0198] In some embodiments, the antibody comprises a V.sub.L sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 302-304. In some aspects, the antibody comprises a V.sub.L sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 302. In some aspects, the antibody comprises a V.sub.L sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 303. In some aspects, the antibody comprises a V.sub.L sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 304.

5.5.3. CDR-L1

[0199] In some embodiments, the antibody comprises a V.sub.L sequence comprising a CDR-L1 sequence, wherein the CDR-L1 sequence comprises, consists of, or consists essentially of a CDR-L1 sequence of an illustrative antibody or V.sub.L sequence provided herein. In some aspects, the CDR-L1 sequence is a CDR-L1 sequence of a V.sub.L sequence provided in SEQ ID NOs.: 367-369.

[0200] In some embodiments, the antibody comprises a V.sub.L sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 299-301. In some aspects, the antibody comprises a V.sub.L sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 299. In some aspects, the antibody comprises a V.sub.L sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 300. In some aspects, the antibody comprises a V.sub.L sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 301.

5.5.4. CDR-L3+CDR-L2

[0201] In some embodiments, the antibody comprises a V.sub.L sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 305-307 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 302-304. In some aspects, the CDR-L3 sequence and the CDR-L2 sequence are both from a single illustrative V.sub.L sequence provided in this disclosure. For example, in some aspects, the CDR-L3 and CDR-L2 are both from a single illustrative V.sub.L sequence selected from SEQ ID NOs.: 367-369.

5.5.5. CDR-L3+CDR-L1

[0202] In some embodiments, the antibody comprises a V.sub.L sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 305-307 and a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 299-301. In some aspects, the CDR-L3 sequence and the CDR-L1 sequence are both from a single illustrative V.sub.L sequence provided in this disclosure. For example, in some aspects, the CDR-L3 and CDR-L1 are both from a single illustrative V.sub.L sequence selected from SEQ ID NOs.: 367-369.

5.5.6. CDR-L1+CDR-L2

[0203] In some embodiments, the antibody comprises a V.sub.L sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 299-301 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 302-304. In some aspects, the CDR-L1 sequence and the CDR-L2 sequence are both from a single illustrative V.sub.L sequence provided in this disclosure. For example, in some aspects, the CDR-L1 and CDR-L2 are both from a single illustrative V.sub.L sequence selected from SEQ ID NOs.: 367-369.

5.5.7. CDR-L1+CDR-L2+CDR-L3

[0204] In some embodiments, the antibody comprises a V.sub.L sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 299-301, a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 302-304, and a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 305-307. In some aspects, the CDR-L1 sequence, CDR-L2 sequence, and CDR-L3 sequence are all from a single illustrative V.sub.L sequence provided in this disclosure. For example, in some aspects, the CDR-L1, CDR-L2, and CDR-L3 are all from a single illustrative V.sub.L sequence selected from SEQ ID NOs.: 367-369.

5.5.8. Variants of V.SUB.L .Sequences Comprising Illustrative CDR-Ls

[0205] In some embodiments, the V.sub.L sequences provided herein comprise a variant of an illustrative CDR-L3, CDR-L2, and/or CDR-L1 sequence provided in this disclosure.

[0206] In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0207] In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0208] In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L1 sequence provided in this disclosure. In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L1 sequences provided in this disclosure. In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

5.6. V.SUB.L .Sequences

[0209] In some embodiments, the antibody comprises, consists of, or consists essentially of a V.sub.L sequence provided in SEQ ID NOs.: 367-369.

[0210] In some embodiments, the antibody comprises a V.sub.L sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs.: 367-369. In some aspects, the antibody comprises a V.sub.L sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 367. In some aspects, the antibody comprises a V.sub.L sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 368. In some aspects, the antibody comprises a V.sub.L sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 369.

5.61. Variants of V.SUB.L .Sequences

[0211] In some embodiments, the V.sub.L sequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative V.sub.L sequence provided in this disclosure.

[0212] In some aspects, the V.sub.L sequence comprises, consists of, or consists essentially of a variant of an illustrative V.sub.L sequence provided in this disclosure. In some aspects, the V.sub.L sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative V.sub.L sequences provided in this disclosure.

[0213] In some embodiments, the V.sub.L sequence comprises, consists of, or consists essentially of any of the illustrative V.sub.L sequences provided in this disclosure having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

5.7. Pairs

5.7.1. CDR-H3 CDR-L3 Pairs

[0214] In some embodiments, the antibody comprises a CDR-H3 sequence and a CDR-L3 sequence. In some aspects, the CDR-H3 sequence is part of a V.sub.H and the CDR-L3 sequence is part of a V.sub.L.

[0215] In some aspects, the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 240-298, and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 305-307.

[0216] In some aspects, the CDR-H3-CDR-L3 pairs are selected from SEQ ID NO: 305 and SEQ ID NO: 240; SEQ ID NO: 305 and SEQ ID NO: 241; SEQ ID NO: 305 and SEQ ID NO: 242; SEQ ID NO: 305 and SEQ ID NO: 243; SEQ ID NO: 305 and SEQ ID NO: 244; SEQ ID NO: 305 and SEQ ID NO: 245; SEQ ID NO: 305 and SEQ ID NO: 246; SEQ ID NO: 305 and SEQ ID NO: 247; SEQ ID NO: 305 and SEQ ID NO: 248; SEQ ID NO: 305 and SEQ ID NO: 249; SEQ ID NO: 305 and SEQ ID NO: 250; SEQ ID NO: 305 and SEQ ID NO: 251; SEQ ID NO: 305 and SEQ ID NO: 252; SEQ ID NO: 305 and SEQ ID NO: 253; SEQ ID NO: 305 and SEQ ID NO: 254; SEQ ID NO: 305 and SEQ ID NO: 255; SEQ ID NO: 305 and SEQ ID NO: 256; SEQ ID NO: 305 and SEQ ID NO: 257; SEQ ID NO: 305 and SEQ ID NO: 258; SEQ ID NO: 305 and SEQ ID NO: 259; SEQ ID NO: 305 and SEQ ID NO: 260; SEQ ID NO: 305 and SEQ ID NO: 261; SEQ ID NO: 305 and SEQ ID NO: 262; SEQ ID NO: 305 and SEQ ID NO: 263; SEQ ID NO: 305 and SEQ ID NO: 264; SEQ ID NO: 305 and SEQ ID NO: 265; SEQ ID NO: 305 and SEQ ID NO: 266; SEQ ID NO: 305 and SEQ ID NO: 267; SEQ ID NO: 305 and SEQ ID NO: 268; SEQ ID NO: 305 and SEQ ID NO: 269; SEQ ID NO: 305 and SEQ ID NO: 270; SEQ ID NO: 305 and SEQ ID NO: 271; SEQ ID NO: 305 and SEQ ID NO: 272; SEQ ID NO: 305 and SEQ ID NO: 273; SEQ ID NO: 305 and SEQ ID NO: 274; SEQ ID NO: 305 and SEQ ID NO: 275; SEQ ID NO: 305 and SEQ ID NO: 276; SEQ ID NO: 305 and SEQ ID NO: 277; SEQ ID NO: 305 and SEQ ID NO: 278; SEQ ID NO: 305 and SEQ ID NO: 279; SEQ ID NO: 305 and SEQ ID NO: 280; SEQ ID NO: 305 and SEQ ID NO: 281; SEQ ID NO: 305 and SEQ ID NO: 282; SEQ ID NO: 305 and SEQ ID NO: 283; SEQ ID NO: 305 and SEQ ID NO: 284; SEQ ID NO: 305 and SEQ ID NO: 285; SEQ ID NO: 305 and SEQ ID NO: 286; SEQ ID NO: 305 and SEQ ID NO: 287; SEQ ID NO: 305 and SEQ ID NO: 288; SEQ ID NO: 305 and SEQ ID NO: 289; SEQ ID NO: 305 and SEQ ID NO: 290; SEQ ID NO: 305 and SEQ ID NO: 291; SEQ ID NO: 305 and SEQ ID NO: 292; SEQ ID NO: 305 and SEQ ID NO: 293; SEQ ID NO: 305 and SEQ ID NO: 294; SEQ ID NO: 305 and SEQ ID NO: 295; SEQ ID NO: 305 and SEQ ID NO: 296; SEQ ID NO: 305 and SEQ ID NO: 297; and SEQ ID NO: 305 and SEQ ID NO: 298.

[0217] In some aspects, the CDR-H3-CDR-L3 pairs are selected from SEQ ID NO: 306 and SEQ ID NO: 240; SEQ ID NO: 306 and SEQ ID NO: 241; SEQ ID NO: 306 and SEQ ID NO: 242; SEQ ID NO: 306 and SEQ ID NO: 243; SEQ ID NO: 306 and SEQ ID NO: 244; SEQ ID NO: 306 and SEQ ID NO: 245; SEQ ID NO: 306 and SEQ ID NO: 246; SEQ ID NO: 306 and SEQ ID NO: 247; SEQ ID NO: 306 and SEQ ID NO: 248; SEQ ID NO: 306 and SEQ ID NO: 249; SEQ ID NO: 306 and SEQ ID NO: 250; SEQ ID NO: 306 and SEQ ID NO: 251; SEQ ID NO: 306 and SEQ ID NO: 252; SEQ ID NO: 306 and SEQ ID NO: 253; SEQ ID NO: 306 and SEQ ID NO: 254; SEQ ID NO: 306 and SEQ ID NO: 255; SEQ ID NO: 306 and SEQ ID NO: 256; SEQ ID NO: 306 and SEQ ID NO: 257; SEQ ID NO: 306 and SEQ ID NO: 258; SEQ ID NO: 306 and SEQ ID NO: 259; SEQ ID NO: 306 and SEQ ID NO: 260; SEQ ID NO: 306 and SEQ ID NO: 261; SEQ ID NO: 306 and SEQ ID NO: 262; SEQ ID NO: 306 and SEQ ID NO: 263; SEQ ID NO: 306 and SEQ ID NO: 264; SEQ ID NO: 306 and SEQ ID NO: 265; SEQ ID NO: 306 and SEQ ID NO: 266; SEQ ID NO: 306 and SEQ ID NO: 267; SEQ ID NO: 306 and SEQ ID NO: 268; SEQ ID NO: 306 and SEQ ID NO: 269; SEQ ID NO: 306 and SEQ ID NO: 270; SEQ ID NO: 306 and SEQ ID NO: 271; SEQ ID NO: 306 and SEQ ID NO: 272; SEQ ID NO: 306 and SEQ ID NO: 273; SEQ ID NO: 306 and SEQ ID NO: 274; SEQ ID NO: 306 and SEQ ID NO: 275; SEQ ID NO: 306 and SEQ ID NO: 276; SEQ ID NO: 306 and SEQ ID NO: 277; SEQ ID NO: 306 and SEQ ID NO: 278; SEQ ID NO: 306 and SEQ ID NO: 279; SEQ ID NO: 306 and SEQ ID NO: 280; SEQ ID NO: 306 and SEQ ID NO: 281; SEQ ID NO: 306 and SEQ ID NO: 282; SEQ ID NO: 306 and SEQ ID NO: 283; SEQ ID NO: 306 and SEQ ID NO: 284; SEQ ID NO: 306 and SEQ ID NO: 285; SEQ ID NO: 306 and SEQ ID NO: 286; SEQ ID NO: 306 and SEQ ID NO: 287; SEQ ID NO: 306 and SEQ ID NO: 288; SEQ ID NO: 306 and SEQ ID NO: 289; SEQ ID NO: 306 and SEQ ID NO: 290; SEQ ID NO: 306 and SEQ ID NO: 291; SEQ ID NO: 306 and SEQ ID NO: 292; SEQ ID NO: 306 and SEQ ID NO: 293; SEQ ID NO: 306 and SEQ ID NO: 294; SEQ ID NO: 306 and SEQ ID NO: 295; SEQ ID NO: 306 and SEQ ID NO: 296; SEQ ID NO: 306 and SEQ ID NO: 297; and SEQ ID NO: 306 and SEQ ID NO: 298.

[0218] In some aspects, the CDR-H3-CDR-L3 pairs are selected from SEQ ID NO: 307 and SEQ ID NO: 240; SEQ ID NO: 307 and SEQ ID NO: 241; SEQ ID NO: 307 and SEQ ID NO: 242; SEQ ID NO: 307 and SEQ ID NO: 243; SEQ ID NO: 307 and SEQ ID NO: 244; SEQ ID NO: 307 and SEQ ID NO: 245; SEQ ID NO: 307 and SEQ ID NO: 246; SEQ ID NO: 307 and SEQ ID NO: 247; SEQ ID NO: 307 and SEQ ID NO: 248; SEQ ID NO: 307 and SEQ ID NO: 249; SEQ ID NO: 307 and SEQ ID NO: 250; SEQ ID NO: 307 and SEQ ID NO: 251; SEQ ID NO: 307 and SEQ ID NO: 252; SEQ ID NO: 307 and SEQ ID NO: 253; SEQ ID NO: 307 and SEQ ID NO: 254; SEQ ID NO: 307 and SEQ ID NO: 255; SEQ ID NO: 307 and SEQ ID NO: 256; SEQ ID NO: 307 and SEQ ID NO: 257; SEQ ID NO: 307 and SEQ ID NO: 258; SEQ ID NO: 307 and SEQ ID NO: 259; SEQ ID NO: 307 and SEQ ID NO: 260; SEQ ID NO: 307 and SEQ ID NO: 261; SEQ ID NO: 307 and SEQ ID NO: 262; SEQ ID NO: 307 and SEQ ID NO: 263; SEQ ID NO: 307 and SEQ ID NO: 264; SEQ ID NO: 307 and SEQ ID NO: 265; SEQ ID NO: 307 and SEQ ID NO: 266; SEQ ID NO: 307 and SEQ ID NO: 267; SEQ ID NO: 307 and SEQ ID NO: 268; SEQ ID NO: 307 and SEQ ID NO: 269; SEQ ID NO: 307 and SEQ ID NO: 270; SEQ ID NO: 307 and SEQ ID NO: 271; SEQ ID NO: 307 and SEQ ID NO: 272; SEQ ID NO: 307 and SEQ ID NO: 273; SEQ ID NO: 307 and SEQ ID NO: 274; SEQ ID NO: 307 and SEQ ID NO: 275; SEQ ID NO: 307 and SEQ ID NO: 276; SEQ ID NO: 307 and SEQ ID NO: 277; SEQ ID NO: 307 and SEQ ID NO: 278; SEQ ID NO: 307 and SEQ ID NO: 279; SEQ ID NO: 307 and SEQ ID NO: 280; SEQ ID NO: 307 and SEQ ID NO: 281; SEQ ID NO: 307 and SEQ ID NO: 282; SEQ ID NO: 307 and SEQ ID NO: 283; SEQ ID NO: 307 and SEQ ID NO: 284; SEQ ID NO: 307 and SEQ ID NO: 285; SEQ ID NO: 307 and SEQ ID NO: 286; SEQ ID NO: 307 and SEQ ID NO: 287; SEQ ID NO: 307 and SEQ ID NO: 288; SEQ ID NO: 307 and SEQ ID NO: 289; SEQ ID NO: 307 and SEQ ID NO: 290; SEQ ID NO: 307 and SEQ ID NO: 291; SEQ ID NO: 307 and SEQ ID NO: 292; SEQ ID NO: 307 and SEQ ID NO: 293; SEQ ID NO: 307 and SEQ ID NO: 294; SEQ ID NO: 307 and SEQ ID NO: 295; SEQ ID NO: 307 and SEQ ID NO: 296; SEQ ID NO: 307 and SEQ ID NO: 297; and SEQ ID NO: 307 and SEQ ID NO: 298.

5.7.1.1. Variants of CDR-H3-CDR-L3 Pairs

[0219] In some embodiments, the CDR-H3-CDR-L3 pairs provided herein comprise a variant of an illustrative CDR-H3 and/or CDR-L1 sequence provided in this disclosure.

[0220] In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0221] In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

5.7.2. CDR-H -CDR-L1 Pairs

[0222] In some embodiments, the antibody comprises a CDR-H1 sequence and a CDR-L1 sequence. In some aspects, the CDR-H1 sequence is part of a V.sub.H and the CDR-L1 sequence is part of a V.sub.L.

[0223] In some aspects, the CDR-H1 sequence is a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 4-62, and the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 299-301.

[0224] In some aspects, the CDR-H1 sequence is a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 63-121, and the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 299-301.

5.7.2.1. Variants of CDR-H1-CDR-L1 Pairs

[0225] In some embodiments, the CDR-H1-CDR-L1 pairs provided herein comprise a variant of an illustrative CDR-H1 and/or CDR-L1 sequence provided in this disclosure.

[0226] In some aspects, the CDR-H1 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H1 sequence provided in this disclosure. In some aspects, the CDR-H1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H1 sequences provided in this disclosure. In some aspects, the CDR-H1 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0227] In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L1 sequence provided in this disclosure. In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L1 sequences provided in this disclosure. In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

5.7.3. CDR-H2 CDR-L2 Pairs

[0228] In some embodiments, the antibody comprises a CDR-H2 sequence and a CDR-L2 sequence. In some aspects, the CDR-H2 sequence is part of a V.sub.H and the CDR-L2 sequence is part of a V.sub.L.

[0229] In some aspects, the CDR-H2 sequence is a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 122-180, and the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 302-304.

[0230] In some aspects, the CDR-H1 sequence is a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 181-239, and the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 302-304.

5.7.3.1. Variants of CDR-H2-CDR-L2 Pairs

[0231] In some embodiments, the CDR-H2-CDR-L2 pairs provided herein comprise a variant of an illustrative CDR-H2 and/or CDR-L2 sequence provided in this disclosure.

[0232] In some aspects, the CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H2 sequence provided in this disclosure. In some aspects, the CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H2 sequences provided in this disclosure. In some aspects, the CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0233] In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

5.7.4. V.sub.H-V.sub.L Pairs

[0234] In some embodiments, the antibody comprises a V.sub.H sequence and a V.sub.L sequence.

[0235] In some aspects, the V.sub.H sequence is a V.sub.H sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 308-366, and the V.sub.L sequence is a V.sub.L sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 367-369.

[0236] In some aspects, the V.sub.H-V.sub.L pairs are selected from SEQ ID NO: 367 and SEQ ID NO: 308; SEQ ID NO: 367 and SEQ ID NO: 309; SEQ ID NO: 367 and SEQ ID NO: 310; SEQ ID NO: 367 and SEQ ID NO: 311; SEQ ID NO: 367 and SEQ ID NO: 312; SEQ ID NO: 367 and SEQ ID NO: 313; SEQ ID NO: 367 and SEQ ID NO: 314; SEQ ID NO: 367 and SEQ ID NO: 315; SEQ ID NO: 367 and SEQ ID NO: 316; SEQ ID NO: 367 and SEQ ID NO: 317; SEQ ID NO: 367 and SEQ ID NO: 318; SEQ ID NO: 367 and SEQ ID NO: 319; SEQ ID NO: 367 and SEQ ID NO: 320; SEQ ID NO: 367 and SEQ ID NO: 321; SEQ ID NO: 367 and SEQ ID NO: 322; SEQ ID NO: 367 and SEQ ID NO: 323; SEQ ID NO: 367 and SEQ ID NO: 324; SEQ ID NO: 367 and SEQ ID NO: 325; SEQ ID NO: 367 and SEQ ID NO: 326; SEQ ID NO: 367 and SEQ ID NO: 327; SEQ ID NO: 367 and SEQ ID NO: 328; SEQ ID NO: 367 and SEQ ID NO: 329; SEQ ID NO: 367 and SEQ ID NO: 330; SEQ ID NO: 367 and SEQ ID NO: 331; SEQ ID NO: 367 and SEQ ID NO: 332; SEQ ID NO: 367 and SEQ ID NO: 333; SEQ ID NO: 367 and SEQ ID NO: 334; SEQ ID NO: 367 and SEQ ID NO: 335; SEQ ID NO: 367 and SEQ ID NO: 336; SEQ ID NO: 367 and SEQ ID NO: 337; SEQ ID NO: 367 and SEQ ID NO: 338; SEQ ID NO: 367 and SEQ ID NO: 339; SEQ ID NO: 367 and SEQ ID NO: 340; SEQ ID NO: 367 and SEQ ID NO: 341; SEQ ID NO: 367 and SEQ ID NO: 342; SEQ ID NO: 367 and SEQ ID NO: 343; SEQ ID NO: 367 and SEQ ID NO: 344; SEQ ID NO: 367 and SEQ ID NO: 345; SEQ ID NO: 367 and SEQ ID NO: 346; SEQ ID NO: 367 and SEQ ID NO: 347; SEQ ID NO: 367 and SEQ ID NO: 348; SEQ ID NO: 367 and SEQ ID NO: 349; SEQ ID NO: 367 and SEQ ID NO: 350; SEQ ID NO: 367 and SEQ ID NO: 351; SEQ ID NO: 367 and SEQ ID NO: 352; SEQ ID NO: 367 and SEQ ID NO: 353; SEQ ID NO: 367 and SEQ ID NO: 354; SEQ ID NO: 367 and SEQ ID NO: 355; SEQ ID NO: 367 and SEQ ID NO: 356; SEQ ID NO: 367 and SEQ ID NO: 357; SEQ ID NO: 367 and SEQ ID NO: 358; SEQ ID NO: 367 and SEQ ID NO: 359; SEQ ID NO: 367 and SEQ ID NO: 360; SEQ ID NO: 367 and SEQ ID NO: 361; SEQ ID NO: 367 and SEQ ID NO: 362; SEQ ID NO: 367 and SEQ ID NO: 363; SEQ ID NO: 367 and SEQ ID NO: 364; SEQ ID NO: 367 and SEQ ID NO: 365; and SEQ ID NO: 367 and SEQ ID NO: 366.

[0237] In some aspects, the V.sub.H-V.sub.L pairs are selected from SEQ ID NO: 368 and SEQ ID NO: 308; SEQ ID NO: 368 and SEQ ID NO: 309; SEQ ID NO: 368 and SEQ ID NO: 310; SEQ ID NO: 368 and SEQ ID NO: 311; SEQ ID NO: 368 and SEQ ID NO: 312; SEQ ID NO: 368 and SEQ ID NO: 313; SEQ ID NO: 368 and SEQ ID NO: 314; SEQ ID NO: 368 and SEQ ID NO: 315; SEQ ID NO: 368 and SEQ ID NO: 316; SEQ ID NO: 368 and SEQ ID NO: 317; SEQ ID NO: 368 and SEQ ID NO: 318; SEQ ID NO: 368 and SEQ ID NO: 319; SEQ ID NO: 368 and SEQ ID NO: 320; SEQ ID NO: 368 and SEQ ID NO: 321; SEQ ID NO: 368 and SEQ ID NO: 322; SEQ ID NO: 368 and SEQ ID NO: 323; SEQ ID NO: 368 and SEQ ID NO: 324; SEQ ID NO: 368 and SEQ ID NO: 325; SEQ ID NO: 368 and SEQ ID NO: 326; SEQ ID NO: 368 and SEQ ID NO: 327; SEQ ID NO: 368 and SEQ ID NO: 328; SEQ ID NO: 368 and SEQ ID NO: 329; SEQ ID NO: 368 and SEQ ID NO: 330; SEQ ID NO: 368 and SEQ ID NO: 331; SEQ ID NO: 368 and SEQ ID NO: 332; SEQ ID NO: 368 and SEQ ID NO: 333; SEQ ID NO: 368 and SEQ ID NO: 334; SEQ ID NO: 368 and SEQ ID NO: 335; SEQ ID NO: 368 and SEQ ID NO: 336; SEQ ID NO: 368 and SEQ ID NO: 337; SEQ ID NO: 368 and SEQ ID NO: 338; SEQ ID NO: 368 and SEQ ID NO: 339; SEQ ID NO: 368 and SEQ ID NO: 340; SEQ ID NO: 368 and SEQ ID NO: 341; SEQ ID NO: 368 and SEQ ID NO: 342; SEQ ID NO: 368 and SEQ ID NO: 343; SEQ ID NO: 368 and SEQ ID NO: 344; SEQ ID NO: 368 and SEQ ID NO: 345; SEQ ID NO: 368 and SEQ ID NO: 346; SEQ ID NO: 368 and SEQ ID NO: 347; SEQ ID NO: 368 and SEQ ID NO: 348; SEQ ID NO: 368 and SEQ ID NO: 349; SEQ ID NO: 368 and SEQ ID NO: 350; SEQ ID NO: 368 and SEQ ID NO: 351; SEQ ID NO: 368 and SEQ ID NO: 352; SEQ ID NO: 368 and SEQ ID NO: 353; SEQ ID NO: 368 and SEQ ID NO: 354; SEQ ID NO: 368 and SEQ ID NO: 355; SEQ ID NO: 368 and SEQ ID NO: 356; SEQ ID NO: 368 and SEQ ID NO: 357; SEQ ID NO: 368 and SEQ ID NO: 358; SEQ ID NO: 368 and SEQ ID NO: 359; SEQ ID NO: 368 and SEQ ID NO: 360; SEQ ID NO: 368 and SEQ ID NO: 361; SEQ ID NO: 368 and SEQ ID NO: 362; SEQ ID NO: 368 and SEQ ID NO: 363; SEQ ID NO: 368 and SEQ ID NO: 364; SEQ ID NO: 368 and SEQ ID NO: 365; and SEQ ID NO: 368 and SEQ ID NO: 366.

[0238] In some aspects, the V.sub.H-V.sub.L pairs are selected from SEQ ID NO: 369 and SEQ ID NO: 308; SEQ ID NO: 369 and SEQ ID NO: 309; SEQ ID NO: 369 and SEQ ID NO: 310; SEQ ID NO: 369 and SEQ ID NO: 311; SEQ ID NO: 369 and SEQ ID NO: 312; SEQ ID NO: 369 and SEQ ID NO: 313; SEQ ID NO: 369 and SEQ ID NO: 314; SEQ ID NO: 369 and SEQ ID NO: 315; SEQ ID NO: 369 and SEQ ID NO: 316; SEQ ID NO: 369 and SEQ ID NO: 317; SEQ ID NO: 369 and SEQ ID NO: 318; SEQ ID NO: 369 and SEQ ID NO: 319; SEQ ID NO: 369 and SEQ ID NO: 320; SEQ ID NO: 369 and SEQ ID NO: 321; SEQ ID NO: 369 and SEQ ID NO: 322; SEQ ID NO: 369 and SEQ ID NO: 323; SEQ ID NO: 369 and SEQ ID NO: 324; SEQ ID NO: 369 and SEQ ID NO: 325; SEQ ID NO: 369 and SEQ ID NO: 326; SEQ ID NO: 369 and SEQ ID NO: 327; SEQ ID NO: 369 and SEQ ID NO: 328; SEQ ID NO: 369 and SEQ ID NO: 329; SEQ ID NO: 369 and SEQ ID NO: 330; SEQ ID NO: 369 and SEQ ID NO: 331; SEQ ID NO: 369 and SEQ ID NO: 332; SEQ ID NO: 369 and SEQ ID NO: 333; SEQ ID NO: 369 and SEQ ID NO: 334; SEQ ID NO: 369 and SEQ ID NO: 335; SEQ ID NO: 369 and SEQ ID NO: 336; SEQ ID NO: 369 and SEQ ID NO: 337; SEQ ID NO: 369 and SEQ ID NO: 338; SEQ ID NO: 369 and SEQ ID NO: 339; SEQ ID NO: 369 and SEQ ID NO: 340; SEQ ID NO: 369 and SEQ ID NO: 341; SEQ ID NO: 369 and SEQ ID NO: 342; SEQ ID NO: 369 and SEQ ID NO: 343; SEQ ID NO: 369 and SEQ ID NO: 344; SEQ ID NO: 369 and SEQ ID NO: 345; SEQ ID NO: 369 and SEQ ID NO: 346; SEQ ID NO: 369 and SEQ ID NO: 347; SEQ ID NO: 369 and SEQ ID NO: 348; SEQ ID NO: 369 and SEQ ID NO: 349; SEQ ID NO: 369 and SEQ ID NO: 350; SEQ ID NO: 369 and SEQ ID NO: 351; SEQ ID NO: 369 and SEQ ID NO: 352; SEQ ID NO: 369 and SEQ ID NO: 353; SEQ ID NO: 369 and SEQ ID NO: 354; SEQ ID NO: 369 and SEQ ID NO: 355; SEQ ID NO: 369 and SEQ ID NO: 356; SEQ ID NO: 369 and SEQ ID NO: 357; SEQ ID NO: 369 and SEQ ID NO: 358; SEQ ID NO: 369 and SEQ ID NO: 359; SEQ ID NO: 369 and SEQ ID NO: 360; SEQ ID NO: 369 and SEQ ID NO: 361; SEQ ID NO: 369 and SEQ ID NO: 362; SEQ ID NO: 369 and SEQ ID NO: 363; SEQ ID NO: 369 and SEQ ID NO: 364; SEQ ID NO: 369 and SEQ ID NO: 365; and SEQ ID NO: 369 and SEQ ID NO: 366.

5.7.4.1. Variants of V.sub.H-V.sub.L Pairs

[0239] In some embodiments, the V.sub.H-V.sub.L pairs provided herein comprise a variant of an illustrative V.sub.H and/or V.sub.L sequence provided in this disclosure.

[0240] In some aspects, the V.sub.H sequence comprises, consists of, or consists essentially of a variant of an illustrative V.sub.H sequence provided in this disclosure. In some aspects, the V.sub.H sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.10% identity with any of the illustrative V.sub.H sequences provided in this disclosure.

[0241] In some embodiments, the V.sub.H sequence comprises, consists of, or consists essentially of any of the illustrative V.sub.H sequences provided in this disclosure having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0242] In some aspects, the V.sub.L sequence comprises, consists of, or consists essentially of a variant of an illustrative V.sub.L sequence provided in this disclosure. In some aspects, the V.sub.L sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative V.sub.L sequences provided in this disclosure.

[0243] In some embodiments, the V.sub.L sequence comprises, consists of, or consists essentially of any of the illustrative V.sub.L sequences provided in this disclosure having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

5.8. Antibodies Comprising All Six CDRs

[0244] In some embodiments, the antibody comprises a CDR-H1 sequence, a CDR-H2 sequence, a CDR-H3 sequence, a CDR-L1 sequence, and a CDR-L3 sequence. In some aspects, the CDR sequences are part of a V.sub.H (for CDR-H) or V.sub.L (for CDR-L).

[0245] In some aspects, the CDR-H1 sequence is a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 4-62; the CDR-H2 sequence is a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 122-180; the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 240-298; the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 299-301; the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 302-304; and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 305-307.

[0246] In some aspects, the CDR-H1 sequence is a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 19; the CDR-H2 sequence is a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 137; the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 255; the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 299-301; the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 302-304; and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 305-307.

[0247] In some aspects, the CDR-H1 sequence is a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 58; the CDR-H2 sequence is a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 176; the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 294; the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 299-301; the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 302-304; and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 305-307.

[0248] In some aspects, the CDR-H1 sequence is a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 63-121; the CDR-H2 sequence is a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 181-239; the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 240-298; the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 299-301; the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 302-304; and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 305-307.

[0249] In some aspects, the CDR-H1 sequence is a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 78; the CDR-H2 sequence is a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 196; the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 255; the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 299-301; the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 302-304; and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 305-307.

[0250] In some aspects, the CDR-H1 sequence is a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 117; the CDR-H2 sequence is a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 235; the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 294; the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 299-301; the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 302-304; and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 305-307.

5.8.1. Variants of Antibodies Comprising All Six CDRs

[0251] In some embodiments, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 provided herein comprise a variant of an illustrative CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and/or CDR-L3 sequence provided in this disclosure.

[0252] In some aspects, the CDR-H1 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia or Kabat CDR-H1 sequence provided in this disclosure. In some aspects, the CDR-H1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia or Kabat CDR-H1 sequences provided in this disclosure. In some aspects, the CDR-H1 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia or Kabat CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0253] In some aspects, the CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia or Kabat CDR-H2 sequence provided in this disclosure. In some aspects, the CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia or Kabat CDR-H2 sequences provided in this disclosure. In some aspects, the CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia or Kabat CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0254] In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0255] In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L1 sequence provided in this disclosure. In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L1 sequences provided in this disclosure. In some aspects, the CDR-L1 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0256] In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure. In some aspects, the CDR-L2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

[0257] In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.

7. Affinity

[0258] In some embodiments, the affinity of the antibody for folate receptor alpha as indicated by K.sub.D, is less than about 10.sup.5 M, less than about 10.sup.6 M, less than about 10.sup.7 M, less than about 10.sup.8 M, less than about 10.sup.9 M, less than about 10.sup.10 M, less than about 10.sup.11 M, or less than about 10.sup.12 M. In some embodiments, the affinity of the antibody is between about 10.sup.7 M and 10.sup.11 M. In some embodiments, the affinity of the antibody is between about 10.sup.7 M and 10.sup.10 M. In some embodiments, the affinity of the antibody is between about 10.sup.7 M and 10.sup.9 M. In some embodiments, the affinity of the antibody is between about 10.sup.7 M and 10.sup.8 M. In some embodiments, the affinity of the antibody is between about 10.sup.8 M and 10.sup.11 M. In some embodiments, the affinity of the antibody is between about 10.sup.8 M and 10.sup.10 M. In some embodiments, the affinity of the antibody is between about 10.sup.9 M and 10.sup.11 M. In some embodiments, the affinity of the antibody is between about 10.sup.9 M and 10.sup.10 M.

[0259] In some embodiments, the affinity of the antibody for human folate receptor alpha, as determined by surface plasmon resonance at 25 C., and as indicated by K.sub.D, is from about 0.3610.sup.9 M to about 2.2110.sup.9 M. In some embodiments, the affinity of the antibody for human folate receptor alpha, as determined by surface plasmon resonance at 25 C., and as indicated by K.sub.D, is from about 8.5510.sup.10 M to about 1.7010.sup.8 M. In some embodiments, the affinity of the antibody for human folate receptor alpha, as determined by surface plasmon resonance at 25 C., and as indicated by K.sub.D, is from about 5.7110.sup.10 M to about 2.5810.sup.8 M. In some embodiments, the affinity of the antibody for human folate receptor alpha is about any of the K.sub.D values reported for human folate receptor alpha in the examples below.

[0260] In some embodiments the antibody has a k.sub.a of at least about 10.sup.4 M.sup.1sec.sup.1. In some embodiments the antibody has a k.sub.a of at least about 10.sup.5 M.sup.1sec.sup.1. In some embodiments the antibody has a k.sub.a of at least about 10.sup.6 M.sup.1sec.sup.1. In some embodiments the antibody has a k.sub.a of at least about 10.sup.7 M.sup.1sec.sup.1. In some embodiments the antibody has a k.sub.a of at least about 10.sup.8 M.sup.1sec.sup.1. In some embodiments the antibody has a k.sub.a of at least about 10.sup.9 M.sup.1sec.sup.1. In some embodiments the antibody has a k.sub.a of between about 10.sup.4 M.sup.1sec.sup.1 and about 10.sup.10 M.sup.1sec-1. In some embodiments the antibody has a k.sub.a of between about 10.sup.5 M.sup.1sec.sup.1 and about 10.sup.10 M.sup.1sec.sup.1. In some embodiments the antibody has a k.sub.a of between about 10.sup.6 M.sup.1sec.sup.1 and about 10.sup.10 M.sup.1sec.sup.1. In some embodiments the antibody has a k.sub.a of between about 10.sup.7 M.sup.1sec.sup.1 and about 10.sup.10 M.sup.1sec.sup.1.

[0261] In some embodiments the antibody has a k.sub.a when associating with human folate receptor alpha, as determined by surface plasmon resonance at 25 C., of from about 4.4410.sup.5 M.sup.1sec.sup.1 to about 1.6110.sup.5 M.sup.1sec.sup.1. In some embodiments the antibody has a k.sub.a when associating with human folate receptor alpha, as determined by surface plasmon resonance at 25 C., of from about 2.9010.sup.5 M.sup.1sec.sup.1 to about 9.6410.sup.9 M.sup.1sec.sup.1. In some embodiments the antibody has a k.sub.a when associating with human folate receptor alpha of about any of the k.sub.a values reported for human folate receptor alpha in the examples below.

[0262] In some embodiments the antibody has a k.sub.a of about 10.sup.5 sec.sup.1 or less. In some embodiments the antibody has a k.sub.a of about 10.sup.4 sec.sup.1 or less. In some embodiments the antibody has a k.sub.a of about 10.sup.3 sec.sup.1 or less. In some embodiments the antibody has a k.sub.a of between about 10.sup.2 sec.sup.1 and about 10.sup.5 sec.sup.1. In some embodiments the antibody has a k.sub.a of between about 10.sup.2 sec.sup.1 and about 10.sup.4 sec.sup.1. In some embodiments the antibody has a k.sub.a of between about 10.sup.3 sec.sup.1 and about 10.sup.5 sec.sup.1.

[0263] In some embodiments the antibody has a k.sub.a when dissociating from human folate receptor alpha, as determined by surface plasmon resonance at 25 C., of from about 8.6610.sup.4 sec.sup.1 to about 1.0810.sup.2 sec.sup.1. In some embodiments the antibody has a k.sub.a when dissociating from human folate receptor alpha, as determined by surface plasmon resonance at 25 C., of from about 2.2810.sup.4 sec.sup.1 to about 4.8210.sup.1 sec.sup.1. In some embodiments the antibody has a k.sub.a when dissociating from human folate receptor alpha of about any of the k.sub.a values reported for human folate receptor alpha in the examples below.

[0264] In some embodiments, the affinity of the antibody for cynomolgus folate receptor alpha, as determined by surface plasmon resonance at 25 C., and as indicated by K.sub.D, is from about 0.1910.sup.9 M to about 2.8410.sup.9 M. In some embodiments, the affinity of the antibody for cynomolgus folate receptor alpha is about any of the K.sub.D values reported for cynomolgus folate receptor alpha in the examples below.

[0265] In some embodiments, the affinity of the antibody for mouse folate receptor alpha, as determined by surface plasmon resonance at 25 C., and as indicated by K.sub.D, is from about 0.510.sup.9 M to about 9.0710.sup.8 M. In some embodiments, the affinity of the antibody for mouse folate receptor alpha is about any of the K.sub.D values reported for mouse folate receptor alpha in the examples below.

[0266] In some aspects, the K.sub.D, k.sub.a, and k.sub.d are determined at 25 C. In some embodiments, the K.sub.D, k.sub.a, and k.sub.d are determined by surface plasmon resonance. In some embodiments, the K.sub.D, k.sub.a, and k.sub.a are determined according to the methods described in the Examples provided herein.

8. Epitope Bins

[0267] In some embodiments, the antibody binds the same epitope as an antibody encompassing any of SEQ ID NOs: 308-366. In some embodiments, the antibody binds the same epitope as an antibody comprising any of the V.sub.H-V.sub.L pairs, above. In some embodiments, the antibody competes for epitope binding with an antibody encompassing any of SEQ ID NOs: 308-366. In some embodiments, the antibody competes for epitope binding with an antibody comprising any of the V.sub.H-V.sub.L pairs, above.

9. Glycosylation Variants

[0268] In certain embodiments, an antibody may be altered to increase, decrease or eliminate the extent to which it is glycosylated. Glycosylation of polypeptides is typically either N-linked or O-linked.

[0269] N-linked glycosylation refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site.

[0270] O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.

[0271] Addition or deletion of N-linked glycosylation sites to the antibody may be accomplished by altering the amino acid sequence such that one or more of the above-described tripeptide sequences is created or removed. Addition or deletion of O-linked glycosylation sites may be accomplished by addition, deletion, or substitution of one or more serine or threonine residues in or to (as the case may be) the sequence of an antibody. 10. Fc Variants

[0272] In certain embodiments, amino acid modifications may be introduced into the Fc region of an antibody provided herein to generate an Fc region variant. In certain embodiments, the Fc region variant possesses some, but not all, effector functions. Such antibodies may be useful, for example, in applications in which the half-life of the antibody in vivo is important, yet certain effector functions are unnecessary or deleterious. Examples of effector functions include complement-dependent cytotoxicity (CDC) and antibody-directed complement-mediated cytotoxicity (ADCC). Numerous substitutions or substitutions or deletions with altered effector function are known in the art.

[0273] In some embodiments, the Fc comprises one or more modifications in at least one of the C.sub.H3 sequences. In some embodiments, the Fc comprises one or more modifications in at least one of the C.sub.H2 sequences. For example, the Fc can include one or modifications selected from the group consisting of. V262E, V262D, V262K, V262R, V262S, V264S, V303R, and V305R. In some embodiments, an Fc is a single polypeptide. In some embodiments, an Fc is multiple peptides, e.g., two polypeptides. Exemplary modifications in the Fc region are described, for example, in International Patent Application No. PCT/US2017/037545, filed Jun. 14, 2017.

[0274] An alteration in in CDC and/or ADCC activity can be confirmed using in vitro and/or in vivo assays. For example, Fc receptor (FcR) binding assays can be conducted to measure FcR binding. The primary cells for mediating ADCC, NK cells, express FcRIII only, whereas monocytes express FcRI, FcRII and FcRIII. FcR expression on hematopoietic cells is summarized in Ravetch and Kinet, Ann. Rev. Immunol., 1991, 9:457-492, incorporated by reference in its entirety.

[0275] Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are provided in U.S. Pat. Nos. 5,500,362 and 5,821,337; Hellstrom et al., Proc. Natl. Acad. Sci. U.S.A., 1986, 83:7059-7063; Hellstrom et al., Proc. Natl. Acad. Sci. U.S.A., 1985, 82:1499-1502; and Bruggemann et al., J Exp. Med., 1987, 166:1351-1361; each of which is incorporated by reference in its entirety. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, using an animal model such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. U.S.A., 1998, 95:652-656, incorporated by reference in its entirety.

[0276] C1q binding assays may also be carried out to confirm that the antibody is unable to bind C1q and hence lacks CDC activity. Examples of C1q binding assays include those described in WO 2006/029879 and WO 2005/100402, each of which is incorporated by reference in its entirety.

[0277] Complement activation assays include those described, for example, in Gazzano-Santoro et al., J. Immunol. Methods, 1996, 202:163-171; Cragg et al., Blood, 2003, 101:1045-1052; and Cragg and Glennie, Blood, 2004, 103:2738-2743; each of which is incorporated by reference in its entirety.

[0278] FcRn binding and in vivo clearance (half-life determination) can also be measured, for example, using the methods described in Petkova et al., Intl. Immunol., 2006, 18:1759-1769, incorporated by reference in its entirety.

12. Preparation of Antibody Conjugates

12.1. Antigen Preparation

[0279] The FOLR1 protein to be used for isolation of the antibodies may be intact FOLR1 or a fragment of FOLR1. The intact FOLR1 protein, or fragment of FOLR1, may be in the form of an isolated protein or protein expressed by a cell. Other forms of FOLR1 useful for generating antibodies will be apparent to those skilled in the art.

12.2. Monoclonal Antibodies

[0280] Monoclonal antibodies may be obtained, for example, using the hybridoma method first described by Kohler et al., Nature, 1975, 256:495-497 (incorporated by reference in its entirety), and/or by recombinant DNA methods (see e.g., U.S. Pat. No. 4,816,567, incorporated by reference in its entirety). Monoclonal antibodies may also be obtained, for example, using phage or yeast-based libraries. See e.g., U.S. Pat. Nos. 8,258,082 and 8,691,730, each of which is incorporated by reference in its entirety.

[0281] In the hybridoma method, a mouse or other appropriate host animal is immunized to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization. Alternatively, lymphocytes may be immunized in vitro. Lymphocytes are then fused with myeloma cells using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell. See Goding J. W., Monoclonal Antibodies: Principles and Practice 3.sup.rd ed. (1986) Academic Press, San Diego, CA, incorporated by reference in its entirety.

[0282] The hybridoma cells are seeded and grown in a suitable culture medium that contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells. For example, if the parental myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which substances prevent the growth of HGPRT-deficient cells.

[0283] Useful myeloma cells are those that fuse efficiently, support stable high-level production of antibody by the selected antibody-producing cells, and are sensitive media conditions, such as the presence or absence of HAT medium. Among these, preferred myeloma cell lines are murine myeloma lines, such as those derived from MOP-21 and MC-11 mouse tumors (available from the Salk Institute Cell Distribution Center, San Diego, CA), and SP-2 or X63-Ag8-653 cells (available from the American Type Culture Collection, Rockville, MD). Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies. See e.g., Kozbor, J Immunol., 1984, 133:3001, incorporated by reference in its entirety.

[0284] After the identification of hybridoma cells that produce antibodies of the desired specificity, affinity, and/or biological activity, selected clones may be subcloned by limiting dilution procedures and grown by standard methods. See Goding, supra. Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640 medium. In addition, the hybridoma cells may be grown in vivo as ascites tumors in an animal.

[0285] DNA encoding the monoclonal antibodies may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the monoclonal antibodies). Thus, the hybridoma cells can serve as a useful source of DNA encoding antibodies with the desired properties. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as bacteria (e.g., E. coli), yeast (e.g., Saccharomyces or Pichia sp.), COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce antibody, to produce the monoclonal antibodies.

12.3. Humanized Antibodies

[0286] Humanized antibodies may be generated by replacing most, or all, of the structural portions of a non-human monoclonal antibody with corresponding human antibody sequences. Consequently, a hybrid molecule is generated in which only the antigen-specific variable, or CDR, is composed of non-human sequence. Methods to obtain humanized antibodies include those described in, for example, Winter and Milstein, Nature, 1991, 349:293-299; Rader et al., Proc. Nat. Acad. Sci. U.S.A., 1998, 95:8910.sup.8915; Steinberger et al., J. Biol. Chem., 2000, 275:36073-36078; Queen et al., Proc. Natd. Acad. Sci. U.S.A., 1989, 86:10029-10033; and U.S. Pat. Nos. 5,585,089, 5,693,761, 5,693,762, and 6,180,370; each of which is incorporated by reference in its entirety.

12.4. Human Antibodies

[0287] Human antibodies can be generated by a variety of techniques known in the art, for example by using transgenic animals (e.g., humanized mice). See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. U.S.A., 1993, 90:2551; Jakobovits et al., Nature, 1993, 362:255-258; Bruggermann et al., Year in Immuno., 1993, 7:33; and U.S. Pat. Nos. 5,591,669, 5,589,369 and 5,545,807; each of which is incorporated by reference in its entirety. Human antibodies can also be derived from phage-display libraries (see e.g., Hoogenboom et al., J Mol. Biol., 1991, 227:381-388; Marks et al., J Mol. Biol., 1991, 222:581-597; and U.S. Pat. Nos. 5,565,332 and 5,573,905; each of which is incorporated by reference in its entirety). Human antibodies may also be generated by in vitro activated B cells (see e.g., U.S. Pat. Nos. 5,567,610 and 5,229,275, each of which is incorporated by reference in its entirety). Human antibodies may also be derived from yeast-based libraries (see e.g., U.S. Pat. No. 8,691,730, incorporated by reference in its entirety).

12.5. Conjugation

[0288] The antibody conjugates can be prepared by standard techniques. In certain embodiments, an antibody is contacted with a payload precursor under conditions suitable for forming a bond from the antibody to the payload to form an antibody-payload conjugate. In certain embodiments, an antibody is contacted with a linker precursor under conditions suitable for forming a bond from the antibody to the linker. The resulting antibody-linker is contacted with a payload precursor under conditions suitable for forming a bond from the antibody-linker to the payload to form an antibody-linker-payload conjugate. In certain embodiments, a payload precursor is contacted with a linker precursor under conditions suitable for forming a bond from the payload to the linker. The resulting payload-linker is contacted with an antibody under conditions suitable for forming a bond from the payload-linker to the antibody to form an antibody-linker-payload conjugate. Suitable linkers for preparing the antibody conjugates are disclosed herein, and exemplary conditions for conjugation are described in the Examples below.

[0289] In some embodiments, an anti-FOLR1 conjugate is prepared by contacting an anti-FOLR1 antibody as disclosed herein with a linker precursor having a structure of any of (A)-(L):

##STR00017## ##STR00018## ##STR00019##

[0290] In some embodiments, the stereochemistry of the linker precursors identified as (A)-(L) is identified with R and S notation for each chiral center, from left to right as depicted in formulas (A1)-(L1) and (A2)-(L2) illustrated below:

##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025##

13. Vectors, Host Cells, and Recombinant Methods

[0291] Embodiments are also directed to the provision of isolated nucleic acids encoding anti-FOLR1 antibodies, vectors and host cells comprising the nucleic acids, and recombinant techniques for the production of the antibodies.

[0292] For recombinant production of the antibody, the nucleic acid(s) encoding it may be isolated and inserted into a replicable vector for further cloning (i.e., amplification of the DNA) or expression. In some aspects, the nucleic acid may be produced by homologous recombination, for example as described in U.S. Pat. No. 5,204,244, incorporated by reference in its entirety.

[0293] Many different vectors are known in the art. The vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence, for example as described in U.S. Pat. No. 5,534,615, incorporated by reference in its entirety.

[0294] Illustrative examples of suitable host cells are provided below. These host cells are not meant to be limiting.

[0295] Suitable host cells include any prokaryotic (e.g., bacterial), lower eukaryotic (e.g., yeast), or higher eukaryotic (e.g., mammalian) cells. Suitable prokaryotes include eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as Escherichia (E. coli), Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella (S. typhimurium), Serratia (S. marcescans), Shigella, Bacilli (B. subtilis and B. licheniformis), Pseudomonas (P. aeruginosa), and Streptomyces. One useful E. coli cloning host is E. coli 294, although other strains such as E. coli B, E. coli X1776, and E. coli W3110 are suitable.

[0296] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are also suitable cloning or expression hosts for anti-FOLR1 antibody-encoding vectors. Saccharomyces cerevisiae, or common baker's yeast, is a commonly used lower eukaryotic host microorganism. However, a number of other genera, species, and strains are available and useful, such as Spodoptera frugiperda (e.g., SF9), Schizosaccharomyces pombe, Kluyveromyces (K lactis, K. fragilis, K. bulgaricus K. wickeramii, K. waltii, K. drosophilarum, K. thermotolerans, and K marxianus), Yarrowia, Pichia pastoris, Candida (C. albicans), Trichoderma reesia, Neurospora crassa, Schwanniomyces (S. occidentalis), and filamentous fungi such as, for example Penicillium, Tolypocladium, and Aspergillus (A. nidulans and A. niger).

[0297] Useful mammalian host cells include COS-7 cells, HEK293 cells; baby hamster kidney (BHK) cells; Chinese hamster ovary (CHO); mouse sertoli cells; African green monkey kidney cells (VERO-76), and the like.

[0298] The host cells used to produce the anti-FOLR1 antibody of this invention may be cultured in a variety of media. Commercially available media such as, for example, Ham's F10, Minimal Essential Medium (MEM), RPMI-1640, and Dulbecco's Modified Eagle's Medium (DMEM) are suitable for culturing the host cells. In addition, any of the media described in Ham et al., Meth. Enz., 1979, 58:44; Barnes et al., Anal. Biochem., 1980, 102:255; and U.S. Pat. Nos. 4,767,704, 4,657,866, 4,927,762, 4,560,655, and 5,122,469, or WO 90/03430 and WO 87/00195 may be used. Each of the foregoing references is incorporated by reference in its entirety.

[0299] Any of these media may be supplemented as necessary with hormones and/or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics, trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other necessary supplements may also be included at appropriate concentrations that would be known to those skilled in the art.

[0300] The culture conditions, such as temperature, pH, and the like, are those previously used with the host cell selected for expression, and will be apparent to the ordinarily skilled artisan.

[0301] When using recombinant techniques, the antibody can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the antibody is produced intracellularly, as a first step, the particulate debris, either host cells or lysed fragments, is removed, for example, by centrifugation or ultrafiltration. For example, Carter et al. (Bio Technology, 1992, 10:163-167) describes a procedure for isolating antibodies which are secreted to the periplasmic space of E. coli. Briefly, cell paste is thawed in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonylfluoride (PMSF) over about 30 min. Cell debris can be removed by centrifugation.

[0302] In some embodiments, the antibody is produced in a cell-free system. In some aspects, the cell-free system is an in vitro transcription and translation system as described in Yin et al., mAbs, 2012, 4:217-225, incorporated by reference in its entirety. In some aspects, the cell-free system utilizes a cell-free extract from a eukaryotic cell or from a prokaryotic cell. In some aspects, the prokaryotic cell is E. coli. Cell-free expression of the antibody may be useful, for example, where the antibody accumulates in a cell as an insoluble aggregate, or where yields from periplasmic expression are low. The antibodies produced in a cell-free system may be aglycosylated depending on the source of the cells.

[0303] Where the antibody is secreted into the medium, supernatants from such expression systems are generally first concentrated using a commercially available protein concentration filter, for example, an Amicon or Millipore Pellcon ultrafiltration unit. A protease inhibitor such as PMSF may be included in any of the foregoing steps to inhibit proteolysis and antibiotics may be included to prevent the growth of adventitious contaminants.

[0304] The antibody composition prepared from the cells can be purified using, for example, hydroxylapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being a particularly useful purification technique. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain that is present in the antibody. Protein A can be used to purify antibodies that are based on human 1, 2, or 4 heavy chains (Lindmark et al., J. Immunol. Meth., 1983, 62:1-13, incorporated by reference in its entirety). Protein G is useful for all mouse isotypes and for human 3 (Guss et al., EMBO J., 1986, 5:1567-1575, incorporated by reference in its entirety).

[0305] The matrix to which the affinity ligand is attached is most often agarose, but other matrices are available. Mechanically stable matrices such as controlled pore glass or poly(styrenedivinyl)benzene allow for faster flow rates and shorter processing times than can be achieved with agarose. Where the antibody comprises a C.sub.H3 domain, the BakerBond ABX resin is useful for purification.

[0306] Other techniques for protein purification, such as fractionation on an ion-exchange column, ethanol precipitation, Reverse Phase HPLC, chromatography on silica, chromatography on heparin Sepharose, chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation are also available, and can be applied by one of skill in the art.

[0307] Following any preliminary purification step(s), the mixture comprising the antibody of interest and contaminants may be subjected to low pH hydrophobic interaction chromatography using an elution buffer at a pH between about 2.5 to about 4.5, generally performed at low salt concentrations (e.g., from about 0 to about 0.25 M salt).

14. Pharmaceutical Compositions and Methods of Administration

[0308] The antibodies and antibody conjugates provided herein can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the antibody conjugates provided herein can be provided in the appropriate pharmaceutical composition and be administered by a suitable route of administration.

[0309] Typically, the VEGF inhibitor is formulated, dosed, and administered according to commercially available instructions.

[0310] The methods provided herein encompass administering pharmaceutical compositions comprising at least one antibody conjugate provided herein and one or more compatible and pharmaceutically acceptable carriers. In this context, the term pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term carrier includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Martin, E. W., Remington's Pharmaceutical Sciences.

[0311] In clinical practice the pharmaceutical compositions or antibody conjugates provided herein may be administered by any route known in the art. Exemplary routes of administration include, but are not limited to, the inhalation, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes. In some embodiments, a pharmaceutical composition or antibody conjugate provided herein is administered parenterally.

[0312] The compositions for parenteral administration can be emulsions or sterile solutions. Parenteral compositions may include, for example, propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters (e.g., ethyl oleate). These compositions can also contain wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, for example using a bacteriological filter, by radiation or by heating. Parenteral compositions can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium.

[0313] In some embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic antibody conjugates.

[0314] The pharmaceutical composition may comprise one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, and one of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific antibody in the dosage form. The composition or single unit dosage form, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), incorporated by reference in its entirety.

[0315] In some embodiments, the pharmaceutical composition comprises an anti-foaming agent. Any suitable anti-foaming agent may be used. In some aspects, the anti-foaming agent is selected from an alcohol, an ether, an oil, a wax, a silicone, a surfactant, and combinations thereof. In some aspects, the anti-foaming agent is selected from a mineral oil, a vegetable oil, ethylene bis stearamide, a paraffin wax, an ester wax, a fatty alcohol wax, a long chain fatty alcohol, a fatty acid soap, a fatty acid ester, a silicon glycol, a fluorosilicone, a polyethylene glycol-polypropylene glycol copolymer, polydimethylsiloxane-silicon dioxide, ether, octyl alcohol, capryl alcohol, sorbitan trioleate, ethyl alcohol, 2-ethyl-hexanol, dimethicone, oleyl alcohol, simethicone, and combinations thereof.

[0316] In some embodiments, the pharmaceutical composition comprises a co-solvent. Illustrative examples of co-solvents include ethanol, poly(ethylene) glycol, butylene glycol, dimethylacetamide, glycerin, and propylene glycol.

[0317] In some embodiments, the pharmaceutical composition comprises a buffer. Illustrative examples of buffers include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate.

[0318] In some embodiments, the pharmaceutical composition comprises a carrier or filler. Illustrative examples of carriers or fillers include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.

[0319] In some embodiments, the pharmaceutical composition comprises a surfactant. Illustrative examples of surfactants include d-alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15 hydroxystearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sodium lauryl sulfate, sorbitan esters, and vitamin E polyethylene(glycol) succinate.

[0320] In some embodiments, the pharmaceutical composition comprises an anti-caking agent. Illustrative examples of anti-caking agents include calcium phosphate (tribasic), hydroxymethyl cellulose, hydroxypropyl cellulose, and magnesium oxide.

[0321] Other excipients that may be used with the pharmaceutical compositions include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, controlled release agents, diluents, dispersing agents, dissolution enhancers, emulsifying agents, gelling agents, ointment bases, penetration enhancers, preservatives, solubilizing agents, solvents, stabilizing agents, and sugars. Specific examples of each of these agents are described, for example, in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), The Pharmaceutical Press, incorporated by reference in its entirety.

[0322] In some embodiments, the pharmaceutical composition comprises a solvent. In some aspects, the solvent is saline solution, such as a sterile isotonic saline solution or dextrose solution. In some aspects, the solvent is water for injection.

[0323] In some embodiments, the pharmaceutical compositions are in a particulate form, such as a microparticle or a nanoparticle. Microparticles and nanoparticles may be formed from any suitable material, such as a polymer or a lipid. In some aspects, the microparticles or nanoparticles are micelles, liposomes, or polymersomes.

[0324] Further provided herein are anhydrous pharmaceutical compositions and dosage forms comprising an antibody conjugate, since, in some embodiments, water can facilitate the degradation of some antibodies.

[0325] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.

[0326] An anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0327] Lactose-free compositions provided herein can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.

[0328] Also provided are pharmaceutical compositions and dosage forms that comprise one or more excipients that reduce the rate by which an antibody or antibody-conjugate will decompose. Such excipients, which are referred to herein as stabilizers, include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

14.1. Parenteral Dosage Forms

[0329] In certain embodiments, provided are parenteral dosage forms. Parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses subjects' natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

[0330] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0331] Excipients that increase the solubility of one or more of the antibodies disclosed herein can also be incorporated into the parenteral dosage forms.

14.2. Dosage and Unit Dosage Forms

[0332] Inhuman therapeutics, the doctor will determine the posology which he considers most appropriate according to a preventive or curative treatment and according to the age, weight, condition and other factors specific to the subject to be treated.

[0333] In certain embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic antibodies.

[0334] The amount of the antibody conjugate or composition which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the antibody is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0335] In certain embodiments, exemplary doses of a composition include milligram or microgram amounts of the antibody per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram). In certain embodiment, the dosage of the antibody conjugate provided herein, based on weight of the antibody, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg or more of a subject's body weight. In certain embodiments, the dosage of the antibody conjugate provided herein, based on weight of the antibody, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is about 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5 mg/kg or more of a subject's body weight. In certain embodiment, the dosage of the VEGF-A inhibitor, such as bevacizumab, provided herein, based on weight of the antibody, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is 10, 11, 12, 13, 14 or 15 mg/kg or more of a subject's body weight. In another embodiment, the dosage of the composition or a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.25 mg to 2.5 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 0.5 to 12 mg, 0.5 to 10 mg, 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

[0336] The dose can be administered according to a suitable schedule, for example, once, two times, three times, or for times weekly. It may be necessary to use dosages of the antibody conjugate outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.

[0337] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the antibodies provided herein are also encompassed by the herein described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.

[0338] In certain embodiments, treatment or prevention can be initiated with one or more loading doses of an antibody conjugate or composition provided herein followed by one or more maintenance doses.

[0339] In certain embodiments, a dose of an antibody conjugate or composition provided herein can be administered to achieve a steady-state concentration of the antibody in blood or serum of the subject. The steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the subject such as height, weight and age.

[0340] In certain embodiments, administration of the same composition may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In certain embodiments, administration of the same composition may be repeated and the administrations may be separated by at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 days.

[0341] In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 days.

15. Therapeutic Applications

[0342] For therapeutic applications, the combinations provided herein can be administered to a mammal, generally a human, in a pharmaceutically acceptable dosage form such as those known in the art and those discussed above. For example, the antibody conjugates may be administered to a human intravenously as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intra-cerebrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, or intratumoral routes. The antibody conjugates also are suitably administered by peritumoral, intralesional, or perilesional routes, to exert local as well as systemic therapeutic effects. The intravenous route may be particularly useful, for example, in the treatment of ovarian tumors.

[0343] The antibody conjugates provided herein may be useful for the treatment of any disease or condition involving folate receptor alpha (FOLR1). In some embodiments, the disease or condition is a disease or condition that can be diagnosed by overexpression of folate receptor alpha. In some embodiments, the disease or condition is a disease or condition that can benefit from treatment with an anti-folate receptor alpha antibody. In some embodiments, the disease or condition is a cancer.

[0344] Any suitable cancer may be treated with the antibody conjugates provided herein. Illustrative suitable cancers include, for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, bile duct cancer, bladder cancer, bone cancer, breast cancer (including triple-negative breast cancer, or TNBC), bronchial tumor, carcinoma of unknown primary origin, cardiac tumor, cervical cancer, chordoma, colon cancer, colorectal cancer, craniopharyngioma, ductal carcinoma, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, fallopian tube carcinoma, fibrous histiocytoma, Ewing sarcoma, eye cancer, germ cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, glioma, head and neck cancer, hepatocellular cancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lung cancer, macroglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, midline tract carcinoma involving NUT gene, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, nasal cavity and par nasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-small cell lung cancer (NSCLC), oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytomas, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, primary peritoneal carcinoma, prostate cancer, rectal cancer, renal cell cancer, renal pelvis and ureter cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, spinal cord tumor, stomach cancer, T-cell lymphoma, teratoid tumor, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer, and Wilms tumor.

[0345] In some embodiments, the disease to be treated with the antibody conjugates provided herein is gastric cancer, colorectal cancer, renal cell carcinoma, cervical cancer, non-small cell lung carcinoma, ovarian cancer, uterine cancer, fallopian tube carcinoma, primary peritoneal carcinoma, uterine corpus carcinoma, endometrial carcinoma, prostate cancer, breast cancer, head and neck cancer, brain carcinoma, liver cancer, pancreatic cancer, mesothelioma, and/or a cancer of epithelial origin. In particular embodiments, the disease is colorectal cancer. In some embodiments, the disease is ovarian cancer. In some embodiments, the disease is breast cancer.

[0346] In some embodiments, the disease is triple-negative breast cancer (TNBC). In some embodiments, the disease is lung cancer. In some embodiments, the disease is non-small cell lung cancer (NSCLC). In some embodiments, the disease is head and neck cancer. In some embodiments, the disease is renal cell carcinoma. In some embodiments, the disease is brain carcinoma. In some embodiments, the disease is endometrial cancer.

16. Kits

[0347] In some embodiments, the combination provided herein is provided in the form of a kit, i.e., a packaged combination of reagents in predetermined amounts with instructions for performing a procedure. In other embodiments, the procedure is a therapeutic procedure.

[0348] In some embodiments, the kit further comprises a solvent for the reconstitution of the anti-FOLR1 antibody conjugate. In some embodiments, the anti-FOLR1 antibody conjugate is provided in the form of a pharmaceutical composition.

[0349] In some embodiments, the kit further comprises a VEGF inhibitor, e.g., bevacizumab or a bevacizumab biosimilar and instructions for use.

[0350] In certain embodiments, the pharmaceutical package or kit comprises a container, a folate receptor alpha (FOLR1) antibody conjugate; a VEGF-A inhibitor; and a package insert comprising instructions to administer the FOLR1 antibody conjugate and the VEGF-A inhibitor according the methods described herein.

EXAMPLES

Example 1

Anti-FOLR1 Antibody Drug Conjugate in Combination with Vegf Trap

[0351] The present example provides results from a study of the combination of an anti-FOLR1 antibody conjugate described herein with bevacizumab in a mouse OV-90 tumor model.

[0352] Mice bearing OV-90 tumors were administered one of the following therapies on treatment day: 2.5 mg/kg Conjugate A, 5.0 mg/kg bevacizumab, or 2.5 mg/kg conjugate A plus 5.0 mg/kg bevacizumab. Some variability was observed with OV-90 tumor growth and response to treatment. The single agent Conjugate A showed little to no activity (FIG. 1, first panel). The single agent solubilized mouse VEGF receptor also showed little to no activity (FIG. 1, first panel, VEGF Trap). Co-administration of Conjugate A and bevacizumab suppressed OV-90 tumor growth (55% TGI). Body weigh change is provided in FIG. 1, second panel.

[0353] In further experiments, mice bearing OV-90 tumors were administered one of the following therapies on treatment day: 5.0 mg/kg Conjugate A, 5.0 mg/kg bevacizumab, or 5.0 mg/kg conjugate A plus 5.0 mg/kg bevacizumab. The combination of a single dose each of 5 mg/kg Conjugate A plus 5 mg/kg bevacizumab significantly improved the TGI to 96% versus Conjugate A (29% TGI, p<0.0001) or bevacizumab (68% TGI, p<0.0054) alone (FIG. 2A). Percent body weight change calculated relative to animal weight at the start of study shows all treatments were well tolerated (FIG. 2B).

Example 2

ANTI-FOLR1 and Bevacizumab in Patients with Advanced Epithelial Ovarian Cancer

[0354] In this study, the pharmacokinetics, safety and efficacy of Conjugate A in combination with bevacizumab (15 mg/kg) are evaluated when given by intravenous (IV) administration for the treatment of advanced epithelial ovarian cancer (including fallopian tube or primary peritoneal cancers).

[0355] Patients include individuals having relapsed platinum resistant ovarian cancer or other high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer.

[0356] Patients are excluded if they have any number of conditions including low grade ovarian carcinoma (grade 1); clear cell, mucinous, endometrioid, sarcomatous, and mixed histology ovarian carcinomas and sarcomatous ovarian carcinomas; prior treatment with Fo1Ra targeting ADCs or ADCs that contain a tubulin inhibitor; prior anticancer therapy (prior to first dose of study drug): including chemotherapy within 3 weeks, PARP inhibitor within 2 weeks, other therapeutic anticancer antibodies within 3 weeks, radio- or toxin-immunoconjugates (e.g. ADCs) within 10 weeks, or radiation therapy/major surgery within 4 weeks of first dose of study drug; preexisting clinically significant ocular disorders; previous solid organ transplantation; bowel obstruction and/or signs/symptoms of bowel obstruction within the preceding 3 months; history of gastrointestinal perforation; residual CTCAE Grade 2 toxicity from prior anticancer therapy; history of CHF; Nephrotic syndrome; sensory or motor neuropathy grade>1; potentially fatal concurrent or recent malignancy; chronic or ongoing active infectious disease requiring systemic treatment; ongoing immunosuppressive therapy, including systemic corticosteroids; clinically significant cardiac disease; significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease; history or clinical signs of meningeal or active central nervous system involvement; known severe chronic obstructive pulmonary disease or asthma (defined as FEV1<40% of expected) or active pneumonitis within 6 months of the first dose of study drug; history of significant cerebrovascular disease such as stroke or TIA within 6 months; known human immunodeficiency virus seropositivity; pregnancy or breastfeeding; positive serology for hepatitis B defined by a positive test for HBsAg; concurrent participation in another therapeutic treatment trial; evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan; history of hemoptysis within 6 months; venous or arterial thromboembolic event within 3 months.

[0357] The study is a modified 33 dose escalation trial where 3 patients are treated in each cohort. The initial dose of Conjugate A is between 3.5 mg/kg and 5.2 mg/kg while the bevacizumab dose is held constant. The dosing regimen will include bevacizumab administered at the dose of 15 mg/kg given together with Conjugate A starting at 3.5 mg/kg. Dosing is given every three weeks for a period of 7 months. Incremental dose increases of ADC Molecule 4 for assigned patient cohorts occur until the incidence of dose-limiting toxicities (DLTs) to determine the recommended phase 2 dose (RP2D) for the combination.

[0358] Patients are screened for Hepatitis B and C serology; Serum or Urine Pregnancy Test (within 7 days of initiating study treatment) and will be monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial.

[0359] Patients are screened weekly during cycles 1-4 and every 3 weeks starting at cycle 5 and EOT for Hematology (Hgb, hematocrit, PT/PTT/fibrinogen, WBC, ANC, platelet), serum chemistry (protein, albumin, creatinine, BUN, total bili, ALP, AST, glucose, sodium, potassium, chloride, calcium, LDH, uric acid, phosphorus. On day 1 of each cycle patients are screened for CPK.

[0360] Patients are monitored to evaluate adverse events, overall response rate (ORR), duration of response (DOR), overall survival (OS), and progression free survival (PFS) will be determined. Patients are monitored for potential drug-drug interactions.

Example 3

[0361] Table 5 provides sequences referred to herein.

TABLE-US-00005 TABLE5 Sequences SEQ ID NO: Molecule Region Scheme Sequence 1 Humanfolate MAQRMTTQLLLLLVWVAVVGEAQTRIAW receptoralpha ARTELLNVCMNAKHHKEKPGPEDKLHEQ (hFOLR1) CRPWRKNACCSTNTSQEAHKDVSYLYRF NWNHCGEMAPACKRHFIQDTCLYECSPN LGPWIQQVDQSWRKERVLNVPLCKEDCE QWWEDCRTSYTCKSNWHKGWNWTSGENK CAVGAACQPFHFYFPTPTVLCNEIWTHS YKVSNYSRGSGRCIQMWFDPAQGNPNEE VARFYAAAMSGAGPWAAWPFLLSLALML LWLLS 2 Cynomolgus MAQRMTTQLLLLLVWVAVVGEAQTRTAR folatereceptor ARTELLNVCMNAKHHKEKPGPEDKLHEQ alpha CRPWKKNACCSTNTSQEAHKDVSYLYRF NWNHCGEMAPACKRHFIQDTCLYECSPN LGPWIQQVDQSWRKERVLNVPLCKEDCE RWWEDCRTSYTCKSNWHKGWNWTSGENK CPVGAACQPFHFYFPTPTVLCNEIWTYS YKVSNYSRGSGRCIQMWFDPAQGNPNEE VARFYAAAMSGAGPWAAWPLLLSLALTL LWLLS 3 Murinefolate MAHLMTVQLLLLVMWMAECAQSRATRAR receptoralpha TELLNVCMDAKHHKEKPGPEDNLHDQCS PWKTNSCCSTNTSQEAHKDISYLYRENW NHCGTMTSECKRHFIQDTCLYECSPNLG PWIQQVDQSWRKERILDVPLCKEDCOQW WEDCQSSFTCKSNWHKGWNWSSGHNECP VGASCHPFTFYFPTSAALCEEIWSHSYK LSNYSRGSGRCIQMWFDPAQGNPNEEVA RFYAEAMSGAGFHGTWPLLCSLSLVLLW VIS 4 SRP1848-A01 CDR-H1 Chothia GFNITRY 5 SRP1848-A02 CDR-H1 Chothia GENISGF 6 SRP1848-A04 CDR-H1 Chothia GENIDQS 7 SRP1848-A06 CDR-H1 Chothia GENIGNS 8 SRP1848-A07 CDR-H1 Chothia GFNIGYH 9 SRP1848-A08 CDR-H1 Chothia GSNIRKH 10 SRP1848-A09 CDR-H1 Chothia GFNIRKQ 11 SRP1848-A10 CDR-H1 Chothia GFNIRKY 12 SRP1848-B01 CDR-H1 Chothia GFNIRNY 13 SRP1848-B03 CDR-H1 Chothia GFNISMK 14 SRP1848-B04 CDR-H1 Chothia SFNISNH 15 SRP1848-B05 CDR-H1 Chothia GFNISNY 16 SRP1848-B06 CDR-H1 Chothia GFNISNY 17 SRP1848-B07 CDR-H1 Chothia GFNISRF 18 SRP1848-B09 CDR-H1 Chothia GENITNY 19 SRP1848-B10 CDR-H1 Chothia GFNTTTK 20 SRP1848-B11 CDR-H1 Chothia GFNIGNN 21 SRP1848-C01 CDR-H1 Chothia GENIGNS 22 SRP1848-C03 CDR-H1 Chothia GFNIGVY 23 SRP1848-C04 CDR-H1 Chothia GFNIRHY 24 SRP1848-C05 CDR-H1 Chothia GFNIRKY 25 SRP1848-C07 CDR-H1 Chothia GFNIRKY 26 SRP1848-C10 CDR-H1 Chothia GENIRTY 27 SRP1848-D02 CDR-H1 Chothia GFNISHN 28 SRP1848-D03 CDR-H1 Chothia GFNIRYF 29 SRP1848-D04 CDR-H1 Chothia GFNISHY 30 SRP1848-D05 CDR-H1 Chothia GENISIS 31 SRP1848-D07 CDR-H1 Chothia GFNISKY 32 SRP1848-D09 CDR-H1 Chothia GENISNY 33 SRP1848-D10 CDR-H1 Chothia GFNISRN 34 SRP1848-E01 CDR-H1 Chothia GFNITNK 35 SRP1848-E02 CDR-H1 Chothia GFNIGKY 36 SRP1848-E03 CDR-H1 Chothia GENIGNY 37 SRP1848-E05 CDR-H1 Chothia GFNIGVY 38 SRP1848-E06 CDR-H1 Chothia GENINRY 39 SRP1848-E07 CDR-H1 Chothia GFNIRKS 40 SRP1848-F01 CDR-H1 Chothia GENIRTY 41 SRP1848-F02 CDR-H1 Chothia GENIRTY 42 SRP1848-F04 CDR-H1 Chothia GFNISNY 43 SRP1848-F05 CDR-H1 Chothia GENISKS 44 SRP1848-F06 CDR-H1 Chothia GENISLS 45 SRP1848-F07 CDR-H1 Chothia GFNISNH 46 SRP1848-F08 CDR-H1 Chothia GFNISNH 47 SRP1848-F09 CDR-H1 Chothia GFNISNH 48 SRP1848-F10 CDR-H1 Chothia GFNISNN 49 SRP1848-F11 CDR-H1 Chothia GFNISNN 50 SRP1848-G01 CDR-H1 Chothia GFNISRH 51 SRP1848-G03 CDR-H1 Chothia GFNISTY 52 SRP1848-G04 CDR-H1 Chothia GFNIHST 53 SRP1848-G06 CDR-H1 Chothia GFNIRST 54 SRP1848-G07 CDR-H1 Chothia GFNIHST 55 SRP1848-G09 CDR-H1 Chothia GFNIRGT 56 SRP1848-G10 CDR-H1 Chothia GFNIRST 57 SRP1848-G11 CDR-H1 Chothia GFNISST 58 SRP1848-H01 CDR-H1 Chothia GFNIRTQ 59 SRP2060-E10 CDR-H1 Chothia GFSLSTFGM 60 SRP2060-E05 CDR-H1 Chothia GFSLSTFGM 61 SRP2060-B01 CDR-H1 Chothia GFSLSTFGM 62 SRP2060-A06 CDR-H1 Chothia GFSLSTFGM 63 SRP1848-A01 CDR-H1 Kabat RYSIH 64 SRP1848-A02 CDR-H1 Kabat GFRIH 65 SRP1848-A04 CDR-H1 Kabat QSSIH 66 SRP1848-A06 CDR-H1 Kabat NSYIH 67 SRP1848-A07 CDR-H1 Kabat YHSIH 68 SRP1848-A08 CDR-H1 Kabat KHSIH 69 SRP1848-A09 CDR-H1 Kabat KQSIH 70 SRP1848-A10 CDR-H1 Kabat KYSIH 71 SRP1848-B01 CDR-H1 Kabat NYSIH 72 SRP1848-B03 CDR-H1 Kabat MKYIH 73 SRP1848-B04 CDR-H1 Kabat NHSIH 74 SRP1848-B05 CDR-H1 Kabat NYYIH 75 SRP1848-B06 CDR-H1 Kabat NYYIH 76 SRP1848-B07 CDR-H1 Kabat RFYIH 77 SRP1848-B09 CDR-H1 Kabat NYYIH 78 SRP1848-B10 CDR-H1 Kabat TKSIH 79 SRP1848-B11 CDR-H1 Kabat NNSIH 80 SRP1848-C01 CDR-H1 Kabat NSYIH 81 SRP1848-C03 CDR-H1 Kabat VYSIH 82 SRP1848-C04 CDR-H1 Kabat HYSIH 83 SRP1848-C05 CDR-H1 Kabat KYSIH 84 SRP1848-C07 CDR-H1 Kabat KYSIH 85 SRP1848-C10 CDR-H1 Kabat TYYIH 86 SRP1848-D02 CDR-H1 Kabat HNYIH 87 SRP1848-D03 CDR-H1 Kabat YFSIH 88 SRP1848-D04 CDR-H1 Kabat HYSIH 89 SRP1848-D05 CDR-H1 Kabat ISYIH 90 SRP1848-D07 CDR-H1 Kabat KYYIH 91 SRP1848-D09 CDR-H1 Kabat NYYIH 92 SRP1848-D10 CDR-H1 Kabat RNSIH 93 SRP1848-E01 CDR-H1 Kabat NKYIH 94 SRP1848-E02 CDR-H1 Kabat KYSIH 95 SRP1848-E03 CDR-H1 Kabat NYYIH 96 SRP1848-E05 CDR-H1 Kabat VYYIH 97 SRP1848-E06 CDR-H1 Kabat RYYIH 98 SRP1848-E07 CDR-H1 Kabat KSSIH 99 SRP1848-F01 CDR-H1 Kabat TYSIH 100 SRP1848-F02 CDR-H1 Kabat TYSIH 101 SRP1848-F04 CDR-H1 Kabat NYSIH 102 SRP1848-F05 CDR-H1 Kabat KSSIH 103 SRP1848-F06 CDR-H1 Kabat LSYIH 104 SRP1848-F07 CDR-H1 Kabat NHSIH 105 SRP1848-F08 CDR-H1 Kabat NHSIH 106 SRP1848-F09 CDR-H1 Kabat NHYIH 107 SRP1848-F10 CDR-H1 Kabat NNSIH 108 SRP1848-F11 CDR-H1 Kabat NNYIH 109 SRP1848-G01 CDR-H1 Kabat RHSIH 110 SRP1848-G03 CDR-H1 Kabat TYYIH 111 SRP1848-G04 CDR-H1 Kabat STDIH 112 SRP1848-G06 CDR-H1 Kabat STDIH 113 SRP1848-G07 CDR-H1 Kabat STDIH 114 SRP1848-G09 CDR-H1 Kabat GTDIH 115 SRP1848-G10 CDR-H1 Kabat STDIH 116 SRP1848-G11 CDR-H1 Kabat STDIH 117 SRP1848-H01 CDR-H1 Kabat TQSIH 118 SRP2060-E10 CDR-H1 Kabat TFGMGVG 119 SRP2060-E05 CDR-H1 Kabat TFGMGVG 120 SRP2060-B01 CDR-H1 Kabat TFGMGVG 121 SRP2060-A06 CDR-H1 Kabat TFGMGVG 122 SRP1848-A01 CDR-H2 Chothia LPESGG 123 SRP1848-A02 CDR-H2 Chothia YPESGA 124 SRP1848-A04 CDR-H2 Chothia YPVDGT 125 SRP1848-A06 CDR-H2 Chothia TPIDGN 126 SRP1848-A07 CDR-H2 Chothia FPVDGT 127 SRP1848-A08 CDR-H2 Chothia YPNDGT 128 SRP1848-A09 CDR-H2 Chothia FPNDGT 129 SRP1848-A10 CDR-H2 Chothia FPIDDI 130 SRP1848-B01 CDR-H2 Chothia YPVDGI 131 SRP1848-B03 CDR-H2 Chothia TPIDGM 132 SRP1848-B04 CDR-H2 Chothia YPVDGI 133 SRP1848-B05 CDR-H2 Chothia SPIDGY 134 SRP1848-B06 CDR-H2 Chothia TPIDGY 135 SRP1848-B07 CDR-H2 Chothia SPYDGF 136 SRP1848-B09 CDR-H2 Chothia TPVDGY 137 SRP1848-B10 CDR-H2 Chothia YPRDGI 138 SRP1848-B11 CDR-H2 Chothia SPIDGF 139 SRP1848-C01 CDR-H2 Chothia TPNDGY 140 SRP1848-C03 CDR-H2 Chothia YPIDGN 141 SRP1848-C04 CDR-H2 Chothia YPGPGN 142 SRP1848-C05 CDR-H2 Chothia FPIDGI 143 SRP1848-C07 CDR-H2 Chothia FPIDGI 144 SRP1848-C10 CDR-H2 Chothia SPIDGY 145 SRP1848-D02 CDR-H2 Chothia TPQDGY 146 SRP1848-D03 CDR-H2 Chothia FPNDGS 147 SRP1848-D04 CDR-H2 Chothia YPRDGI 148 SRP1848-D05 CDR-H2 Chothia SPIDGY 149 SRP1848-D07 CDR-H2 Chothia SPNDGY 150 SRP1848-D09 CDR-H2 Chothia SPNDGY 151 SRP1848-D10 CDR-H2 Chothia SPNDGT 152 SRP1848-E01 CDR-H2 Chothia TPFDGF 153 SRP1848-E02 CDR-H2 Chothia YPNDGN 154 SRP1848-E03 CDR-H2 Chothia TPRDGF 155 SRP1848-E05 CDR-H2 Chothia TPNDGY 156 SRP1848-E06 CDR-H2 Chothia TPNDGY 157 SRP1848-E07 CDR-H2 Chothia FPYDGS 158 SRP1848-F01 CDR-H2 Chothia FPNDGT 159 SRP1848-F02 CDR-H2 Chothia FPNDGT 160 SRP1848-F04 CDR-H2 Chothia YPIDGI 161 SRP1848-F05 CDR-H2 Chothia YPNDGS 162 SRP1848-F06 CDR-H2 Chothia SPIDGN 163 SRP1848-F07 CDR-H2 Chothia YPNDGI 164 SRP1848-F08 CDR-H2 Chothia YPVDGI 165 SRP1848-F09 CDR-H2 Chothia SPLDGY 166 SRP1848-F10 CDR-H2 Chothia FPNDGY 167 SRP1848-F11 CDR-H2 Chothia TPIDGN 168 SRP1848-G01 CDR-H2 Chothia APNDGS 169 SRP1848-G03 CDR-H2 Chothia TPSDGF 170 SRP1848-G04 CDR-H2 Chothia TPAGGA 171 SRP1848-G06 CDR-H2 Chothia TPAGGA 172 SRP1848-G07 CDR-H2 Chothia TPAGGA 173 SRP1848-G09 CDR-H2 Chothia TPAGGA 174 SRP1848-G10 CDR-H2 Chothia TPAGGA 175 SRP1848-G11 CDR-H2 Chothia TPAGGA 176 SRP1848-H01 CDR-H2 Chothia FPIDGI 177 SRP2060-E10 CDR-H2 Chothia WWDDD 178 SRP2060-E05 CDR-H2 Chothia WWDDD 179 SRP2060-B01 CDR-H2 Chothia WWDDD 180 SRP2060-A06 CDR-H2 Chothia WWDDD 181 SRP1848-A01 CDR-H2 Kabat GILPESGGTSYADSVKG 182 SRP1848-A02 CDR-H2 Kabat GIYPESGATYYADSVKG 183 SRP1848-A04 CDR-H2 Kabat VIYPVDGTTDYADSVKG 184 SRP1848-A06 CDR-H2 Kabat GITPIDGNTDYADSVKG 185 SRP1848-A07 CDR-H2 Kabat EIFPVDGTTDYADSVKG 186 SRP1848-A08 CDR-H2 Kabat SIYPNDGTTDYADSVKG 187 SRP1848-A09 CDR-H2 Kabat SIFPNDGTTDYADSVKG 188 SRP1848-A10 CDR-H2 Kabat DIFPIDDITDYADSVKG 189 SRP1848-B01 CDR-H2 Kabat EIYPVDGITDYADSVKG 190 SRP1848-B03 CDR-H2 Kabat GITPIDGMTDYADSVKG 191 SRP1848-B04 CDR-H2 Kabat EIYPVDGITDYADSVKG 192 SRP1848-B05 CDR-H2 Kabat GISPIDGYTDYADSMKG 193 SRP1848-B06 CDR-H2 Kabat GITPIDGYTDYADSVKG 194 SRP1848-B07 CDR-H2 Kabat GISPYDGFTDYADSVKG 195 SRP1848-B09 CDR-H2 Kabat GITPVDGYTDYADRVKG 196 SRP1848-B10 CDR-H2 Kabat EIYPRDGITDYADSVKG 197 SRP1848-B11 CDR-H2 Kabat DISPIDGFTDYADSVKG 198 SRP1848-C01 CDR-H2 Kabat GVTPNDGYTDYADSVKG 199 SRP1848-C03 CDR-H2 Kabat EIYPIDGNTDYADSVKG 200 SRP1848-C04 CDR-H2 Kabat EIYPGPGNTDYADSVKG 201 SRP1848-C05 CDR-H2 Kabat DIFPIDGINDYADSVKG 202 SRP1848-C07 CDR-H2 Kabat DIFPIDGITDYADSVKG 203 SRP1848-C10 CDR-H2 Kabat GISPIDGYTDYADSMKG 204 SRP1848-D02 CDR-H2 Kabat GITPQDGYTDYADSVKG 205 SRP1848-D03 CDR-H2 Kabat DIFPNDGSTDYADSVKG 206 SRP1848-D04 CDR-H2 Kabat EIYPRDGITDYADSVKG 207 SRP1848-D05 CDR-H2 Kabat GISPIDGYTDYADSVKG 208 SRP1848-D07 CDR-H2 Kabat GISPNDGYTDYADSVKG 209 SRP1848-D09 CDR-H2 Kabat GISPNDGYTDYADSVKG 210 SRP1848-D10 CDR-H2 Kabat WISPNDGTTDYADSVKG 211 SRP1848-E01 CDR-H2 Kabat GITPFDGFTDYADSVKG 212 SRP1848-E02 CDR-H2 Kabat EIYPNDGNTDYADSVKG 213 SRP1848-E03 CDR-H2 Kabat GITPRDGFTDYADSVKG 214 SRP1848-E05 CDR-H2 Kabat GITPNDGYTDYADSVKG 215 SRP1848-E06 CDR-H2 Kabat GITPNDGYTDYADSVEG 216 SRP1848-E07 CDR-H2 Kabat EIFPYDGSTDYADNVKG 217 SRP1848-F01 CDR-H2 Kabat SIFPNDGTTDYADSVKG 218 SRP1848-F02 CDR-H2 Kabat SIFPNDGTTDYADSVKG 219 SRP1848-F04 CDR-H2 Kabat EIYPIDGITDYADSVKG 220 SRP1848-F05 CDR-H2 Kabat EIYPNDGSTDYADSVKG 221 SRP1848-F06 CDR-H2 Kabat GISPIDGNTDYADSVKG 222 SRP1848-F07 CDR-H2 Kabat EIYPNDGITDYADSVKG 223 SRP1848-F08 CDR-H2 Kabat EIYPVDGITDYADSVKG 224 SRP1848-F09 CDR-H2 Kabat GISPLDGYTDYADSVKG 225 SRP1848-F10 CDR-H2 Kabat SIFPNDGYTDYADSVKG 226 SRP1848-F11 CDR-H2 Kabat GITPIDGNTDYADSVKG 227 SRP1848-G01 CDR-H2 Kabat WIAPNDGSTDYADSVKG 228 SRP1848-G03 CDR-H2 Kabat GITPSDGFTDYADSVKG 229 SRP1848-G04 CDR-H2 Kabat YITPAGGATFYADSVKG 230 SRP1848-G06 CDR-H2 Kabat YITPAGGATYYADNVKG 231 SRP1848-G07 CDR-H2 Kabat YITPAGGATWYADSVKG 232 SRP1848-G09 CDR-H2 Kabat YITPAGGATFYADSVKG 233 SRP1848-G10 CDR-H2 Kabat YITPAGGATYYADSVKG 234 SRP1848-G11 CDR-H2 Kabat YITPAGGATWYADSVKG 235 SRP1848-H01 CDR-H2 Kabat DIFPIDGITDYADSVKG 236 SRP2060-E10 CDR-H2 Kabat HIWWDDDKYYHPALKG 237 SRP2060-E05 CDR-H2 Kabat HIWWDDDKYYHPALKG 238 SRP2060-B01 CDR-H2 Kabat HIWWDDDKYYHPALKG 239 SRP2060-A06 CDR-H2 Kabat HIWWDDDKYYYPALKG 240 SRP1848-A01 CDR-H3 HIYPWDWFSNYVLDY 241 SRP1848-A02 CDR-H3 HLYVWDWVLDHVLDY 242 SRP1848-A04 CDR-H3 GAWSWRSGYGYYIDY 243 SRP1848-A06 CDR-H3 GAWSWRSGYGYYIDY 244 SRP1848-A07 CDR-H3 GFWAWRSGYGYYLDY 245 SRP1848-A08 CDR-H3 GSWFWRAGYGYYLDY 246 SRP1848-A09 CDR-H3 GSWFWRSGYGYFLEY 247 SRP1848-A10 CDR-H3 GSWSWPSGHSYYLDY 248 SRP1848-B01 CDR-H3 GFWSWPSGYSYFLDY 249 SRP1848-B03 CDR-H3 GSWSWPSGYSYYLDY 250 SRP1848-B04 CDR-H3 GRYSWRAGYSYYLDY 251 SRP1848-B05 CDR-H3 GSWFWQSGYGYYLDY 252 SRP1848-B06 CDR-H3 GFWSWPSGYGYYQDY 253 SRP1848-B07 CDR-H3 GSWSWPAGYGYYQDY 254 SRP1848-B09 CDR-H3 GAWSWRSGYGYYMDY 255 SRP1848-B10 CDR-H3 GGWHWRSGYSYYLDY 256 SRP1848-B11 CDR-H3 GSWSWRAGYGYYLDY 257 SRP1848-C01 CDR-H3 GSWFWRAGYGYYLDY 258 SRP1848-C03 CDR-H3 GSWAWRSGYSYYLDY 259 SRP1848-C04 CDR-H3 GSLSWRAGYGYYLDY 260 SRP1848-C05 CDR-H3 GSWSWKAGYGYYLDY 261 SRP1848-C07 CDR-H3 GSWSWPAGYGYYQDY 262 SRP1848-C10 CDR-H3 GSWSWPAGYGYYLDY 263 SRP1848-D02 CDR-H3 GAWSWRAGYGYYLDY 264 SRP1848-D03 CDR-H3 GHWSWPSGYWYYLDY 265 SRP1848-D04 CDR-H3 GYWFWRSGYGYYLDY 266 SRP1848-D05 CDR-H3 GSWSWRAGYGYYLDY 267 SRP1848-D07 CDR-H3 GFWAWRSGYGYYLDY 268 SRP1848-D09 CDR-H3 GSWSWRHGYGYYLDY 269 SRP1848-D10 CDR-H3 GAWSWRSGYGYYIDY 270 SRP1848-E01 CDR-H3 GSWSWPAGYGYYQDY 271 SRP1848-E02 CDR-H3 GSWSWRSGYGYYLDY 272 SRP1848-E03 CDR-H3 GSWSWPAGHSYYLDY 273 SRP1848-E05 CDR-H3 GFWAWRSGYGYYLDY 274 SRP1848-E06 CDR-H3 GTWSWPSGHSYYLDY 275 SRP1848-E07 CDR-H3 GAWSWRSGYGYYIDY 276 SRP1848-F01 CDR-H3 GSWAWRAGYSYYLDY 277 SRP1848-F02 CDR-H3 GSWSWQAGYGYYLDY 278 SRP1848-F04 CDR-H3 GSWFWRSGYGYYLDY 279 SRP1848-F05 CDR-H3 GSWAWRSGYSYFLDY 280 SRP1848-F06 CDR-H3 GFWAWRSGYGYYLDY 281 SRP1848-F07 CDR-H3 GSWDWRSGYSYYLDY 282 SRP1848-F08 CDR-H3 GSWYWQSGYSYYLDY 283 SRP1848-F09 CDR-H3 GAWSWRSGYGYYIDY 284 SRP1848-F10 CDR-H3 GSWFWRSGYGYYLDY 285 SRP1848-F11 CDR-H3 GSWYWRAGYGYYLDY 286 SRP1848-G01 CDR-H3 GSWAWRSGYSYFLDY 287 SRP1848-G03 CDR-H3 GSWSWPSGHGYFLDY 288 SRP1848-G04 CDR-H3 YPYWFAGYMDY 289 SRP1848-G06 CDR-H3 QPYWFAGYMDY 290 SRP1848-G07 CDR-H3 YPFWFAGYMDY 291 SRP1848-G09 CDR-H3 HEYWFSGYMDY 292 SRP1848-G10 CDR-H3 YPYWFAGYIDY 293 SRP1848-G11 CDR-H3 YPYWFSGYMDY 294 SRP1848-H01 CDR-H3 GSWSWPSGMDYYLDY 295 SRP2060-E10 CDR-H3 NHFPHYYGSSHWYFNV 296 SRP2060-E05 CDR-H3 NHFPHYYGSSHWYFNV 297 SRP2060-B01 CDR-H3 NHFPHYYGSSHWYFNV 298 SRP2060-A06 CDR-H3 NHFPHYYGSSHWYFDV 299 trastuzumab CDR-L1 RASQDVNTAVA 300 H6D1-LC4 CDR-L1 KASQDINSYLS 301 H6D1-LC5 CDR-L1 KASQDINSYLS 302 trastuzumab CDR-L2 SASFLYS 303 H6D1-LC4 CDR-L3 RANRLVD 304 H6D1-LC5 CDR-L2 RANRLVD 305 trastuzumab CDR-L3 QQHYTTPPT 306 H6D1-LC4 CDR-L3 LQYDEFPYT 307 H6D1-LC5 CDR-L3 LQYDEFPYT 308 SRP1848-A01 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ITRYSIHWVRQAPGKGLEWVAGILPESG GTSYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARHIYPWDWFSNYVLD YWGQGTLVTVSS 309 SRP1848-A02 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISGFRIHWVRQAPGKGLEWVAGIYPESG ATYYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARHLYVWDWVLDHVLD YWGQGTLVTVSS 310 SRP1848-A04 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IDQSSIHWVRQAPGKGLEWVGVIYPVDG TTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGAWSWRSGYGYYID YWGQGTLVTVSS 311 SRP1848-A06 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IGNSYIHWVRQAPGKGLEWVGGITPIDG NTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGAWSWRSGYGYYID YWGQGTLVTVSS 312 SRP1848-A07 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IGYHSIHWVRQAPGKGLEWVGEIFPVDG TTDYADSVKGRFTISADTSKNTAYLHMN SLRAEDTAVYYCARGFWAWRSGYGYYLD YWGQGTLVTVSS 313 SRP1848-A08 VH EVQLVESGGGLVQPGGSLRLSCAASGSN IRKHSIHWVRQAPGKGLEWVGSIYPNDG TTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWFWRAGYGYYLD YWGQGTLVTVSS 314 SRP1848-A09 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IRKQSIHWVRQAPGKGLEWVGSIFPNDG TTDYADSVKGRFTISADTSKNTAYLQVN SLRAEDTAVYYCARGSWFWRSGYGYFLE YWGQGTLVTVSS 315 SRP1848-A10 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IRKYSIHWARQAPGKGLEWVGDIFPIDD ITDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWPSGHSYYLD YWGQGTLVTVSS 316 SRP1848-B01 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IRNYSIHWVRQAPGKGLEWVGEIYPVDG ITDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGFWSWPSGYSYFLD YWGQGTLVTVSS 317 SRP1848-B03 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISMKYIHWVRQAPGKGLEWVGGITPIDG MTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWPSGYSYYLD YWGQGTLVTVSS 318 SRP1848-B04 VH EVQLVESGGGLVQPGGSLRLSCAASSEN ISNHSIHWVRQAPGKGLEWVGEIYPVDG ITDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGRYSWRAGYSYYLD YWGQGTLVTVSS 319 SRP1848-B05 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISNYYIHWVRQAPGKGLEWVGGISPIDG YTDYADSMKGRFTISADTSKNTAYLQMS SLRAEDTAVYYCARGSWFWQSGYGYYLD YWGQGTLVTVSS 320 SRP1848-B06 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISNYYIHWVRQAPGKGLEWVGGITPIDG YTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGFWSWPSGYGYYQD YWGQGTLVTVSS 321 SRP1848-B07 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISRFYIHWVRQAPGKGLEWVGGISPYDG FTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWPAGYGYYQD YWGQGTLVTVSS 322 SRP1848-B09 VH EVQLVESGGGLVQPGGSLRLSCAAGGEN ITNYYIHWVRQAPGKGLEWVGGITPVDG YTDYADRVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGAWSWRSGYGYYMD YWGQGTLVTVSS 323 SRP1848-B10 VH EVQLVESGGGLVQPGGSLRLSCAASGEN TTTKSIHWVRQAPGKGLEWVGEIYPRDG ITDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGGWHWRSGYSYYLD YWGQGTLVTVSS 324 SRP1848-B11 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IGNNSIHWVRQAPGKGLEWVGDISPIDG FTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWRAGYGYYLD YWGQGTLVTVSS 325 SRP1848-C01 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IGNSYIHWVRQAPGKGLEWVGGVTPNDG YTDYADSVKGRFTISADTSKNTTYLQMN SLRAEDTAVYYCARGSWFWRAGYGYYLD YWGQGALVTVSS 326 SRP1848-C03 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IGVYSIHWVRQAPGKGLEWVGEIYPIDG NTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWAWRSGYSYYLD YWGQGTLVTVSS 327 SRP1848-C04 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IRHYSIHWVRQAPGKGLEWVGEIYPGPG NTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSLSWRAGYGYYLD YWGQGTLVTVSS 328 SRP1848-C05 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IRKYSIHWVRQAPGKGLEWVGDIFPIDG INDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWKAGYGYYLD YWGQGTLVTVSS 329 SRP1848-C07 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IRKYSIHWVRQAPGKGLEWVGDIFPIDG ITDYADSMKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWPAGYGYYQD YWGQGTLVTVSS 330 SRP1848-C10 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IRTYYIHWVRQAPGKGLEWVGGISPIDG YTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWPAGYGYYLD YWGQGTLVTVSS 331 SRP1848-D02 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISHNYIHWVRQAPGKGLEWVGGITPQDG YTDYADSVKGRFTISADTSKNTAYLQMN RLRAEDTAVYYCARGAWSWRAGYGYYLD YWGQGTLVTVSS 332 SRP1848-D03 VH EVQLVESGGGVVQPGGSLRLSCAASGEN IRYFSIHWVRQAPGKGLEWVGDIFPNDG STDYADSVKGRFTISADTSKNTAYLQMN SLRAEETAVYYCARGHWSWPSGYWYYLD YWGQGTLVTVSS 333 SRP1848-D04 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISHYSIHWVRQAPGKGLEWVGEIYPRDG ITDYADSVKGRFTISADTSKNTAYLQMN SLSAEDTAVYYCARGYWFWRSGYGYYLD YWGQGTLVTVSS 334 SRP1848-D05 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISISYIHWVRQAPGKGLEWVGGISPIDG YTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWRAGYGYYLD YWGQGTLVTVSS 335 SRP1848-D07 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISKYYIHWVRQAPGKGLEWVGGISPNDG YTDYADSVKGRFAISADTSKNTAYLQMN SLRAEDTAVYYCARGFWAWRSGYGYYLD YWGQGTLVTVSS 336 SRP1848-D09 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISNYYIHWVRQAPGKGLEWVGGISPNDG YTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWRHGYGYYLD YWGQGTLVTVSS 337 SRP1848-D10 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISRNSIHWVRQAPGKGLEWVGWISPNDG TTDYADSVKGRFTISADGSKNTAYLQMN SLRAEDTAVYYCARGAWSWRSGYGYYID YWGQGTLVTVSS 338 SRP1848-E01 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ITNKYIHWVRQAPGKGLEWVGGITPFDG FTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWPAGYGYYQD YWGQGTLVTVSS 339 SRP1848-E02 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IGKYSIHWVRQAPGKGLEWVGEIYPNDG NTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWRSGYGYYLD YWGQGTLVTVSS 340 SRP1848-E03 VH EVQLVESGGGLAQPGGSLRLSCAASGEN IGNYYIHWVRQAPGKGLEWVGGITPRDG FTDYADSVKGRFTISADTSKNTAYLQVN SLRAEDTAVYYCARGSWSWPAGHSYYLD YWGQGTLVTVSS 341 SRP1848-E05 VH EVQLVESGGGLVQPGGSLRVSCAASGEN IGVYYIHWVRQAPGKGLEWVGGITPNDG YTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGFWAWRSGYGYYLD YWGQGTLVTVSS 342 SRP1848-E06 VH EVQLVESGGGLVQPSGSLRLSCAASGEN INRYYIHWVRQAPGKGLEWVGGITPNDG YTDYADSVEGRFTTSADTSKNTAYLQMN SLRAEDTAVYYCARGTWSWPSGHSYYLD YWGQGTLVTVSS 343 SRP1848-E07 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IRKSSIHWVRQAPGKGLEWVGEIFPYDG STDYADNVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGAWSWRSGYGYYID YWGQGTLVTVSS 344 SRP1848-F01 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IRTYSIHWVRQAPGKGLEWVGSIFPNDG TTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWAWRAGYSYYLD YWGQGTLVTVSS 345 SRP1848-F02 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IRTYSIHWVRQAPGKGLEWVGSIFPNDG TTDYADSVKGRLTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWQAGYGYYLD YWGQGTLVTVSS 346 SRP1848-F04 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISNYSIHWVRQAPGKGLEWVGEIYPIDG ITDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWFWRSGYGYYLD YWGQGTLVTVSS 347 SRP1848-F05 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISKSSIHWVRQAPGKGLEWVGEIYPNDG STDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWAWRSGYSYFLD YWGQGTLVTVSS 348 SRP1848-F06 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISLSYIHWVRQAPGKGLEWVGGISPIDG NTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGFWAWRSGYGYYLD YWGQGTLVTVSS 349 SRP1848-F07 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISNHSIHWVRQAPGKGLEWVGEIYPNDG ITDYADSVKGRFTISADTSKNTAYLQMN SLSAEDTAVYYCARGSWDWRSGYSYYLD YWGQGTLVTVSS 350 SRP1848-F08 VH EVQLVESGGGLVQPGGSLRLSCAAGGEN ISNHSIHWVRQAPGKGVEWVGEIYPVDG ITDYADSVKGRFTISADTSKNTAYLRMN SLRAEDTAVYYCARGSWYWQSGYSYYLD YWGQGTLVTVSS 351 SRP1848-F09 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISNHYIHWVRQAPGKGLEWVGGISPLDG YTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGAWSWRSGYGYYID YWGQGTLVTVSS 352 SRP1848-F10 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISNNSIHWVRQAPGKGLEWVGSIFPNDG YTDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWFWRSGYGYYLD YWGQGTLVTVSS 353 SRP1848-F11 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISNNYIHWVRQAPGKGLEWVGGITPIDG NTDYADSVKGRFTISADTSMNTAYLQMN SLRAEDTAVYYCARGSWYWRAGYGYYLD YWGQGALVTVSS 354 SRP1848-G01 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISRHSIHWVRQAPGKGLEWVGWIAPNDG STDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWAWRSGYSYFLD YWGQGTLVTVSS 355 SRP1848-G03 VH EVQLVESGGGLVQPGGSLRLSCAASGEN ISTYYIHWVRQAPGKGLEWVGGITPSDG FTDYADSVKGRSTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWPSGHGYFLD YWGQGTLVTVSS 356 SRP1848-G04 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IHSTDIHWVRQAPGKGLEWVAYITPAGG ATFYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARYPYWFAGYMDYWGQ GTLVTVSS 357 SRP1848-G06 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IRSTDIHWVRQAPGKGLEWVAYITPAGG ATYYADNVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARQPYWFAGYMDYWGQ GTLVTVSS 358 SRP1848-G07 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IHSTDIHWVRQAPGKGLEWVAYITPAGG ATWYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARYPFWFAGYMDYWGQ GTLVTVSS 359 SRP1848-G09 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IRGTDIHWVRQAPGKGLEWVAYITPAGG ATFYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARHEYWFSGYMDYWGQ GTLVTVSS 360 SRP1848-G10 VH EVQLVESGGGLVQPGSSLRLSCAASGEN IRSTDIHWVRQAPGKGLEWVAYITPAGG ATYYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARYPYWFAGYIDYWGQ GTLVTVSS 361 SRP1848-G11 EVQLVESGGGLVQPGGSLRLSCAASGEN ISSTDIHWVRQAPGKGLEWVAYITPAGG ATWYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARYPYWFSGYMDYWGQ GTLVTVSS 362 SRP1848-H01 VH EVQLVESGGGLVQPGGSLRLSCAASGEN IRTQSIHWVRQAPGKGLEWIGDIFPIDG ITDYADSVKGRFTISADTSKNTAYLQMN SLRAEDTAVYYCARGSWSWPSGMDYYLD YWGQGTLVTVSS 363 SRP2060-E10 VH EVQLLESGGGLVQPGGSLRLSCAFSGFS LSTFGMGVGWVRQAPGKGLEWVSHIWWD DDKYYHPALKGRFTISKDNSKNTVYLOM NSLRAEDTAVYYCGRNHFPHYYGSSHWY FNVWGQGTTVTVSS 364 SRP2060-E05 VH EVQLLESGGGLVQPGGSLRLSCAFSGFS LSTFGMGVGWVRQAPGKGLEWVSHIWWD DDKYYHPALKGRFTVSKDNSKNTVYLQM NSLRAEDTAVYYCGRNHFPHYYGSSHWY FNVWGQGTTVTVSS 365 SRP2060-B01 VH EVQLLESGGGLVQPGGSLRLSCALSGFS LSTFGMGVGWVRQATGKGLEWVSHIWWD DDKYYHPALKGRFTISKDNSKNTVHLQM NSLRAEDTAVYYCGRNHFPHYYGSSHWY FNVWGQGTTVTVSS 366 SRP2060-A06 VH EVQLLESGGGLVQPGGSLRLSCAFSGFS LSTFGMGVGWVRQAPGKGLEWVGHIWWD DDKYYYPALKGRFTISKDNSKNTVYLOM NSLRAEDTAVYYCGRNHFPHYYGSSHWY FDVWGQGTTVTVSS 367 trastuzumab VL DIQMTQSPSSLSASVGDRVTITCRASQD VNTAVAWYQQKPGKAPKLLIYSASFLYS GVPSRFSGSRSGTDFTLTISSLOPEDFA TYYCQQHYTTPPTFGQGTKVEIK 368 H6D1-LC4 VL EIVMTQSPATLSLSPGERATLSCKASQD INSYLSWYQQKPGQAPRLLIYRANRLVD GIPARFSGSGSGTDYTLTISSLEPEDFA VYYCLQYDEFPYTFGGGTKVEIK 369 H6D1-LC5 VL DIQMTQSPSTLSASVGDRVTITCKASQD INSYLSWYQQKPGKAPKLLIYRANRLVD GVPSRFSGSGSGTEFTLTISSLQPDDFA TYYCLQYDEFPYTFGGGTKVEIK 370 HumanIgG1HC ASTKGPSVFPLAPSSKSTSGGTAALGCL Constant VKDYFPEPVTVSWNSGALTSGVHTFPAV LOSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKENWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK 371 HumanIgGLC RTVAAPSVFIFPPSDEQLKSGTASVVCL ConstantCkappa LNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC 372 MouseIgG1HC AKTTPPSVYPLAPGSAAQTNSMVTLGCL Constant VKGYFPEPVTVTWNSGSLSSGVHTFPAV LOSDLYTLSSSVTVPSSTWPSETVTCNV AHPASSTKVDKKIVPRDCGCKPCICTVP EVSSVFIFPPKPKDVLTITLTPKVTCVV VDISKDDPEVQFSWFVDDVEVHTAQTOP REEQFNSTFRSVSELPIMHQDWLNGKEF KCRVNSAAFPAPIEKTISKTKGRPKAPQ VYTIPPPKEQMAKDKVSLTCMITDFFPE DITVEWQWNGQPAENYKNTQPIMDTDGS YFVYSKLNVQKSNWEAGNTFTCSVLHEG LHNHHTEKSLSHSPG 373 MouseIgGLC RADAAPTVSIFPPSSEQLTSGGASVVCF ConstantCkappa LNNFYPKDINVKWKIDGSERQNGVLNSW TDQDSKDSTYSMSSTLTLTKDEYERHNS YTCEATHKTSTSPIVKSFNRNEC 374 KappaLC HMTVAAPSVFIFPPSDEQLKSGTASVVC LLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSENRGEC 375 LambdaLD GQPKAAPSVTLFPPSSEELQANKATLVC LISDFYPGAVTVAWKADSSPVKAGVETT TPSKQSNNKYAASSYLSLTPEQWKSHRS YSCQVTHEGSTVEKTVAPTECS 376 FlagHisTag GSGDYKDDDDKGSGHHHHHH 377 Linker GGGGSGGGGSGGGGS 378 Linker AAGSDQEPKSS 379 1848-B10-VH- scFv MEVQLVESGGGLVQPGGSLRLSCAASGF (G4S)3-VL NTTTKSIHWVRQAPGKGLEWVGEIYPRD GITDYADSVKGRFTISADTSKNTAYLQM NSLRAEDTAVYYCARGGWHWRSGYSYYL DYWGQGTLVTVSSGGGGSGGGGSGGGGS DIQMTQSPSSLSASVGDRVTITCRASQD VNTAVAWYQQKPGKAPKLLIYSASFLYS GVPSRFSGSRSGTDFTLTISSLOPEDFA TYYCQQHYTTPPTFGQGTKVEIK 380 1848-B10-VL- scFv MDIQMTQSPSSLSASVGDRVTITCRASQ (G4S)3-VH DVNTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSRSGTDFTLTISSLOPEDF ATYYCQQHYTTPPTFGQGTKVEIKGGGG SGGGGSGGGGSEVQLVESGGGLVQPGGS LRLSCAASGENTTTKSIHWVRQAPGKGL EWVGEIYPRDGITDYADSVKGRFTISAD TSKNTAYLQMNSLRAEDTAVYYCARGGW HWRSGYSYYLDYWGQGTLVTVSS 381 1848-B10-VH- scFv-Fc MEVQLVESGGGLVQPGGSLRLSCAASGF (G4S)3-VL NTTTKSIHWVRQAPGKGLEWVGEIYPRD GITDYADSVKGRFTISADTSKNTAYLQM NSLRAEDTAVYYCARGGWHWRSGYSYYL DYWGQGTLVTVSSGGGGSGGGGSGGGGS DIQMTQSPSSLSASVGDRVTITCRASQD VNTAVAWYQQKPGKAPKLLIYSASFLYS GVPSRFSGSRSGTDFTLTISSLOPEDFA TYYCQQHYTTPPTFGQGTKVEIKAAGSD QEPKSSDKTHTCPPCPAPELLGGPSVEL FPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGK 382 1848-B10-VL- scFv-Fc MDIQMTQSPSSLSASVGDRVTITCRASQ (G4S)3-VH DVNTAVAWYQQKPGKAPKLLIYSASFLY SGVPSRFSGSRSGTDFTLTISSLQPEDF ATYYCQQHYTTPPTFGQGTKVEIKGGGG SGGGGSGGGGSEVQLVESGGGLVQPGGS LRLSCAASGENTTTKSIHWVRQAPGKGL EWVGEIYPRDGITDYADSVKGRFTISAD TSKNTAYLQMNSLRAEDTAVYYCARGGW HWRSGYSYYLDYWGQGTLVTVSSAAGSD QEPKSSDKTHTCPPCPAPELLGGPSVEL FPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGK

Equivalents

[0362] The disclosure set forth above may encompass multiple distinct inventions with independent utility. Although each of these inventions has been disclosed in its preferred form(s), the specific embodiments thereof as disclosed and illustrated herein are not to be considered in a limiting sense, because numerous variations are possible. The subject mailer of the inventions includes all novel and nonobvious combinations and subcombinations of the various elements, features, functions, and/or properties disclosed herein. The following claims particularly point out certain combinations and subcombinations regarded as novel and nonobvious. Inventions embodied in other combinations and subcombinations of features, functions, elements, and/or properties may be claimed in this application, in applications claiming priority from this application, or in related applications. Such claims, whether directed to a different invention or to the same invention, and whether broader, narrower, equal, or different in scope in comparison to the original claims, also are regarded as included within the subject matter of the inventions of the present disclosure.

[0363] One or more features from any embodiments described herein or in the figures may be combined with one or more features of any other embodiments described herein or in the figures without departing from the scope of the invention.

[0364] All publications, patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.