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HUMANIZED CLDN18.2 ANTIBODIES

20230030674 · 2023-02-02

    Inventors

    Cpc classification

    International classification

    Abstract

    The invention provides humanized antibodies binding to CLDN18.2 with a high affinity. Further, the antibodies do not exhibit cross-reactivity to CLDN18.1. The invention also provides nucleic acids, vectors, host cells and medical uses.

    Claims

    1. An antibody or fragment thereof binding to CLDN18.2, which comprises: HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.

    2. The antibody or fragment thereof of claim 1, comprising: a. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 9 and SEQ ID NO: 18, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; b. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 10 and SEQ ID NO: 19, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; c. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 10 and SEQ ID NO: 20, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 30, respectively; d. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 12 and SEQ ID NO: 21, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 26, SEQ ID NO: 5 and SEQ ID NO: 30, respectively; e. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 13 and SEQ ID NO: 18, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 31, respectively; f. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 8, SEQ ID NO: 14 and SEQ ID NO: 22, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; g. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 15 and SEQ ID NO: 23, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 27, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; h. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 16 and SEQ ID NO: 23, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; or i. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 8, SEQ ID NO: 17 and SEQ ID NO: 24, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 28, SEQ ID NO: 5 and SEQ ID NO: 31, respectively.

    3. The antibody or fragment thereof of claim 1, comprising: a. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 32; b. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 34; c. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 35; d. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 37; e. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 39; f. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 41; g. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 42; h. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 44 or i. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 45; and j. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 33; k. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 36; l. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 38; m. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 40; n. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 43; or o. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 46; preferably comprising: p. a VH sequence of SEQ ID NO: 32; q. a VH sequence of SEQ ID NO: 34; r. a VH sequence of SEQ ID NO: 35; s. a VH sequence of SEQ ID NO: 37; t. a VH sequence of SEQ ID NO: 39; u. a VH sequence of SEQ ID NO: 41; v. a VH sequence of SEQ ID NO: 42; w. a VH sequence of SEQ ID NO: 44 or x. a VH sequence of SEQ ID NO: 45; and y. a VL sequence of SEQ ID NO: 33; z. a VL sequence of SEQ ID NO: 36; aa. a VL sequence of SEQ ID NO: 38; bb. a VL sequence of SEQ ID NO: 40; cc. a VL sequence of SEQ ID NO: 43; or dd. a VL sequence of SEQ ID NO: 46.

    4. The antibody or fragment thereof of claim 1, comprising: a. a VH sequence of SEQ ID NO: 32 and a VL sequence of SEQ ID NO: 33; b. a VH sequence of SEQ ID NO: 34 and a VL sequence of SEQ ID NO: 33; c. a VH sequence of SEQ ID NO: 35 and a VL sequence of SEQ ID NO: 36; d. a VH sequence of SEQ ID NO: 37 and a VL sequence of SEQ ID NO: 38; e. a VH sequence of SEQ ID NO: 39 and a VL sequence of SEQ ID NO: 40; f. a VH sequence of SEQ ID NO: 41 and a VL sequence of SEQ ID NO: 33; g. a VH sequence of SEQ ID NO: 42 and a VL sequence of SEQ ID NO: 43; h. a VH sequence of SEQ ID NO: 44 and a VL sequence of SEQ ID NO: 33; or i. a VH sequence of SEQ ID NO: 45 and a VL sequence of SEQ ID NO: 46. j.

    5. The antibody or fragment thereof of claim 1, consisting of: a. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 49 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 50; b. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 51 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 50; c. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 52 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 53; d. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 54 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 55; e. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 56 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 57; f. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 58 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 50; g. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 59 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 60; h. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 61 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 50; or i. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 62 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 63; preferably consisting of: j. the heavy chain sequence of SEQ ID NO: 49 and light chain sequence of SEQ ID NO: 50; k. the heavy chain sequence of SEQ ID NO: 51 and light chain sequence of SEQ ID NO: 50; l. the heavy chain sequence of SEQ ID NO: 52 and light chain sequence of SEQ ID NO: 53; m. the heavy chain sequence of SEQ ID NO: 54 and light chain sequence of SEQ ID NO: 55; n. the heavy chain sequence of SEQ ID NO: 56 and light chain sequence of SEQ ID NO: 57; o. the heavy chain sequence of SEQ ID NO: 58 and light chain sequence of SEQ ID NO: 50; p. the heavy chain sequence of SEQ ID NO: 59 and light chain sequence of SEQ ID NO: 60; q. the heavy chain sequence of SEQ ID NO: 61 and light chain sequence of SEQ ID NO: 50; or r. the heavy chain sequence of SEQ ID NO: 62 and light chain sequence of SEQ ID NO: 63.

    6. An antibody or fragment thereof that competes for binding with an antibody or fragment thereof of claim 1.

    7. The antibody or fragment thereof of claim 1, wherein the format of the antibody or fragment thereof is selected from the group consisting of IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, synthetic IgG, IgM, F(ab).sub.2, Fv, scFv, IgGACH2, F(ab′).sub.2, scFvCH3, Fab, VL, VH, scFv4, scFv3, scFv2, dsFv, Fv, scFv-Fc, (scFv).sub.2, a non-depleting IgG, a diabody, and a bivalent antibody, or Fe-engineered versions thereof.

    8. The antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof (i) is humanized; (ii) is isolated; and/or (iii) does not bind to CLDN18.1.

    9. The antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof exhibits increased binding to CLDN18.2 as compared to a reference antibody, optionally wherein increased binding is measured as EC50 value and/or maxMFI value by flow cytometry titration on cells expressing CLDN18.2, preferably wherein the cells are HEK293T cells or PA-TU-8988-High cells, wherein the reference antibody comprises a heavy chain sequence of SEQ ID NO: 47 and a light chain sequence of SEQ ID NO: 48.

    10. The antibody or fragment of claim 9, wherein (i) the measured EC50 value of the antibody is at least 10% lower, at least 20% lower, at least 40% lower, at least 50% lower or at least 75% lower than the EC50 value of a reference antibody; and/or (ii) the measured maxMFI value of the antibody is at least 10% higher, at least 20% higher, at least 40% higher, at least 50% higher or at least 75% higher than the maxMFI value of a reference antibody; wherein the reference antibody comprises a heavy chain sequence of SEQ ID NO: 47 and a light chain sequence of SEQ ID NO: 48.

    11. A nucleic acid encoding the antibody or fragment thereof of claim 1.

    12. A vector comprising the nucleic acid of claim 11.

    13. A host cell comprising the nucleic acid of claim 11.

    14. A method comprising administering the antibody or fragment thereof of claim 1, to a subject a. suffering from, b. at risk of developing, and/or c. being diagnosed for a neoplastic disease.

    15. The method of claim 14, wherein the neoplastic disease is selected from the group consisting of pancreatic, gastric, esophageal, ovarian and lung cancer.

    16. A host cell comprising the vector of claim 12.

    17. A method comprising administering the nucleic acid of claim 11 to a subject a. suffering from, b. at risk of developing, and/or c. being diagnosed for a neoplastic disease.

    18. A method comprising administering the vector of claim 12 to a subject a. suffering from, b. at risk of developing, and/or c. being diagnosed for a neoplastic disease.

    19. A method comprising administering host cell of claim 13 to a subject a. suffering from, b. at risk of developing, and/or c. being diagnosed for a neoplastic disease.

    Description

    DESCRIPTION OF DRAWINGS

    [0097] FIG. 1: FACS binding assay of humanized antibodies and IMAB362. Binding of selected antibodies to huCLDN1.2 and huCLDN18.1 was tested in HEK293T cells stably expressing huCLDN18.2 or huCLDN18.1. Parental HEK293T cells not expressing the target protein were used as negative control. 1A: A: IMAB362, B: hGBA-1, C: hGBA-2, D: hGBA-3, E: hGBA-4, F: hGBA-5, G: hGBA-6, H: hGBA-7, I: hGBA-8, J: GBA-9, K: secondary antibody alone, L: pan-CLDN18 antibody; 1B: Bar graph showing the Mean Fluorescent Intensity (MFI) of the FACS binding data for each humanized antibody, compared to IMAB362, on parental HEK293T cells and HEK293T cells expressing huCLDN18.2 or huCLDN18.1.

    [0098] FIG. 2: 2A-D: ELISA binding assay on humanized antibodies, compared to IMAB362. The ELISA binding assay was performed on lipoparticles bearing CLDN18.2 or null-lipoparticles without CLDN18.2.

    [0099] FIG. 3: Sorting of PA-TU-8988S cells for expression levels of CLDN18.2. 3A: FACS profile of PA-TU-9888S stained with IMAB362. 3B: FACS profile of PA-TU-8988S cells sorted by FACS for medium and high expression of CLDN18.2.

    [0100] FIG. 4: FC titration assay on PA-TU-8988S-High cells (4A-D) and HEK-293T expressing huCLDN18.2 (4E-H).

    EXAMPLES

    Example 1: Humanization of Fab Fragments

    [0101] Techniques to humanize monoclonal antibodies have been well-established. The Handbook of Therapeutic Antibodies, Second Edition, gives ample information on humanization of monoclonal antibodies (Saldanha 2014), bioinformatic tools for analysis such antibodies (Martin and Allemn 2014) or development and manufacture of therapeutic antibodies (Jacobi et al. 2014). In brief, the variable domain sequences of the parental IMAB362 antibody were analyzed to reveal the closest human germlines. Next, a structural analysis of the variable regions of IMAB362 was performed to reveal the best fitting Fv model, followed by structural analysis of CDR grafting by in-silico modeling. Based on these in-silico modeling, humanized VH and VL domains were designed. Combinations of the humanized VH and VL domains were cloned and produced as Fab and IgG1 antibodies and screened for their binding by ELISA and AlphaLISA™ to CLDN18.2-expressing lipoparticles and by flow cytometry with CLDN18.1- and CLDN18.2-expressing pre-B cell L11 (Waldmeier et al. 2016) and HEK293T (ATCC CRL-3216) cell lines. After testing and comparison to IMAB362, one VH and VL combination was selected and a library was designed in scFv format, performing further humanization including the CDRs. The scFv library was further screened by ELISA and AlphaLISA™ to CLDN18.2-expressing lipoparticles and by flow cytometry with CLDN18.1- and CLDN18.2-expressing pre-B cell L11 cell lines. Humanization of IMAB362 thus resulted in the humanized antibodies hGBA-1, hGBA-2, hGBA-3, hGBA-4, hGBA-5, hGBA-6, hGBA-7, hGBA-8 and hGBA-9 antibodies (see Table 3), collectively named hGBA antibodies herein.

    TABLE-US-00003 TABLE 3 nucleic acid and amino-acid sequences of selected antibodies NAME SEQUENCE SEQ ID NO hGBA-1 HCDR1 GYSFTSYWIG SEQ ID NO: 7 HCDR2 GNIYPGASDTRYA SEQ ID NO: 9 HCDR3 ARLWRGNSFDY SEQ ID NO: 18 VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 32 GLEWMGNIYPGASDTRYAPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCARLWRGNSFDYWGQGTLVTVSS Heavy chain EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 49 GLEWMGNIYPGASDTRYAPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCARLWRGNSFDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK HCDR1 ggctatagctttacatcatattggattgga SEQ ID NO: 85 HCDR2 gggaacatttaccctggggcatcggatacgcgatacgca SEQ ID NO: 86 HCDR3 gcgagactttggcgggggaatagcttcgactac SEQ ID NO: 87 VH gaagtccaactggtccaatccggcgcggaggttaagaagcccg SEQ ID NO: 128 gagaatcgctgaagatctcatgcaaagggagcggctatagctt tacatcatattggattggatgggtcaggcaaatgccggggaag gggctggaatggatggggaacatttaccctggggcatcggata cgcgatacgcacctagctttcaagggcaagtcacaatttcggc ggacaagagcatctcaacggcatacctgcaatggtcgagcttg aaggcatctgatactgcaatgtactactgcgcgagactttggc gggggaatagcttcgactactgggggcagggtaccctggttac ggtctcgagc LCDR1 KSSQSLLNSGNQKNYLA SEQ ID NO: 25 LCDR2 WASTRES SEQ ID NO: 5 LCDR3 QNDYSYPFT SEQ ID NO: 29 VL DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQ SEQ ID NO: 33 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPFTFGQGTKVEIK Light chain DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQ SEQ ID NO: 50 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC LCDR1 aaaagctcccaaagcctattgaactcgggaaaccaaaagaatt SEQ ID NO: 88 acttggca LCDR2 tgggcaagcacccgagagagc SEQ ID NO: 89 LCDR3 caaaacgactattcatacccattcaca SEQ ID NO: 90 VL gacattgtgatgacgcaaagccccgattcgctggctgtatcgc SEQ ID NO: 129 taggggagcgcgctacgatcaattgcaaaagctcccaaagcct attgaactcgggaaaccaaaagaattacttggcatggtatcaa caaaaaccggggcaaccgccgaagctgctgatctattgggcaa gcacccgagagagcggtgtcccggaccgatttagcgggagcgg atcgggcaccgacttcacgctgacaataagctcattgcaagcc gaggatgtggcggtctattattgccaaaacgactattcatacc cattcacattcgggcaaggtaccaaggtcgagatcaag hGBA-2 HCDR1 GYSFTSYWIG SEQ ID NO: 7 HCDR2 GNIYPGDADTRYA SEQ ID NO: 10 HCDR3 ARMWRGNSFDY SEQ ID NO: 19 VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 34 GLEWMGNIYPGDADTRYAPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCARMWRGNSFDYWGQGTLVTVSS Heavy chain EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 51 GLEWMGNIYPGDADTRYAPSFQGQVTISADKS1STAYLQWSSL KASDTAMYYCARMWRGNSFDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK HCDR1 ggatattcatttacaagctactggatcgga SEQ ID NO: 91 HCDR2 ggaaatatataccccggagacgcggacacgagatacgca SEQ ID NO: 92 HCDR3 gcgcggatgtggcgcggcaatagctttgactac SEQ ID NO: 93 VH gaagtccaactggtccaatctggagcggaagtcaagaagcctg SEQ ID NO: 130 gggagagcctgaaaatttcatgcaaggggagcggatattcatt tacaagctactggatcggatgggtccggcaaatgccggggaag ggcttggaatggatgggaaatatataccccggagacgcggaca cgagatacgcaccgagctttcaagggcaggtcaccattagcgc tgataaatcgatttcaaccgcatatctgcaatggtcatcgctg aaggcctccgacaccgcgatgtactattgcgcgcggatgtggc gcggcaatagctttgactactgggggcagggtaccctcgtcac ggtctcgagc LCDR1 KSSQSLLNSGNQKNYLA SEQ ID NO: 25 LCDR2 WASTRES SEQ ID NO: 5 LCDR3 QNDYSYPFT SEQ ID NO: 29 VL DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQ SEQ ID NO: 33 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPFTFGQGTKVEIK Light chain DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQ SEQ ID NO: 50 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC LCDR1 aaaagctcccaaagcctattgaactcgggaaaccaaaagaatt SEQ ID NO: 88 acttggca LCDR2 tgggcaagcacccgagagagc SEQ ID NO: 89 LCDR3 caaaacgactattcatacccattcaca SEQ ID NO: 90 VL gacattgtgatgacgcaaagccccgattcgctggctgtatcgc SEQ ID NO: 129 taggggagcgcgctacgatcaattgcaaaagctcccaaagcct attgaactcgggaaaccaaaagaattacttggcatggtatcaa caaaaaccggggcaaccgccgaagctgctgatctattgggcaa gcacccgagagagcggtgtcccggaccgatttagcgggagcgg atcgggcaccgacttcacgctgacaataagctcattgcaagcc gaggatgtggcggtctattattgccaaaacgactattcatacc cattcacattcgggcaaggtaccaaggtcgagatcaag hGBA-3 HCDR1 GYSFTSYWIG SEQ ID NO: 7 HCDR2 GIIYPGASDTNYA SEQ ID NO: 11 HCDR3 ARIWRGNSFDY SEQ ID NO: 20 VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 35 GLEWMGIIYPGASDTNYAPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCARIWRGNSFDYWGQGTLVTVSS Heavy chain EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 52 GLEWMGIIYPGASDTNYAPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCARIWRGNSFDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK HCDR1 ggctatagctttacatcatattggattgga SEQ ID NO: 85 HCDR2 gggatcatctatccgggggcatccgataccaactatgcg SEQ ID NO: 94 HCDR3 gctaggatttggcgaggaaatagctttgattat SEQ ID NO: 95 VH gaggtccaactggtccaaagcggcgcggaggtcaagaagccgg SEQ ID NO: 131 gagaatccctgaagattagctgcaaaggctccggctatagctt tacatcatattggatcggatgggtcagacaaatgccgggaaag ggacttgaatggatggggatcatctatccgggggcatccgata ccaactatgcgccgagcttccaagggcaggtcacgatatccgc ggataaatcgattagcaccgcatatctgcaatggagctcgctg aaggcatccgacaccgcgatgtactactgcgctaggatttggc gaggaaatagctttgattattgggggcagggtacccttgtcac ggtctcgagc LCDR1 KSSQSLLNSGNQKNYLA SEQ ID NO: 25 LCDR2 WASTRES SEQ ID NO: 5 LCDR3 QNDYSYPLT SEQ ID NO: 29 VL DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQ SEQ ID NO: 36 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPLTFGQGTKVEIK Light chain DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQ SEQ ID NO: 53 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC LCDR1 aagagctcgcaaagtttgctgaactccgggaaccaaaagaatt SEQ ID NO: 96 acctggca LCDR2 tgggcatcaacgcgggaaagc SEQ ID NO: 97 LCDR3 caaaacgactactcctatccgctgacc SEQ ID NO: 98 VL gacattgtcatgacgcaaagccccgactcgctggccgtctcac SEQ ID NO: 132 tgggggagcgggcgacaatcaactgcaagagctcgcaaagttt gctgaactccgggaaccaaaagaattacctggcatggtatcaa caaaagccggggcaacccccgaagctgctgatatattgggcat caacgcgggaaagcggagtcccggatagatttagcggatctgg atcggggaccgacttcacgctgacgatatctagccttcaagcc gaggatgtggctgtatattattgccaaaacgactactcctatc cgctgaccttcgggcaaggtaccaaggtcgagatcaag hGBA-4 HCDR1 GYSFTSYWIG SEQ ID NO: 7 HCDR2 GIIYPGDAYTRYS SEQ ID NO: 12 HCDR3 TRLWRGNSFDA SEQ ID NO: 21 VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 37 GLEWMGIIYPGDAYTRYSPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCTRLWRGNSFDAWGQGTLVTVSS Heavy chain EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 54 GLEWMGIIYPGDAYTRYSPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCTRLWRGNSFDAWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK HCDR1 ggatactcatttacatcatactggatagga SEQ ID NO: 99 HCDR2 gggattatataccccggcgacgcttacactcgatattcg SEQ ID NO: 100 HCDR3 acgaggctatggagggggaatagctttgatgcc SEQ ID NO: 101 VH gaagtccaactagtccaaagcggagccgaagtcaagaaaccgg SEQ ID NO: 133 gggagagccttaagatctcatgcaaggggagcggatactcatt tacatcatactggataggatgggtcagacaaatgcccggcaag gggctggaatggatggggattatataccccggcgacgcttaca ctcgatattcgccatcattccaagggcaggtcacgatatcggc cgataaatcgatatccacggcatacctgcaatggagctcactg aaagcatctgatacggcaatgtattattgcacgaggctatgga gggggaatagctttgatgcctgggggcagggtaccctggtcac ggtctcgagc LCDR1 KSSQSLLNSGNQKNYLT SEQ ID NO: 26 LCDR2 WASTRES SEQ ID NO: 5 LCDR3 QNDYSYPLT SEQ ID NO: 30 VL DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQ SEQ ID NO: 38 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPLTFGQGTKVEIK Light chain DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQ SEQ ID NO: 55 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC LCDR1 aagagctcccaaagcctattgaactcgggaaatcaaaagaatt SEQ ID NO: 102 atctgaca LCDR2 tgggcctcgacaagggagagc SEQ ID NO: 103 LCDR3 caaaatgactactcatacccgctgaca SEQ ID NO: 104 VL gacatagttatgacacaatcgccggatagcctcgcggtcagcc SEQ ID NO: 134 ttggagagcgggcgacgatcaactgcaagagctcccaaagcct attgaactcgggaaatcaaaagaattatctgacatggtatcaa caaaagccggggcaaccaccgaaactgctgatctattgggcct cgacaagggagagcggagtcccggaccgcttctctggatcggg aagcgggactgacttcacgctgaccataagctcgctgcaagcc gaggacgtcgccgtctattattgccaaaatgactactcatacc cgctgacatttggccaaggtaccaaggtcgagatcaag hGBA-5 HCDR1 GYSFTSYWIG SEQ ID NO: 7 HCDR2 GIIYPGAAYTRYA SEQ ID NO: 13 HCDR3 ARLWRGNSFDY SEQ ID NO: 18 VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 39 GLEWMGIIYPGAAYTRYAPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCARLWRGNSFDYWGQGTLVTVSS Heavy chain EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 56 GLEWMGIIYPGAAYTRYAPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCARLWRGNSFDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK HCDR1 ggatatagctttacgagctactggatcgga SEQ ID NO: 105 HCDR2 gggataatataccccggagcggcatacacgagatatgcg SEQ ID NO: 106 HCDR3 gcgagactatggcgcgggaactcatttgattac SEQ ID NO: 107 VH gaggtgcaactggtacaatccggggcggaagtgaagaagccgg SEQ ID NO: 135 gggaatcgctgaagataagctgcaaaggctctggatatagctt tacgagctactggatcggatgggtcaggcaaatgccggggaag ggactggaatggatggggataatataccccggagcggcataca cgagatatgcgccgagcttccaagggcaagtgacaataagcgc ggacaaatcgattagcacggcatatctgcaatggtcctcgctg aaggcgagcgataccgcaatgtactattgcgcgagactatggc gcgggaactcatttgattactgggggcagggtaccctagtgac ggtctcgagc LCDR1 KSSQSLLNSGNQKNYLA SEQ ID NO: 25 LCDR2 WASTRES SEQ ID NO: 5 LCDR3 QQDYSYPFT SEQ ID NO: 31 VL DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQ SEQ ID NO: 40 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQQDYSYPFTFGQGTKVEIK Light chain DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQ SEQ ID NO: 57 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQQDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC LCDR1 aaatcatcgcaatcattgctaaattcggggaaccaaaagaatt SEQ ID NO: 108 atttggca LCDR2 tgggcatccacgagagaatcg SEQ ID NO: 109 LCDR3 caacaagattattcatacccatttaca SEQ ID NO: 110 VL gacattgtcatgacgcaaagcccggatagcctggctgtatcgc SEQ ID NO: 136 tgggggagagagcgacgatcaactgcaaatcatcgcaatcatt gctaaattcggggaaccaaaagaattatttggcatggtatcaa caaaagccggggcaaccgccgaaactgctgatttactgggcat ccacgagagaatcgggagtcccggaccgatttagcggatctgg gagcgggaccgatttcacgctgaccattagctcgctgcaagcg gaggatgtggcggtctattactgccaacaagattattcatacc catttacatttgggcaaggtaccaaggtcgagatcaag hGBA-6 HCDR1 GYTFTSYWIG SEQ ID NO: 8 HCDR2 GNIYPGASYTRYS SEQ ID NO: 14 HCDR3 TRQWRGNSFDY SEQ ID NO: 22 VH EVQLVQSGAEVKKPGESLKISCKGSGYTFTSYWIGWVRQMPGK SEQ ID NO: 41 GLEWMGNIYPGASYTRYSPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCTRQWRGNSFDYWGQGTLVTVSS Heavy chain EVQLVQSGAEVKKPGESLKISCKGSGYTFTSYWIGWVRQMPGK SEQ ID NO: 58 GLEWMGNIYPGASYTRYSPSFQGQVTISADKS1STAYLQWSSL KASDTAMYYCTRQWRGNSFDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK HCDR1 ggatatacatttacatcttactggatcgga SEQ ID NO: 111 HCDR2 gggaacatttatcctggcgcgagctatacgcgctat SEQ ID NO: 112 HCDR3 acccggcaatggaggggcaatagctttgactac SEQ ID NO: 113 VH gaagtacaattggttcaatcgggggccgaagtcaagaagccgg SEQ ID NO: 137 gggaatcgctgaagatatcctgcaaggggagcggatatacatt tacatcttactggatcggatgggtcagacaaatgcccggaaag gggcttgaatggatggggaacatttatcctggcgcgagctata cgcgctatagcccgagcttccaagggcaggtcacgattagcgc cgacaagagcatttcgacggcatacctgcaatggagctcgctg aaagcatcggatacggcaatgtattactgcacccggcaatgga ggggcaatagctttgactactgggggcagggtaccctagtcac ggtctcgagc LCDR1 KSSQSLLNSGNQKNYLA SEQ ID NO: 25 LCDR2 WASTRES SEQ ID NO: 5 LCDR3 QNDYSYPFT SEQ ID NO: 29 VL DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQ SEQ ID NO: 33 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPFTFGQGTKVEIK Light chain DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQ SEQ ID NO: 50 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC LCDR1 aaaagctcccaaagcctattgaactcgggaaaccaaaagaatt SEQ ID NO: 88 acttggca LCDR2 tgggcaagcacccgagagagc SEQ ID NO: 89 LCDR3 caaaacgactattcatacccattcaca SEQ ID NO: 90 VL gacattgtgatgacgcaaagccccgattcgctggctgtatcgc SEQ ID NO: 129 taggggagcgcgctacgatcaattgcaaaagctcccaaagcct attgaactcgggaaaccaaaagaattacttggcatggtatcaa caaaaaccggggcaaccgccgaagctgctgatctattgggcaa gcacccgagagagcggtgtcccggaccgatttagcgggagcgg atcgggcaccgacttcacgctgacaataagctcattgcaagcc gaggatgtggcggtctattattgccaaaacgactattcatacc cattcacattcgggcaaggtaccaaggtcgagatcaag hGBA-7 HCDR1 GYSFTSYWIG SEQ ID NO: 7 HCDR2 GNIYPGEAYTRYS SEQ ID NO: 15 HCDR3 TRLWRGNSFDY SEQ ID NO: 23 VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 42 GLEWMGNIYPGEAYTRYSPSFQGQVTISADKS1STAYLQWSSL KASDTAMYYCTRLWRGNSFDYWGQGTLVTVSS Heavy chain EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 59 GLEWMGNIYPGEAYTRYSPSFQGQVTISADKS1STAYLQWSSL KASDTAMYYCTRLWRGNSFDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK HCDR1 ggatattcctttacatcatactggatcggc SEQ ID NO: 114 HCDR2 gggaacatatatcccggagaagcctatacgagatactcg SEQ ID NO: 115 HCDR3 acgcgactatggaggggaaatagctttgactat SEQ ID NO: 116 VH gaagttcaattggtccaatctggagccgaagtcaagaagcccg SEQ ID NO: 138 gagaatcgctgaagattagctgcaaggggagcggatattcctt tacatcatactggatcggctgggtcagacaaatgcccggaaag ggactggaatggatggggaacatatatcccggagaagcctata cgagatactcgccatcatttcaaggacaggtcaccataagcgc ggacaagagcataagcaccgcatacctgcaatggagctcgctg aaggcatcggacaccgccatgtattactgcacgcgactatgga ggggaaatagctttgactattgggggcagggtaccttagtcac ggtctcgagc LCDR1 KSSQSVLNSGNQKNYLT SEQ ID NO: 27 LCDR2 WASTRES SEQ ID NO: 5 LCDR3 QNDYSYPFT SEQ ID NO: 29 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLNSGNQKNYLTWYQ SEQ ID NO: 43 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPFTFGQGTKVEIK Light chain DIVMTQSPDSLAVSLGERATINCKSSQSVLNSGNQKNYLTWYQ SEQ ID NO: 60 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC LCDR1 aagagctcccaatcagtcctgaactctgggaatcaaaagaatt SEQ ID NO: 117 acctgaca LCDR2 tgggcgagcacgagggagagc SEQ ID NO: 118 LCDR3 caaaatgattattcataccccttcaca SEQ ID NO: 119 VL gatatagtaatgactcaatcacccgatagcttggctgtgagcc SEQ ID NO: 139 tgggagaaagagctacaatcaactgcaagagctcccaatcagt cctgaactctgggaatcaaaagaattacctgacatggtatcaa caaaagcccggacaaccgccgaagctgctgatctactgggcga gcacgagggagagcggagtcccggatcgattttctggctccgg gagcggaaccgacttcacactgactattagctcgctgcaagcg gaggacgtcgccgtctactattgccaaaatgattattcatacc ccttcacatttgggcaaggtaccaaggtcgagatcaag hGBA-8 HCDR1 GYSFTSYWIG SEQ ID NO: 7 HCDR2 GNIYPSESYTNYA SEQ ID NO: 16 HCDR3 TRLWRGNSFDY SEQ ID NO: 23 VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 44 GLEWMGNIYPSESYTNYAPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCTRLWRGNSFDYWGQGTLVTVSS Heavy chain EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGK SEQ ID NO: 61 GLEWMGNIYPSESYTNYAPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCTRLWRGNSFDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK HCDR1 ggatactcctttacatcatattggatcgga SEQ ID NO: 120 HCDR2 ggaaacatatatccgagcgaatcatatacgaactacgcg SEQ ID NO: 121 HCDR3 acgaggctatggagggggaatagcttcgactat SEQ ID NO: 122 VH gaggtgcaactagtgcaatcgggggccgaagtgaagaaacctg SEQ ID NO: 140 gggaatcgctgaagatatcatgcaaggggagcggatactcctt tacatcatattggatcggatgggtcaggcaaatgccggggaag gggctggaatggatgggaaacatatatccgagcgaatcatata cgaactacgcgccgagctttcaaggacaagtcacgatatccgc ggataaatcgatatcgaccgcatacctgcaatggagctcgctg aaggcttccgacactgcgatgtattactgcacgaggctatgga gggggaatagcttcgactattgggggcagggtaccctggtgac ggtctcgagc LCDR1 KSSQSLLNSGNQKNYLA SEQ ID NO: 25 LCDR2 WASTRES SEQ ID NO: 5 LCDR3 QNDYSYPFT SEQ ID NO: 29 VL DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQ SEQ ID NO: 33 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPFTFGQGTKVEIK Light chain DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQ SEQ ID NO: 50 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQNDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC LCDR1 aaaagctcccaaagcctattgaactcgggaaaccaaaagaatt SEQ ID NO: 88 acttggca LCDR2 tgggcaagcacccgagagagc SEQ ID NO: 89 LCDR3 caaaacgactattcatacccattcaca SEQ ID NO: 90 VL gacattgtgatgacgcaaagccccgattcgctggctgtatcgc SEQ ID NO: 129 taggggagcgcgctacgatcaattgcaaaagctcccaaagcct attgaactcgggaaaccaaaagaattacttggcatggtatcaa caaaaaccggggcaaccgccgaagctgctgatctattgggcaa gcacccgagagagcggtgtcccggaccgatttagcgggagcgg atcgggcaccgacttcacgctgacaataagctcattgcaagcc gaggatgtggcggtctattattgccaaaacgactattcatacc cattcacattcgggcaaggtaccaaggtcgagatcaagt hGBA-9 HCDR1 gytftsywig SEQ ID NO HCDR2 GIIYPSAAYTRYA SEQ ID NO: 17 HCDR3 TRMWRGNSFDY SEQ ID NO: 24 VH EVQLVQSGAEVKKPGESLKISCKGSGYTFTSYWIGWVRQMPGK SEQ ID NO: 45 GLEWMGIIYPSAAYTRYAPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCTRMWRGNSFDYWGQGTLVTVSS Heavy chain EVQLVQSGAEVKKPGESLKISCKGSGYTFTSYWIGWVRQMPGK SEQ ID NO: 62 GLEWMGIIYPSAAYTRYAPSFQGQVTISADKSISTAYLQWSSL KASDTAMYYCTRMWRGNSFDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK HCDR1 ggatatacattcacgagctactggatagga SEQ ID NO HCDR2 ggaatcatatatccttccgcggcatatacgcgatatgcg SEQ ID NO: 124 HCDR3 acgcggatgtggaggggaaatagctttgattac SEQ ID NO: 125 VH gaagtccaattagtccaatcgggggccgaggtcaagaagccgg SEQ ID NO: 141 gggaatcgctcaagataagctgcaagggatcgggatatacatt cacgagctactggataggatgggtcaggcaaatgccggggaag gggctggaatggatgggaatcatatatccttccgcggcatata cgcgatatgcgccatcatttcaaggacaggtcacgataagcgc cgacaagagcattagcaccgcatacctgcaatggtcgagcctt aaggcatcggacaccgcgatgtactactgcacgcggatgtgga ggggaaatagctttgattactgggggcagggtaccctagtcac ggtctcgagc LCDR1 KSSQSVLNSGNQKNYLA SEQ ID NO: 28 LCDR2 WASTRES SEQ ID NO: 5 LCDR3 QQDYSYPFT SEQ ID NO: 31 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLNSGNQKNYLAWYQ SEQ ID NO: 46 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQQDYSYPFTFGQGTKVEIK Light chain DIVMTQSPDSLAVSLGERATINCKSSQSVLNSGNQKNYLAWYQ SEQ ID NO: 63 QKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQQDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC LCDR1 aagagctcgcaatcggtcctgaatagcgggaaccaaaagaatt SEQ ID NO: 126 atctggcc LCDR2 tgggcgagcacgagggagagc SEQ ID NO: 118 LCDR3 caacaagactactcatacccatttaca SEQ ID NO: 127 VL gacatcgtcatgacgcaaagcccggactcgctggcggtctcgc SEQ ID NO: 142 tgggggagcgggccacaataaattgcaagagctcgcaatcggt cctgaatagcgggaaccaaaagaattatctggcctggtatcaa caaaagccggggcaaccaccgaagctgctaatctattgggcga gcacgagggagagcggagtccccgatcgatttagcggatcggg aagcgggaccgatttcacgctgacgatttcgagcctacaagcc gaggatgtggcggtctattactgccaacaagactactcatacc catttacatttggacaaggtaccaaggtcgagatcaag

    [0102] The antibodies described in further Examples 2 to 4 were modified to contain a RLPXTGG tag (SEQ ID NO: 143) at the C-terminal end of the HC and/or a GGGGSLPXTGG tag (SEQ ID NO: 144) at the C-terminal end of the LC, where X is any of the 20 natural amino acids. The C-terminal lysine (K) on the HC was in this case replaced by the Arginine (R) of the tag. The addition of the tags did not change the affinity and selectivity to CLDN18.2 of the antibodies.

    Example 2: FACS Binding Analysis of Humanized mAbs

    [0103] The HEK293T (ATCC CRL-3216) cell line does not endogenously express CLDN18.1 or CLDN18.2. Therefore, in order to test antibody binding activity, CLDN18.1 and CLDN18.2 were overexpressed in the HEK293T cell line. Cells were co-transected by electroporation with a transposase expression construct (pcDNA3.1-by-mPB), a construct bearing transposable full-length huCLDN18. 1 (pPB-Puro-huCldn18.1) or huCLDN18.2 (pPB-Puro-huCldn18.2) along with puromycin expression cassette and a construct carrying EGFP as transfection control (pEGFP-N3). Upon transfection, cells were allowed to recover for two days in growth media at 37° C. in a humidified incubator in a 5% CO.sub.2 atmosphere. Transfection was verified by FC analysis of the EGFP expression. Cells expressing huCLDN18.1 or huCLDN18.2 were then selected by the addition of puromycin into culture at 1 μg/ml, and further expanded to allow the generation of frozen stocks in FCS with 10% DMSO. The expression of huCLDN18.2 in the transfected HEK293T cells was analyzed by FACS. In brief, HEK293T cells were trypsinized and collected by centrifugation, resuspended in PBS/2% FCS and stained for huCLDN18.2 using IMAB362 as primary antibody at 2 μg/ml on ice for 30 min and, upon washing in PBS/2% FCS, stained with PE-labelled anti-human Fcγ-specific IgG goat antibody (eBioscience) as secondary antibody for 30 min on ice. Upon further wash, resuspended stained cells in ice-cold FACS buffer were analyzed using a FACSCalibur™ instrument (see FIG. 1A). Un-transfected parental cells, not expressing CLDN18.2, were used as negative control. The expression of CLDN18.1 was analyzed in a similar fashion, using a proprietary pan-CLDN18 antibody recognizing CLDN18.1 and CLDN18.2. Any pan-CLDN18 antibody usable for flow cytometry measurement would also be adequate such as antibody anti Claudin-18/CLDN18 (C-term) provided by OriGene Technologies (catalog number AP50944PU-N), CLDN18 (C-Term) Rabbit pAb from MyBioSource (catalog number MBS8555451) or the CLDN18 Antibody from ProSci (catalog number 63-847).

    [0104] The HEK293T cells stably expressing huCLDN18.1 and huCLDN18.2 were consequently used to test the binding specificity of the humanized antibodies hGBA-1, hGBA-2, hGBA-3, hGBA-4, hGBA-5, hGBA-6, hGBA-7, hGBA-8 and hGBA-9 to CLDN18.2 and not to huCLDN18.1. The cells were stained on ice for 30 min using the antibodies at 2 μg/ml and, upon washing in FACS buffer (PBS/2% FCS), stained with PE-labelled anti-human Fcγ-specific IgG goat antibody (eBioscience) as secondary antibody for 30 min on ice. Expression of CLDN18.1 in the HEK293T cells stably expressing huCLDN18.1 was verified with a pan-CLDN18 antibody (see FIG. 1, panel L) and expression of CLDN18.2 in the HEK293T cells stably expressing huCLDN18.2 was verified with the IMAB362 (see FIG. 1, panel A). FIG. 1 shows that all humanized antibodies bind specifically to huCLDN18.2 expressed by HEK293T cells, and not to huCLDN18.1. Furthermore, all humanized antibodies bind to huCLDN18.2 stronger than the parental antibody IMAB362.

    Example 3: ELISA Binding Analysis of Humanized mAbs

    [0105] The binding affinity to CLDN18.2 of the humanized antibodies (hGBA) was tested in an ELISA assay with lipoparticles bearing CLDN18.2 as source of antigen. CLDN18.2-lipoparticles and Null-lipoparticles (without antigen as a negative control) were used to coat 96-well plates at a final concentration of 10 U/ml. Upon washing with PBS/0.05% Tween-20 (PBS-T) and blocking with PBS-T/3% BSA for at least 1 h at 37° C., 1:3 serial dilutions of hGBA and IMAB362 antibodies with a starting concentration of 2 μg/ml in PBS-T/1% BSA were added to the coated wells and incubated for at least 1 h at 37° C. The presence of bound antibodies was revealed through binding of an HRP-goat anti-human secondary antibody diluted in PBS-T/1% BSA, development with Sigma-Fast OPD as peroxidase substrate and the reaction was stopped by adding 2M H.sub.2SO.sub.4, followed by reading the OD at 490 nm on an ELISA plate reader. Representative binding curves are shown in FIG. 2. Surprisingly, the binding curves in FIG. 2 show that all humanized antibodies (hGBA-1 to hGBA-9) bind to CLDN18.2-lipoparticles with a higher affinity than IMAB362, shown by a higher maximal binding value.

    Example 4: FC Titration on HEK293T and PA-TU-8988 High Cells

    [0106] PA-TU-89885 cells (Creative Bioarray, catalog number CSC-00326) expressing high levels of CLDN18.2 were selected by FACS. Herein, these cells are designated as PA-TU-89885-High cells. Based on FACS staining with IMAB362, the PA-TU-8988S cell population expresses different levels of CLDN18.2, with a high and a medium level of expression (see FIG. 3A). In order to have a more homogenous cell population, the cells were sorted by FACS to select only cells with a higher CLDN18.2 expression. In brief, PA-TU-8988S cells suspended in FACS buffer (PBS, 2% FCS) were incubated on ice for 30 min with IMAB362 at 2 μg/ml. After wash in FACS buffer, the cells were incubated with the PE-labeled Fcγ specific IgG goat anti-human secondary antibody (eBioscience) on ice for 30 min. After wash, the stained cells were resuspended in FACS buffer, analyzed and sorted by a FACSAria™ instrument, separating medium expressing cells (FIG. 3B) from high expressing cells (FIG. 3B). After sorting, the collected PA-TU-89885-High cells were resuspended in growth media, expanded in growth media and frozen aliquots were preserved in liquid N.sub.2.

    [0107] In order to quantify the affinity of the antibodies to CLDN18.2, 250×10.sup.3 cells/well of HEK293T cells overexpressing CLDN18.2 or PA-TU-8988-High cells were seeded in FC buffer (PBS/2% FCS) into 96-well plates and allowed to settle by centrifugation. IMAB362 and hGBA antibodies to be tested were diluted at 4 μg/ml, followed by 1:4 serial dilutions and incubated with the platted cells for 30 min at 4° C. A PE-coupled secondary anti-human IgG antibody was added to the cells for additional 30 min at 4° C. after washes with the FACS buffer, followed by further washes with FC buffer. The cells were then resuspended in 100 μl FC buffer and measured with a FACSCalibur™ cell analyzer (BD Biosciences, USA). The FC analysis (see FIG. 4 and Table 4) shows that all hGBA antibodies have a stronger binding affinity to CLDN18.2 (reflected by a higher Max MFI for all tested new antibodies, see Table 4) than IMAB362, in both cell lines. The binding affinity of all hGBA antibodies is similar between each other but is significantly higher than the parental antibody IMAB362.

    TABLE-US-00004 TABLE 4 Maximum MFI and EC50 (μg/ml) measured on all the hGBA and IMAB362 antibodies on the HEK293T cells lines overexpressing CLDN18.2 and on the PA-TU-8988S-High cell lines. HEK293T-CLDN18.2 PA-TU-8988S-High Max MFI EC50 (μg/ml) Max MFI EC50 (μg/ml) Antibody EXP. 2 EXP. 2 EXP. 2 EXP. 2 IMAB362 1968 0.3878 1046 0.5082 hGBA1 3031 0.2586 2527 0.4439 hGBA2 2967 0.2486 2403 0.5836 hGBA3 2750 0.2734 2156 0.3525 hGBA4 2790 0.3575 2011 0.4123 hGBA5 3321 0.3052 2560 0.1593 hGBA6 2888 0.2567 2236 0.1913 hGBA7 3250 0.4196 2318 0.3232 hGBA8 2704 0.187 2366 0.3034 hGBA9 3124 0.2414 2445 0.286

    [0108] The invention is also described by the following embodiments: [0109] 1. An antibody or fragment thereof binding to CLDN18.2, which comprises: HCDR1, HCDR2 and HCR3 sequences of SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively. [0110] 2. The antibody or fragment thereof of embodiment 1, comprising: [0111] a. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 9 and SEQ ID NO: 18, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; [0112] b. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 10 and SEQ ID NO: 19, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; [0113] c. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 10 and SEQ ID NO: 20, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 30, respectively; [0114] d. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 12 and SEQ ID NO: 21, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 26, SEQ ID NO: 5 and SEQ ID NO: 30, respectively; [0115] e. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 13 and SEQ ID NO: 18, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 31, respectively; [0116] f. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 8, SEQ ID NO: 14 and SEQ ID NO: 22, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; [0117] g. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 15 and SEQ ID NO: 23, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 27, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; [0118] h. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 16 and SEQ ID NO: 23, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; or [0119] i. the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 8, SEQ ID NO: 17 and SEQ ID NO: 24, respectively and the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 28, SEQ ID NO: 5 and SEQ ID NO: 31, respectively. [0120] 3. The antibody or fragment thereof of embodiments 1 and 2, comprising: [0121] a. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 32; [0122] b. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 34; [0123] c. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 35; [0124] d. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 37; [0125] e. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 39; [0126] f. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 41; [0127] g. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 42; [0128] h. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 44 or [0129] i. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 45; [0130] and [0131] j. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 33; [0132] k. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 36; [0133] l. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 38; [0134] m. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 40; [0135] n. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 43; or [0136] o. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 46. [0137] 4. The antibody or fragment thereof of any one of embodiments 1 to 3, comprising: [0138] a. a VH sequence of SEQ ID NO: 32; [0139] b. a VH sequence of SEQ ID NO: 34; [0140] c. a VH sequence of SEQ ID NO: 35; [0141] d. a VH sequence of SEQ ID NO: 37; [0142] e. a VH sequence of SEQ ID NO: 39; [0143] f. a VH sequence of SEQ ID NO: 41; [0144] g. a VH sequence of SEQ ID NO: 42; [0145] h. a VH sequence of SEQ ID NO: 44; or [0146] i. a VH sequence of SEQ ID NO: 45; [0147] and [0148] j. a VL sequence of SEQ ID NO: 33; [0149] k. a VL sequence of SEQ ID NO: 36; [0150] l. a VL sequence of SEQ ID NO: 38; [0151] m. a VL sequence of SEQ ID NO: 40; [0152] n. a VL sequence of SEQ ID NO: 43; or [0153] o. a VL sequence of SEQ ID NO: 46. [0154] 5. The antibody or fragment thereof of any one of embodiments 1 to 4, comprising: [0155] a. a VH sequence of SEQ ID NO: 32 and a VL sequence of SEQ ID NO: 33; [0156] b. a VH sequence of SEQ ID NO: 34 and a VL sequence of SEQ ID NO: 33; [0157] c. a VH sequence of SEQ ID NO: 35 and a VL sequence of SEQ ID NO: 36; [0158] d. a VH sequence of SEQ ID NO: 37 and a VL sequence of SEQ ID NO: 38; [0159] e. a VH sequence of SEQ ID NO: 39 and a VL sequence of SEQ ID NO: 40; [0160] f. a VH sequence of SEQ ID NO: 41 and a VL sequence of SEQ ID NO: 33; [0161] g. a VH sequence of SEQ ID NO: 42 and a VL sequence of SEQ ID NO: 43; [0162] h. a VH sequence of SEQ ID NO: 44 and a VL sequence of SEQ ID NO: 33; or [0163] i. a VH sequence of SEQ ID NO: 45 and a VL sequence of SEQ ID NO: 46. [0164] 6. The antibody or fragment thereof of any one of embodiments 1 to 5, consisting of: [0165] a. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 49 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 50; [0166] b. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 51 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 50; [0167] c. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 52 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 53; [0168] d. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 54 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 55; [0169] e. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 56 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 57; [0170] f. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 58 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 50; [0171] g. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 59 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 60; [0172] h. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 61 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 50; or [0173] i. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 62 and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 63. [0174] 7. The antibody or fragment thereof of any one of embodiments 1 to 6, consisting of: [0175] a. the heavy chain sequence of SEQ ID NO: 49 and light chain sequence of SEQ ID NO: 50; [0176] b. the heavy chain sequence of SEQ ID NO: 51 and light chain sequence of SEQ ID NO: 50; [0177] c. the heavy chain sequence of SEQ ID NO: 52 and light chain sequence of SEQ ID NO: 53; [0178] d. the heavy chain sequence of SEQ ID NO: 54 and light chain sequence of SEQ ID NO: 55; [0179] e. the heavy chain sequence of SEQ ID NO: 56 and light chain sequence of SEQ ID NO: 57; [0180] f. the heavy chain sequence of SEQ ID NO: 58 and light chain sequence of SEQ ID NO: 50; [0181] g. the heavy chain sequence of SEQ ID NO: 59 and light chain sequence of SEQ ID NO: 60; [0182] h. the heavy chain sequence of SEQ ID NO: 61 and light chain sequence of SEQ ID NO: 50; or [0183] i. the heavy chain sequence of SEQ ID NO: 62 and light chain sequence of SEQ ID NO: 63. [0184] 8. An antibody or fragment thereof that competes for binding with an antibody or fragment thereof of any one of embodiments 1 to 7. [0185] 9. The antibody or fragment thereof of any one of embodiments 1 to 8, wherein the format of the antibody or fragment thereof is selected from the group consisting of IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, synthetic IgG, IgM, F(ab).sub.2, Fv, scFv, IgGACH2, F(ab′).sub.2, scFvCH3, Fab, VL, VH, scFv4, scFv3, scFv2, dsFv, Fv, scFv-Fc, (scFv).sub.2, a non-depleting IgG, a diabody, and a bivalent antibody, or Fc-engineered versions thereof. [0186] 10. The antibody or fragment thereof of any one of embodiments 1 to 9, wherein the antibody or fragment thereof is humanized. [0187] 11. The antibody or fragment thereof of any one of embodiments 1 to 10, wherein the antibody or fragment thereof is isolated. [0188] 12. The antibody or fragment thereof of any one of embodiments 1 to 11, wherein the antibody or fragment thereof does not bind to CLDN18.1. [0189] 13. The antibody or fragment thereof of any one of embodiments 1 to 12, wherein the antibody or fragment thereof exhibits increased binding to CLDN18.2 as compared to antibody IMAB362. [0190] 14. The antibody or fragment of embodiment 13 wherein increased binding is measured as EC50 value and/or maxMFI value by flow cytometry titration on cells expressing CLDN18.2, preferably wherein the cells are HEK293T cells or PA-TU-8988-High cells. [0191] 15. The antibody or fragment of embodiment 14, wherein the measured EC50 value of the antibody is at least 10% lower, at least 20% lower, at least 40% lower, at least 50% lower or at least 75% lower than the EC50 value of antibody IMAB362. [0192] 16. The antibody or fragment of embodiment 14, wherein the measured maxMFI value of the antibody is at least 10% higher, at least 20% higher, at least 40% higher, at least 50% higher or at least 75% higher than the maxMFI value of antibody IMAB362. [0193] 17. A nucleic acid encoding the antibody or fragment thereof of any of embodiments 1 to 16. [0194] 18. A vector comprising the nucleic acid of embodiment 17. [0195] 19. A host cell comprising the nucleic acid of embodiment 17 or a vector of embodiment 18. [0196] 20. The antibody or fragment thereof of any one of embodiments 1 to 16, the nucleic acid of embodiment 17, the vector of embodiment 18 or the host cell of embodiment 19 for use in the treatment of a subject [0197] a. suffering from, [0198] b. at risk of developing, and/or [0199] c. being diagnosed for a neoplastic disease. [0200] 21. The antibody or fragment thereof for the use of embodiment 20, wherein the neoplastic disease is selected from the group consisting of pancreatic, gastric, esophageal, ovarian and lung cancer.

    TABLE-US-00005 SEQUENCES SEQ ID NO: 1 GYXFTSYWIG X in 3.sup.rd position is T or S SEQ ID NO: 2 GXIYPXXXXTXYX X in 2.sup.nd position is N or I; X in 6.sup.th position is S or G; X in 7.sup.th position is A, E or D; X in 8.sup.th position is A or S; X in 9.sup.th position is Y or D; X in 11.sup.th position is N or R; X in last position is A or S SEQ ID NO: 3 XRXWRGNSFDX X in 1st position is A or T; X in 3rd position is L, M, I or Q; X in last last position is A or Y SEQ ID NO: 4 KSSQSXLNSGNQKNYLX X in 6th position is L or V; X in last position is T or A SEQ ID NO: 5 WASTRES SEQ ID NO: 6 QXDYSYPXT X in 2nd position is N or Q; X in L or F SEQ ID NO: 7 GYSFTSYWIG SEQ ID NO: 8 GYTFTSYWIG SEQ ID NO: 9 GNIYPGASDTRYA SEQ ID NO: 10 GNIYPGDADTRYA SEQ ID NO: 11 GIIYPGASDTNYA SEQ ID NO: 12 GIIYPGDAYTRYS SEQ ID NO: 13 GIIYPGAAYTRYA SEQ ID NO: 14 GNIYPGASYTRYS SEQ ID NO: 15 GNIYPGEAYTRYS SEQ ID NO: 16 GNIYPSESYTNYA SEQ ID NO: 17 GIIYPSAAYTRYA SEQ ID NO: 18 ARLWRGNSFDY SEQ ID NO: 19 ARMWRGNSFDY SEQ ID NO: 20 ARIWRGNSFDY SEQ ID NO: 21 TRLWRGNSFDA SEQ ID NO: 22 TRQWRGNSFDY SEQ ID NO: 23 TRLWRGNSFDY SEQ ID NO: 24 TRMWRGNSFDY SEQ ID NO: 25 KSSQSLLNSGNQKNYLA SEQ ID NO: 26 KSSQSLLNSGNQKNYLT SEQ ID NO: 27 KSSQSVLNSGNQKNYLT SEQ ID NO: 28 KSSQSVLNSGNQKNYLA SEQ ID NO: 29 QNDYSYPFT SEQ ID NO: 30 QNDYSYPLT SEQ ID NO: 31 QQDYSYPFT SEQ ID NO: 21 hGBA-1 HC variable region EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPGASDTRYAPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCARLWRGNSFDYWGQGTLVTVSS SEQ ID NO: 33 hGBA-1, hGBA-2, hGBA-6 , hGBA-8 LC variable region DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQNDYSYPFTFGQGTKVEIK SEQ ID NO: 34 hGBA-2 HC variable region EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPGDADTRYAPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCARMWRGNSFDYWGQGTLVTVSS SEQ ID NO: 35 hGBA-3 HC variable region EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGASDTNYAPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCARIWRGNSFDYWGQGTLVTVSS SEQ ID NO: 36 hGBA-3 LC variable region DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQNDYSYPLTFGQGTKVEIK SEQ ID NO: 37 hGBA-4 HC variable region EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDAYTRYSPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCTRLWRGNSFDAWGQGTLVTVSS SEQ ID NO: 38 hGBA-4 LC variable region DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQNDYSYPLTFGQGTKVEIK SEQ ID NO: 39 hGBA-5 HC variable region EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGAAYTRYAPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCARLWRGNSFDYWGQGTLVTVSS SEQ ID NO: 40 hGBA-5 LC variable region DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQQDYSYPFTFGQGTKVEIK SEQ ID NO: 41 hGBA-6 HC variable region EVQLVQSGAEVKKPGESLKISCKGSGYTFTSYWIGWVRQMPGKGLEWMGNIYPGASYTRYSPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCTRQWRGNSFDYWGQGTLVTVSS SEQ ID NO: 42 hGBA-7 HC variable region EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPGEAYTRYSPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCTRLWRGNSFDYWGQGTLVTVSS SEQ ID NO: 43 hGBA-7 LC variable region DIVMTQSPDSLAVSLGERATINCKSSQSVLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQNDYSYPFTFGQGTKVEIK SEQ ID NO: 44 hGBA-8 HC variable region EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPSESYTNYAPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCTRLWRGNSFDYWGQGTLVTVSS SEQ ID NO: 45 hGBA-9 HC variable region EVQLVQSGAEVKKPGESLKISCKGSGYTFTSYWIGWVRQMPGKGLEWMGIIYPSAAYTRYAPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCTRMWRGNSFDYWGQGTLVTVSS SEQ ID NO: 46 hGBA-9LC variable region DIVMTQSPDSLAVSLGERATINCKSSQSVLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQQDYSYPFTFGQGTKVEIK SEQ ID NO: 47 IMAB362 HC full QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSDSYTNYNQKFKDKATLTVDKSSSTAYMQLSSPTSE DSAVYYCTRSWRGNSFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK SEQ ID NO: 48 IMAB362 LC full DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDL AVYYCQNDYSYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 49 hGBA-1 HC full EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPGASDTRYAPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCARLWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK SEQ ID NO: 50 hGBA-1, hGBA-2, hGBA-6, hGBA-8 LC full DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQNDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 51 hGBA-2 HC full EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPGDADTRYAPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCARMWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK SEQ ID NO: 52 hGBA-3 HC full EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGASDTNYAPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCARIWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK SEQ ID NO: 53 hGBA-3 LC full DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQNDYSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 54 hGBA-4 HC full EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDAYTRYSPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCTRLWRGNSFDAWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK SEQ ID NO: 55 hGBA-4 LC full DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQNDYSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 56 hGBA-5 HC full EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGAAYTRYAPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCARLWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK SEQ ID NO: 57 hGBA-5 LC full DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQQDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 58 hGBA-6 HC full EVQLVQSGAEVKKPGESLKISCKGSGYTFTSYWIGWVRQMPGKGLEWMGNIYPGASYTRYSPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCTRQWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK SEQ ID NO: 59 hGBA-7 HC full EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPGEAYTRYSPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCTRLWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK SEQ ID NO: 60 hGBA-7 LC full DIVMTQSPDSLAVSLGERATINCKSSQSVLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQNDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 61 hGBA-8 HC full EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPSESYTNYAPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCTRLWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK SEQ ID NO: 62 hGBA-9 HC full EVQLVQSGAEVKKPGESLKISCKGSGYTFTSYWIGWVRQMPGKGLEWMGIIYPSAAYTRYAPSFQGQVTISADKSISTAYLQWSSLKAS DTAMYYCTRMWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK SEQ ID NO: 63 hGBA-9, LC full DIVMTQSPDSLAVSLGERATINCKSSQSVLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQQDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 64 constant heavy chain-CH1 + Fc domain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 65 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC SEQ ID NO: 66 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 67 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 68 DQWSTQDLYN SEQ ID NO: 69 NNPVTAVFNYQ SEQ ID NO: 70 STQDLYNNPVTAVF SEQ ID NO: 71 TNFWMSTANMYTG SEQ ID NO: 72 ALMIVGIVLGAIGLLV SEQ ID NO: 73 RIGSMEDSAKANMTLTSGIMFIVS SEQ ID NO: 74 METDTLLLWVLLLWVPGSTGDAAQPARRARRTKLGTELGSTPVWWNSADGRMDQWSTQDLYNNPVTAVFNYQGLWRSCVRESSGFTECR GYFTLLGLPAMLQAVRAAIQHSGGRSRRARTKTHLRRGSE SEQ ID NO: 75 MDQWSTQDLYNNPVT SEQ ID NO: 76 LYNNPVTAVFNYQGL SEQ ID NO: 77 VFNYQGLWRSCVRES SEQ ID NO: 78 QGLWRSCVRESSGFT SEQ ID NO: 79 RSCVRESSGFTECRG SEQ ID NO: 80 TEDEVQSYPSKHDYV SEQ ID NO: 81 EVQSYPSKHDYV SEQ ID NO: 82 consensus including IMAB362 HC CDR1 GYXFTSYWIX X in 3.sup.rd position is T or S, X in the last position is G or N SEQ ID NO: 83 consensus including IMAB362 HC CDR2 GXIYPXXXXTXYX X in 2.sup.nd position is N or I; X in 6.sup.th position is S or G; X in 7.sup.th position is A, E or D; X in 8.sup.th position is A or S; X in 9.sup.th position is Yor D; X in 11.sup.th position is N or R; X in last position is A, N or S SEQ ID NO: 84 consensus including IMAB362 HC CDR3 XRXWRGNSFDX X in 1.sup.st position is A or T; X in 3.sup.rd position is L, M, I, S or Q; X in last position is A or Y SEQ ID NO: 85 ggctatagctttacatcatattggattgga SEQ ID NO: 86 gggaacatttaccctggggcatcggatacgcgatacgca SEQ ID NO: 87 gcgagactttggcggggggaatagcttcgactac SEQ ID NO: 88 aaaagctcccaaagcctattgaactcgggaaaccaaaagaattacttggca SEQ ID NO: 89 tgggcaagcacccgagagagc SEQ ID NO: 90 caaaacgactattcatacccattcaca SEQ ID NO: 91 ggatattcatttacaagctactggatcgga SEQ ID NO: 92 ggaaatatataccccggagacgcggacacgagatacgca SEQ ID NO: 93 gcgcggatgtggcgcggcaatagctttgactac SEQ ID NO: 94 gggatcatctatccggggggcatccgataccaactatgcg SEQ ID NO: 95 gctaggatttggcgaggaaatagctttgattat SEQ ID NO: 96 aagagctcgcaaagtttgctgaactccgggaaccaaaagaattacctggca SEQ ID NO: 97 tgggcatcaacgcgggaaagc SEQ ID NO: 98 caaaacgactactcctatccgctgacc SEQ ID NO: 99 ggatactcatttacatcatactggatagga SEQ ID NO: 100 gggattatataccccggcgacgcttacactcgatattcg SEQ ID NO: 101 acgaggctatggagggggaatagctttgatgcc SEQ ID NO: 102 aagagctcccaaagcctattgaactcgggaaatcaaaagaattatctgaca SEQ ID NO: 103 tgggcctcgacaagggagagc SEQ ID NO: 104 caaaatgactactcatacccgctgac SEQ ID NO: 105 ggatatagctttacgagctactggatcgga SEQ ID NO: 106 gggataatataccccggagcggcatacacgagatatgcg SEQ ID NO: 107 gcgagactatggcgcgggaactcatttgattac SEQ ID NO: 108 aaatcatcgcaatcattgctaaattcggggaaccaaaagaattatttggca SEQ ID NO: 109 tgggcatccacgagagaatcg SEQ ID NO: 110 caacaagattattcatacccatttaca SEQ ID NO: 111 ggatatacatttacatcttactggatcgga SEQ ID NO: 112 gggaacatttatcctggcgcgagctatacgcgctat SEQ ID NO: 113 acccggcaatggaggggcaatagctttgactac SEQ ID NO: 114 ggatattcctttacatcatactggatcggc SEQ ID NO: 115 gggaacatatatcccggagaagcctatacgagatactcg SEQ ID NO: 116 acgcgactatggaggggaaatagctttgactat SEQ ID NO: 117 aagagctcccaatcagtcctgaactctgggaatcaaaagaattacctgaca SEQ ID NO: 118 tgggcgagcacgagggagagc SEQ ID NO: 119 caaaatgattattcataccccttcaca SEQ ID NO: 120 ggatactcctttacatcatattggatcgga SEQ ID NO: 121 ggaaacatatatccgagcgaatcatatacgaactacgcg SEQ ID NO: 122 acgaggctatggagggggaatagcttcgactat SEQ ID NO: 123 ggatatacattcacgagctactggatagga SEQ ID NO: 124 ggaatcatatatccttccgcggcatatacgcgatatgcg SEQ ID NO: 125 acgcggatgtggaggggaaatagctttgattac SEQ ID NO: 126 aagagctcgcaatcggtcctgaatagcgggaaccaaaagaattatctggcc SEQ ID NO: 127 caacaagactactcatacccatttaca SEQ ID NO: 128 gaagtccaactggtccaatccggcgcggaggttaagaagcccggagaatcgctgaagatctcatgcaaagggagcggctatagctttac atcatattggattggatgggtcaggcaaatgccggggaaggggctggaatggatggggaacatttaccctggggcatcggatacgcgat acgcacctagctttcaagggcaagtcacaatttcggcggacaagagcatctcaacggcatacctgcaatggtcgagcttgaaggcatct gatactgcaatgtactactgcgcgagactttggcgggggaatagcttcgactactgggggcagggtaccctggttacggtctcgagc SEQ ID NO: 129 gacattgtgatgacgcaaagccccgattcgctggctgtatcgctaggggagcgcgctacgatcaattgcaaaagctcccaaagcctatt gaactcgggaaaccaaaagaattacttggcatggtatcaacaaaaaccggggcaaccgccgaagctgctgatctattgggcaagcaccc gagagagcggtgtcccggaccgatttagcgggagcggatcgggcaccgacttcacgctgacaataagctcattgcaagccgaggatgtg gcggtctattattgccaaaacgactattcatacccattcacattcgggcaaggtaccaaggtcgagatcaag SEQ ID NO: 130 gaagtccaactggtccaatctggagcggaagtcaagaagcctggggagagcctgaaaatttcatgcaaggggagcggatattcatttac aagctactggatcggatgggtccggcaaatgccggggaagggcttggaatggatgggaaatatataccccggagacgcggacacgagat acgcaccgagctttcaagggcaggtcaccattagcgctgataaatcgatttcaaccgcatatctgcaatggtcatcgctgaaggcctcc gacaccgcgatgtactattgcgcgcggatgtggcgcggcaatagctttgactactgggggcagggtaccctcgtcacggtctcgagc SEQ ID NO: 131 gaggtccaactggtccaaagcggcgcggaggtcaagaagccgggagaatccctgaagattagctgcaaaggctccggctatagctttac atcatattggatcggatgggtcagacaaatgccgggaaagggacttgaatggatggggatcatctatccgggggcatccgataccaact atgcgccgagcttccaagggcaggtcacgatatccgcggataaatcgattagcaccgcatatctgcaatggagctcgctgaaggcatcc gacaccgcgatgtactactgcgctaggatttggcgaggaaatagctttgattattgggggcagggtacccttgtcacggtctcgagc SEQ ID NO: 132 gacattgtcatgacgcaaagccccgactcgctggccgtctcactgggggagcgggcgacaatcaactgcaagagctcgcaaagtttgct gaactccgggaaccaaaagaattacctggcatggtatcaacaaaagccggggcaacccccgaagctgctgatatattgggcatcaacgc gggaaagcggagtcccggatagatttagcggatctggatcggggaccgacttcacgctgacgatatctagccttcaagccgaggatgtg gctgtatattattgccaaaacgactactcctatccgctgaccttcgggcaaggtaccaaggtcgagatcaag SEQ ID NO: 133 gaagtccaactagtccaaagcggagccgaagtcaagaaaccgggggagagccttaagatctcatgcaaggggagcggatactcatttac atcatactggataggatgggtcagacaaatgcccggcaaggggctggaatggatggggattatataccccggcgacgcttacactcgat attcgccatcattccaagggcaggtcacgatatcggccgataaatcgatatccacggcatacctgcaatggagctcactgaaagcatct gatacggcaatgtattattgcacgaggctatggagggggaatagctttgatgcctgggggcagggtaccctggtcacggtctcgagc SEQ ID NO: 134 gacatagttatgacacaatcgccggatagcctcgcggtcagccttggagagcgggcgacgatcaactgcaagagctcccaaagcctatt gaactcgggaaatcaaaagaattatctgacatggtatcaacaaaagccggggcaaccaccgaaactgctgatctattgggcctcgacaa gggagagcggagtcccggaccgcttctctggatcgggaagcgggactgacttcacgctgaccataagctcgctgcaagccgaggacgtc gccgtctattattgccaaaatgactactcatacccgctgacatttggccaaggtaccaaggtcgagatcaag SEQ ID NO: 135 gaggtgcaactggtacaatccggggcggaagtgaagaagccgggggaatcgctgaagataagctgcaaaggctctggatatagctttac gagctactggatcggatgggtcaggcaaatgccggggaagggactggaatggatggggataatataccccggagcggcatacacgagat atgcgccgagcttccaagggcaagtgacaataagcgcggacaaatcgattagcacggcatatctgcaatggtcctcgctgaaggcgagc gataccgcaatgtactattgcgcgagactatggcgcgggaactcatttgattactgggggcagggtaccctagtgacggtctcgagc SEQ ID NO: 136 gacattgtcatgacgcaaagcccggatagcctggctgtatcgctgggggagagagcgacgatcaactgcaaatcatcgcaatcattgct aaattcggggaaccaaaagaattatttggcatggtatcaacaaaagccggggcaaccgccgaaactgctgatttactgggcatccacga gagaatcgggagtcccggaccgatttagcggatctgggagcgggaccgatttcacgctgaccattagctcgctgcaagcggaggatgtg gcggtctattactgccaacaagattattcatacccatttacatttgggcaaggtaccaaggtcgagatcaag SEQ ID NO: 137 gaagtacaattggttcaatcgggggccgaagtcaagaagccgggggaatcgctgaagatatcctgcaaggggagcggatatacatttac atcttactggatcggatgggtcagacaaatgcccggaaaggggcttgaatggatggggaacatttatcctggcgcgagctatacgcgct atagcccgagcttccaagggcaggtcacgattagcgccgacaagagcatttcgacggcatacctgcaatggagctcgctgaaagcatcg gatacggcaatgtattactgcacccggcaatggaggggcaatagctttgactactgggggcagggtaccctagtcacggtctcgagc SEQ ID NO: 138 gaagttcaattggtccaatctggagccgaagtcaagaagcccggagaatcgctgaagattagctgcaaggggagcggatattcctttac atcatactggatcggctgggtcagacaaatgcccggaaagggactggaatggatggggaacatatatcccggagaagcctatacgagat actcgccatcatttcaaggacaggtcaccataagcgcggacaagagcataagcaccgcatacctgcaatggagctcgctgaaggcatch gacaccgccatgtattactgcacgcgactatggaggggaaatagctttgactattgggggcagggtaccttagtcacggtctcgagc SEQ ID NO: 139 gatatagtaatgactcaatcacccgatagcttggctgtgagcctgggagaaagagctacaatcaactgcaagagctcccaatcagtcct gaactctgggaatcaaaagaattacctgacatggtatcaacaaaagcccggacaaccgccgaagctgctgatctactgggcgagcacga gggagagcggagtcccggatcgattttctggctccgggagcggaaccgacttcacactgactattagctcgctgcaagcggaggacgtc gccgtctactattgccaaaatgattattcataccccttcacatttgggcaaggtaccaaggtcgagatcaag SEQ ID NO: 140 gaggtgcaactagtgcaatcgggggccgaagtgaagaaacctggggaatcgctgaagatatcatgcaaggggagcggatactcctttac atcatattggatcggatgggtcaggcaaatgccggggaaggggctggaatggatgggaaacatatatccgagcgaatcatatacgaact acgcgccgagctttcaaggacaagtcacgatatccgcggataaatcgatatcgaccgcatacctgcaatggagctcgctgaaggcttcc gacactgcgatgtattactgcacgaggctatggagggggaatagcttcgactattgggggcagggtaccctggtgacggtctcgagc SEQ ID NO: 141 gaagtccaattagtccaatcgggggccgaggtcaagaagccgggggaatcgctcaagataagctgcaagggatcgggatatacattcac gagctactggataggatgggtcaggcaaatgccggggaaggggctggaatggatgggaatcatatatccttccgcggcatatacgcgat atgcgccatcatttcaaggacaggtcacgataagcgccgacaagagcattagcaccgcatacctgcaatggtcgagccttaaggcatcg gacaccgcgatgtactactgcacgcggatgtggaggggaaatagctttgattactgggggcagggtaccctagtcacggtctcgagc SEQ ID NO: 142 gacatcgtcatgacgcaaagcccggactcgctggcggtctcgctgggggagcgggccacaataaattgcaagagctcgcaatcggtcct gaatagcgggaaccaaaagaattatctggcctggtatcaacaaaagccggggcaaccaccgaagctgctaatctattgggcgagcacga gggagagcggagtccccgatcgatttagcggatcgggaagcgggaccgatttcacgctgacgatttcgagcctacaagccgaggatgtg gcggtctattactgccaacaagactactcatacccatttacatttggacaaggtaccaaggtcgagatcaag SEQ ID NO: 143 sortase tag RLPXTGG X is any of the 20 natural amino acids SEQ ID NO: 144 sortase tag GGGGSLPXTGG X is any of the 20 natural amino acids

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