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PLASMODIUM SPOROZOITE NPDP PEPTIDES AS VACCINE AND TARGET NOVEL MALARIA VACCINES AND ANTIBODIES BINDING TO

20200093909 · 2020-03-26

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention provides a fragment of plasmodium circumsporozoite protein according to SEQ ID NO: 1, for example for use in a malaria vaccine. The present invention also provides nucleic acids encoding a fragment of plasmodium circumsporozoite protein according to SEQ ID NO: 1, compositions comprising a fragment of plasmodium circumsporozoite protein according to SEQ ID NO: 1 and antibodies binding to a fragment of plasmodium circumsporozoite protein according to SEQ ID NO: 1. The antibodies according to the present invention bind specifically to P. falciparum sporozoites and may be used in the treatment and/or prevention of malaria.

    Claims

    1. A peptide comprising or consisting of the amino acid sequence according to SEQ ID NO: 1.

    2.-3. (canceled)

    4. The peptide according to claim 1, wherein the peptide comprises or consists of an amino acid sequence according to SEQ ID NO: 23 or shares at least 72%, at least 77%, at least 83%, at least 88%, or at least 94% sequence identity with SEQ ID NO. 23.

    5.-11. (canceled)

    12. A method of preventing and/or treating malaria, the method comprising administering to a subject in need thereof a composition comprising the peptide according to claim 1.

    13. A method of eliciting an immune response in a subject, the method comprising administering to the subject a composition comprising the peptide according to claim 1.

    14.-34. (canceled)

    35. An antibody, or an antigen-binding fragment thereof, specifically binding to a peptide according to claim 1.

    36.-38. (canceled)

    39. The antibody, or the antigen-binding fragment thereof, according to claim 35, wherein the antibody, or antigen binding fragment thereof, comprises an Fc moiety.

    40. The antibody, or the antigen-binding fragment thereof, according to claim 35, wherein the variable region of the heavy chain of the antibody, or of the antigen-binding fragment thereof, is encoded by a nucleic acid comprising a gene of the VH3 gene family.

    41.-46. (canceled)

    47. The antibody, or the antigen-binding fragment thereof, according to claim 35, wherein the antibody, or the antigen-binding fragment thereof, comprises CDRH1, CDRH2, and CDRH3 amino acid sequences and CDRL1, CDRL2, and CDRL3 amino acid sequences (i) according to SEQ ID NOs: 64-68 and 70; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (ii) according to SEQ ID NOs: 64-67 and 69-70; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (iii) according to SEQ ID NOs: 82-86 and 88; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (iv) according to SEQ ID NOs: 82-85 and 87-88; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (v) according to SEQ ID NOs: 136-140 and 142; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (vi) according to SEQ ID NOs: 136-139 and 141-142; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (vii) according to SEQ ID NOs: 154-158 and 160; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (viii) according to SEQ ID NOs: 154-157 and 159-160; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (ix) according to SEQ ID NOs: 206-210 and 212; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (x) according to SEQ ID NOs: 206-209 and 211-212; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xi) according to SEQ ID NOs: 224-228 and 230; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xii) according to SEQ ID NOs: 224-227 and 229-230; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xiii) according to SEQ ID NOs: 258-262 and 264; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xiv) according to SEQ ID NOs: 258-261 and 263-264; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xv) according to SEQ ID NOs: 276-280 and 282; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xvi) according to SEQ ID NOs: 276-279 and 281-282; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xvii) according to SEQ ID NOs: 294-298 and 300; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xviii) according to SEQ ID NOs: 294-297 and 299-300; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity.

    48. (canceled)

    49. The antibody, or the antigen-binding fragment thereof, according to claim 35, wherein the antibody, or the antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 71 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 72 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (ii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 89 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 90 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (iii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 143 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 144 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (iv) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 161 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 162 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (v) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 213 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 214 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (vi) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 231 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 232 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (vii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 265 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 266 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (viii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 283 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 284 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (ix) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 301 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 302 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity.

    50. (canceled)

    51. An antibody, or an antigen-binding fragment thereof, that is capable of binding to a P. falciparum sporozoite.

    52. The antibody, or an antigen-binding fragment thereof, according to claim 51, wherein the antibody, or the antigen-binding fragment thereof, is capable of binding to a Plasmodium circumsporozoite protein according to SEQ ID NO: 24.

    53.-56. (canceled)

    57. The antibody, or the antigen-binding fragment thereof, according to claim 51, wherein the antibody, or the antigen-binding fragment thereof, comprises CDRH1, CDRH2, and CDRH3 amino acid sequences and CDRL1, CDRL2, and CDRL3 amino acid sequences (i) according to SEQ ID NOs: 64-68 and 70; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (ii) according to SEQ ID NOs: 64-67 and 69-70; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (iii) according to SEQ ID NOs: 82-86 and 88; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (iv) according to SEQ ID NOs: 82-85 and 87-88; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (v) according to SEQ ID NOs: 136-140 and 142; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (vi) according to SEQ ID NOs: 136-139 and 141-142; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (vii) according to SEQ ID NOs: 154-158 and 160; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (viii) according to SEQ ID NOs: 154-157 and 159-160; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (ix) according to SEQ ID NOs: 206-210 and 212; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (x) according to SEQ ID NOs: 206-209 and 211-212; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xi) according to SEQ ID NOs: 224-228 and 230; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xii) according to SEQ ID NOs: 224-227 and 229-230; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xiii) according to SEQ ID NOs: 258-262 and 264; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xiv) according to SEQ ID NOs: 258-261 and 263-264; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xv) according to SEQ ID NOs: 276-280 and 282; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xvi) according to SEQ ID NOs: 276-279 and 281-282; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xvii) according to SEQ ID NOs: 294-298 and 300; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xviii) according to SEQ ID NOs: 294-297 and 299-300; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xix) according to SEQ ID NOs: 28-32 and 34; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xx) according to SEQ ID NOs: 28-31 and 33-34; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xxi) according to SEQ ID NOs: 46-50 and 52; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xxii) according to SEQ ID NOs: 46-49 and 51-52; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xxiii) according to SEQ ID NOs: 100-104 and 106; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xxiv) according to SEQ ID NOs: 100-103 and 105-106; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xxv) according to SEQ ID NOs: 118-122 and 124; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xxvi) according to SEQ ID NOs: 118-121 and 123-124; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xxvii) according to SEQ ID NOs: 172-176 and 178; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xxviii) according to SEQ ID NOs: 172-177; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xxix) according to SEQ ID NOs: 188-192 and 194; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xxx) according to SEQ ID NOs: 188-191 and 193-194; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xxxi) according to SEQ ID NOs: 242-247; or functional sequence variants thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity.

    58. (canceled)

    59. The antibody, or the antigen-binding fragment thereof, according to claim 51, wherein the antibody, or the antigen-binding fragment thereof, comprises (i) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 71 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 72 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (ii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 89 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 90 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (iii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 143 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 144 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (iv) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 161 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 162 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (v) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 213 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 214 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (vi) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 231 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 232 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (vii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 265 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 266 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (viii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 283 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 284 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (ix) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 301 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 302 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (x) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 35 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 36 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xi) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 53 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 54 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 107 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 108 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xiii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 125 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 126 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xiv) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 178 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 179 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xv) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 195 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 196 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or (xvi) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 248 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 249 or a functional sequence variant thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity.

    60. (canceled)

    61. The antibody, or the antigen-binding fragment thereof, according to claim 51, wherein the antibody, or the antigen-binding fragment thereof, is a purified antibody, a single chain antibody, Fab, Fab, F(ab)2, Fv or scFv.

    62.-64. (canceled)

    65. A nucleic acid molecule comprising a polynucleotide encoding the antibody, or the antigen-binding fragment thereof, according to claim 51.

    66. (canceled)

    67. A vector comprising the nucleic acid molecule according to claim 65.

    68. A cell expressing the antibody, or the antigen-binding fragment thereof, according to claim 51; or comprising a vector comprising a nucleic acid molecule comprising a polynucleotide encoding said antibody, or antigen-binding fragment thereof.

    69. A pharmaceutical composition comprising: (i) the antibody, or the antigen binding fragment thereof, according to claim 51, (ii) a nucleic acid molecule comprising a polynucleotide encoding the antibody, or the antigen-binding fragment thereof, of (i), (iii) a vector comprising the nucleic acid molecule of (ii), and/or (iv) a cell according expressing the antibody, or the antigen-binding fragment thereof, of (i); or comprising the vector of (iii).

    70.-71. (canceled)

    72. A method for monitoring the quality of an anti-malaria vaccine, the method comprising contacting the vaccine with the antibody, or the antigen-binding fragment thereof, according to claim 51 and determining whether the vaccine contains a specific epitope of the antibody or antigen-binding fragment in the correct conformation.

    73. A method of diagnosing malaria in a subject, the method comprising contacting a sample from the subject with the antibody, or the antigen-binding fragment thereof, according to claim 51 or of a nucleic acid molecule comprising a polynucleotide encoding said antibody, or antigen binding fragment thereof, and detecting whether an antibody-antigen complex has been formed.

    74. A kit of parts comprising: (i) at least one antibody, or the antigen-binding fragment thereof, according to claim 51, (ii) at least one nucleic acid molecule comprising a polynucleotide encoding the antibody, or the antigen-binding fragment thereof, of (i), (iii) at least one vector comprising the nucleic acid molecule of (ii), (iv) at least one cell expressing the antibody, or the antigen-binding fragment thereof, of (i); or comprising the vector of (iii), or (v) at least one pharmaceutical composition comprising the antibody, or the antigen-binding fragment thereof, of (i), the nucleic acid molecule of (ii) the vector of (iii), and/or the cell of (iv).

    75. A method of preventing and/or treating malaria in a subject, wherein the method comprises administering to a subject in need thereof: (i) the antibody, or the antigen-binding fragment thereof, according to claim 51, (ii) the nucleic acid molecule comprising a polynucleotide encoding the antibody, or the antigen-binding fragment thereof, of (i), (iii) the vector comprising the nucleic acid molecule of (ii), (iv) the cell expressing the antibody, or the antigen-binding fragment thereof, of (i); or comprising the vector of (iii), or (v) the pharmaceutical composition comprising the antibody, or the antigen-binding fragment thereof, of (i), the nucleic acid molecule of (ii), the vector of (iii), and/or the cell of (iv).

    Description

    BRIEF DESCRIPTION OF THE FIGURES

    [0495] In the following a brief description of the appended figures will be given. The figures are intended to illustrate the present invention in more detail. However, they are not intended to limit the subject matter of the invention in any way.

    [0496] FIG. 1 shows for Example 1 exemplary staining of P. falciparum sporozoites by monoclonal antibodies MGG1, MGG2, MGG3, MGG4 and MGG8 (each of them based on VH/VL genes of antibodies isolated from Donor G) and by control antibody BKC3. The sporozoites were labeled with SYBR Green I and incubated with the monoclonal antibodies. Antibody detection was conducted with anti-human IgG conjugated to a fluorophore.

    [0497] FIG. 2 shows for Example 2 (A) a schematic overview over the assay used and (B) the inhibition of sporozoite traversal and invasion (ISTI) of hepatocytes by human monoclonal antibodies MGG1, MGG2, MGG3, MGG4, MGG8, MGH1, MGH2, MGH3 and for control antibody 2A10.

    [0498] FIG. 3 shows for Example 2 (A) a schematic overview over the experimental design of the in vivo humanized mouse model of sporozoite invasion and (B) the in vivo reduction of sporozoites by the selected antibodies MGG4, MGG8, MGH1, MGH2 and MGH3.

    [0499] FIG. 4 shows for Example 3 (A) a schematic overview over P. falciparum circumsporozoite protein. SP, signal peptide; RI, region I. (B) Sequence of PfCSP (isolate NF54, Uniprot accession number P19597; SEQ ID NO: 24). The functionally important region I is shown in bold. (C Sequence of CSP peptides that were tested for binding by antibodies: 22-110-peptide (SEQ ID NO: 27), NPDP-peptide (SEQ ID NO: 23), and NANP-peptide (SEQ ID NO: 26). Amino acids belonging to region I are shown in bold.

    [0500] FIG. 5 shows for Example 3 the binding of monoclonal antibodies to different peptides by ELISA. Different dilutions of the antibodies were tested for binding to the CSP peptides (sequences are shown in FIG. 4) and EC50 values were calculated for each antibody. The antibodies that were tested in the in vivo mouse model are boxed. The two antibodies that showed the best protection in this model (MGG4 and MGH2) showed good binding to the NPDP peptide and used VH3-30. All of the other antibodies that bound strongly to NPDP (with an EC50<100 ng/mL) also used VH3-30. One antibody, MGV3, bound relatively weakly to NPDP and 22-110 but not to the NANP repeat region.

    [0501] FIG. 6 shows for Example 4 the binding of monoclonal antibodies MGV3, MGG4, MGU5 and MGG1 to overlapping peptides from CSP. Only the region of CSP that showed binding by the monoclonal antibodies are shown.

    [0502] FIG. 7 shows for Example 5 the inhibition of binding of MGV3 by different monoclonal antibodies. Inhibition of binding is calculated by the median fluorescence intensity (FI) of IgG binding to sporozoites. MGU3 is an antibody that binds to the C-terminus of CSP, MGV3 binds to the NPDP region at the N-terminus, and the remaining antibodies bind to the repeat region of CSP.

    [0503] FIG. 8 shows for Example 6 the identification of antibodies binding to a C-terminal binding site in CSP. Briefly, C-terminal peptide 282-383 was coated at a concentration of 1 g/ml, and the B cell supernatants were tested from a 1/3 dilution to a 1/648 dilution. MGU3 can bind to the peptide, while MGU1, MGU5 and MGU8 are shown as examples of antibodies that cannot bind to the peptide.

    EXAMPLES

    [0504] In the following, particular examples illustrating various embodiments and aspects of the invention are presented. However, the present invention shall not to be limited in scope by the specific embodiments described herein. The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. The present invention, however, is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the invention only, and methods which are functionally equivalent are within the scope of the invention. Indeed, various modifications of the invention in addition to those described herein will become readily apparent to those skilled in the art from the foregoing description, accompanying figures and the examples below. All such modifications fall within the scope of the appended claims.

    Example 1: Isolation of Human Monoclonal Antibodies that Bind to P. falciparum Sporozoites

    [0505] Four Tanzanian donors (identified as donors G, H, U and V) who were protected from malaria challenge were selected for isolation of human monoclonal antibodies. To this end, peripheral blood mononuclear cells (PBMCs) were isolated from blood samples of the four donors. IgG memory B cells were isolated from frozen peripheral blood mononuclear cells (PBMCs) by magnetic cell sorting. The B cells were incubated with 0.5 g/mL of anti-CD19-PECy7 antibodies for 20 min on ice and then incubated with mouse anti-PE microbeads for 30 min on ice. The cells were then stained with 3.75 g/mL goat Alexa Fluor 647-conjugated anti-human IgG for 20 min on ice and sorted by FACS. As previously described in Traggiai et al. (2004) Nat Med. 10, 871-875, sorted B cells were immortalized with Epstein-Barr virus (EBV) and plated in single cell cultures in the presence of CpG and irradiated PBMC-feeder cells. After 14 days, culture supernatants were screened using a high-throughput flow cytometer for their capacity to stain sporozoites. In this assay, the sporozoites were labelled with 6.25SYBR Green I and incubated with the B cell culture supernatants at a 1/2 dilution for 30 min at room temperature. Without any washing step, the sporozoites were then incubated with 1 g/mL of goat Alexa Fluor 647-conjugated anti-human IgG for 1 h at 4 C. and analyzed by flow cytometry.

    [0506] For sporozoite staining using recombinant monoclonal antibodies, the sporozoites were stained with 6.25SYBR Green I and incubated with the monoclonal antibodies for 30 min at room temperature. The sporozoites were then washed once and stained with 2.5 g/mL of goat Alexa Fluor 647-conjugated anti-human IgG for 30 min at room temperature and analyzed by flow cytometry.

    [0507] An example of sporozoite staining is shown in FIG. 1. FIG. 1 shows exemplary staining of P. falciparum sporozoites by monoclonal antibodies MGG1, MGG2, MGG3, MGG4 and MGG5 (each of them based on VH/VL genes of antibodies isolated from Donor G) and by a negative control antibody.

    [0508] Positive cultures were expanded and the VH and VL genes from individual clones were sequenced and cloned into human IgG1, igK and IgA expression vectors (kindly provided by Michel Nussenzweig, Rockefeller University, New York, US) essentially as described (Tiller T, Meffre E, Yurasov S, Tsuiji M, Nussenzweig M C, Wardemann H (2008) Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J Immunol Methods 329: 112-124) and expressed by transient transfection of Expi293F Cells using polyethylenimine (PEI).

    [0509] Table 5 below shows exemplary human monoclonal antibodies that were found to bind to P. falciparum sporozoites, along with their VH and VL usage (see Tables 1 and 2 for SEQ ID NOs):

    TABLE-US-00042 Heavy chain Light chain VH JH VL JL Donor G MGG1 VH3-20 JH6 VL1-51 JL3 MGG2 VH3-74 JH5 VL7-46 JL2/JL3 MGG3 VH3-30 JH2 VK2-29 JK1 MGG4 VH3-30 JH3 VK4-1 JK4 MGG8 VH3-73 JH5 VK2D-29 JK1 Donor H MGH1 VH1-2 JH4 VK2-30 JK2 MGH2 VH3-30 JH4 VK2-30 JK1 MGH3 VH3-21 JH4 VK1-47 JK3 Donor U MGU1 VH3-30 JH3 VL4-69 JL3 MGU3 VH3-48 JH4 VK1-33 JK4 MGU5 VH3-30 JH3 VK1-33 JK4 MGU8 VH3-30 JH3 VK1-33 JK1/JK4 MGU10 VH3-30 JH3 VL4-69 JL3 MGU11 VH3-33 JH3 VK2-30 JK3 MGU12 VH3-30 JH3 VK1-5 JK1 Donor V MGV3 VH3-66 JH6 VK3-20 JK2

    Example 2: Several Monoclonal Antibodies Show Potent In Vitro and In Vivo Anti-Sporozoite Function

    [0510] During the liver stage of the Plasmodium life cycle, sporozoites often traverse hepatocytes before productive invasion of target hepatocytes. Exemplary monoclonal antibodies MGG1, MGG2, MGG3, MGG4, MGG8, MGH1, MGH2 and MGH3 (see Tables 1 and 2 for SEQ ID NOs) were tested in vitro for their ability to inhibit sporozoite traversal and invasion of hepatocytes. To this end, a quantitative flow-cytometry-based assay was used, which is described in Kaushansky A, Rezakhani N, Mann H, Kappe S H, 2012: Development of a quantitative flow cytometry-based assay to assess infection by Plasmodium falciparum sporozoites. Mol Biochem Parasitol. 183(1):100-3. A schematic overview over this assay is shown in FIG. 2A. Briefly, in this assay, the hepatocyte HC04 cell line was infected with P. falciparum sporozoites in the presence of FITC-dextran. Sporozoite traversal was measured by the uptake of FITC-dextran, which can enter hepatocytes with membranes injured during traversal. Sporozoite invasion was measured by staining of sporozoites in hepatocytes with an anti-circumsporozoite protein (anti-CSP) antibody. As a control, murine monoclonal antibody 2A10, which targets the NANP repeat region of the circumsporozoite protein (Zavala F. et al., 1983, J. Exp. Med. 157: 1947-1957; Wirtz R. A. et al, 1987, Bulletin of the World Health Organization 65(1): 39-45), was used.

    [0511] Results are shown in FIG. 2B. Here, the percentage of sporozoite invasion or traversal in the presence of a monoclonal antibody of interest relative to when irrelevant IgG is added is measured. A low percentage signifies good inhibition by the monoclonal antibody. In this assay, MGG4, MGH1, MGH2 and MGH3 showed the highest inhibition of sporozoite invasion. Hence, these antibodies, along with MGG8, were selected for further testing.

    [0512] Selected monoclonal antibodies were then tested in the FRG huHEP liver-chimeric mouse model, essentially as described in Sack et al. (Sack et al., 2014, Infection and Immunity 82(2): 808-817. Model for in vivo assessment of humoral protection against malaria sporozoite challenge by passive transfer of monoclonal antibodies and immune serum) and, in particular, also in Vaughan et al. (Vaughan et al., 2012, J Clin Invest 122, 3618-3628. The FRG huHEP liver-chimeric mouse model measures sporozoite invasion and liver-stage parasite multiplication in mice with humanized livers). A schematic overview over the experimental design is shown in FIG. 3A. In this model, the antibodies were first injected into mice, which were then infected by P. falciparum sporozoites by mosquito bite 16-24 h later. Liver parasite burden was then detected by imaging six days after infection.

    [0513] Results are shown in FIG. 3B. The liver burden in mice injected with a monoclonal antibody of interest was measured and calculated as a percentage of the liver burden in mice injected with non-specific IgG. The largest reduction of liver burden was observed in mice injected with antibody MGG4 or MGH2 (showing only 2.5% and 5.5% liver burden as compared to negative control mice, respectively).

    Example 3: Potent Monoclonal Antibodies Show Distinct Patterns of Binding to CSP and Use VH3-30

    [0514] Plasmodium circumsporozoite protein (CSP) is an immunodominant protein that coats the entire sporozoite surface and that plays an important role in sporozoite function. As shown in FIG. 4A, this protein contains an N-terminal segment starting with a signal peptide (SP) and ending with Region I (RI). Region I is a pentapeptide (KLKQP; SEQ ID NO: 25) that is involved in binding to hepatocytes and mosquito salivary glands. In CSP, region I is followed by an NANP repeat region that is the immunodominant site for antibodies and a C-terminal thrombospondin-like domain that contains T cell epitopes (FIG. 4A). FIG. 48 shows an exemplary sequence of the circumsporozoite protein of P. falciparum isolate NF54 (SEQ ID NO: 24).

    [0515] An antigen-agnostic approach as described in Example 1 was used to identify any antibody that can bind to the sporozoite surface. In that approach, it was found that all of the antibodies shown in Table 5 bound to CSP, confirming the immunodominance of this protein (data not shown).

    [0516] Next, the binding of the antibodies to peptides from different parts of CSP as shown in FIG. 4C was tested. In this assay, half-area 96-well ELISA plates were coated with whole recombinant CSP (SEQ ID NO: 24; 1 g/mL), NANP-peptide (SEQ ID NO: 26; 2 g/mL), NPDP-peptide (SEQ ID NO: 23; 5 g/mL) or 22-110-peptide (SEQ ID NO: 27; 1 g/mL) overnight at 4 C. The plates were blocked with 1% bovine serum albumin in PBS and incubated with titrated antibodies, followed by AP-conjugated goat anti-human IgG. The plates were then washed, substrate (p-NPP) is added and the plates were read at 405 nm.

    [0517] Results are shown in FIG. 5 with the antibodies that were tested in the in vivo mouse model shown in a box. Interestingly, out of the five antibodies tested in the in vivo assay (MGG4, MGG8, MGH1, MGH2, MGH3), the two antibodies that showed the best function in the in vivo assay (MGG4, MGH2, see Example 2) bound well to the NPDP-peptide (SEQ ID NO: 23), i.e. in CSP at the junction between the N-terminus and the NANP repeat region. The other three antibodies tested in the in vivo assay (MGG8, MGH1, MGH3) showed only poor or negligible binding to this region. In contrast, the affinity of binding to a peptide containing only the repeat region or to whole CSP did not distinguish between the antibodies with different functional capacity in the in vivo assay.

    [0518] Interestingly, the CSP region to which the most potent antibodies MGG4 and MGH2 bind to, i.e. the junction between the N-terminus and the NANP repeat region, is not included in the leading malaria vaccine RTS,S. Rather, RTS,S incorporates the C-terminal half of the NANP repeat region and the C-terminal domain. The present data suggest that the junction between the N-terminus and the NANP repeat region is an important target of antibodies from protected individuals that show the most potent function in an in vivo model. Without being bound to any theory, the inventors assume that this region may be important due to its proximity to Region I, which is thought to be a target of parasite proteases that cleave the N-terminus of CSP during invasion of hepatocytes (Coppi et al. (2011) J Exp Med208, 341-356; Coppi et al. (2005) J Exp Med201, 27-33).

    [0519] Further antibodies, which bound well to the NPDP-peptide (SEQ ID NO: 23) include MGG3, MGU5, MGU8 and MGU12.

    [0520] Furthermore, all of the antibodies that bound well to the NPDP-peptide (MGG4, MGH2, MGG3, MGU5, MGU8 and MGU12) used VH3-30, suggesting that the usage of this VH is preferential for binding to this key region.

    [0521] One antibody, MGV3, was found to bind relatively weakly to the NPDP-peptide and to the 22-110-peptide, but not to the NANP-peptide. This indicates that antibody MGV3 recognizes the N-terminus of CSP and the NPDP-region, but not to the NANP repeat region. Accordingly, MGV3 appears to bind slightly N-terminal as compared to the binding site of MGG4, MGH2, MGG3, MGU5, MGU8 and MGU12.

    [0522] Other antibodies were found to bind well to the NANP-peptide, but weakly, if at all, to the NPDP-peptide and the 22-110-peptide, thereby indicating a binding site in the (middle of the) NANP-repeat region. Such antibodies include MGU11, MGU1, MGH3, MGH1, MGG8 and, to a lesser extent, MGG2 and MGG1.

    [0523] Only antibody MGU3 showed no binding to any of the CSP-peptides used (22-110, NPDP-peptide, NANP-peptide), although it showed binding to the entire PfCSP. This may indicate a binding site for MGU3, which is located C-terminal of the NANP-repeat in CSP.

    Example 4: Fine Epitope Mapping of Monoclonal Antibodies

    [0524] To identify the precise region of CSP targeted by the monoclonal antibodies, linear epitope mappings of selected antibodies were performed against CSP (PEPperMAP by PEPperPRINT GmbH, Heidelberg, Germany). To this end, antibodies MGV3, MGG4, MGU5 and MGG1 were tested for binding to an array of 15-aa CSP peptides (shifted by a single amino acid) covering the entire protein (FIG. 6). Briefly, the sequence of circumsporozoite protein (CSP) was elongated by neutral GSGSGSG linkers (SEQ ID NO: 28) at the C- and N-terminus to avoid truncated peptides. The elongated antigen sequence was translated into linear 15 amino acid peptides with a peptide-peptide overlap of 14 amino acids (FIG. 6). The resulting CSP peptide microarrays contained 457 different peptides printed in duplicate (914 peptide spots), additional custom control peptides (2 spots each control), c-Myc controls (2 spots) and a frame of HA control peptides (82 spots). The CSP peptide microarrays were incubated with the antibody samples at concentrations 1 g/ml, 10 g/ml and 100 g/ml in incubation buffer followed by staining with secondary and control antibodies as well as read-out with a LI-COR Odyssey Imaging System. Quantification of spot intensities and peptide annotation were done with PepSlide Analyzer.

    [0525] Results are shown in FIG. 6. It was found that MGV3, a peptide that recognizes the N-terminus and the NPDP peptide (FIG. 5) but not the NANP repeat region, appears to bind to a NPDP motif, whereas MGG4 and MGU5 are able to bind to the first NANP repeat close to this region.

    Example 5: Inhibition of Binding of MGV3 to Intact Sporozoites

    [0526] Next, it was tested whether monoclonal antibodies MGG1, MGG4, MGU5 and MGU3 could inhibit the binding of MGV3 to intact sporozoites in a blocking-of-binding (BOB) assay. In this assay, sporozoites were stained with 3.3SYBR Green I and incubated with titrated monoclonal antibodies (from 0.1 to 100 g/mL) for 20 min at room temperature. Without washing, the sporozoites were subsequently incubated with 10 g/mL of biotin-labeled MGV3 for 20 min at room temperature. The sporozoites were washed twice, incubated with streptavidin conjugated to Alexa Fluor 647 for 20 min at room temperature, and analyzed by flow cytometry. The decrease in median fluorescence intensity (median FI) in the Alexa Fluor 647 channel was used to measure the degree of inhibition of binding of biotinylated MGV3.

    [0527] Results are shown in FIG. 7. It was found that MGG4 and MGU5, which bind well to the NPDP peptide and could bind to the first NANP repeat based on the peptide array results (FIG. 6), could inhibit binding by MGV3, while MGG1, which bound further away from the N-terminus, could not efficiently inhibit binding. This confirms the results of Examples 3 and 4 that antibodies binding to the NDPD-peptide, such as MGG4 and MGU5, bind to a more N-terminal region of CSP than those antibodies, which do not bind to the NDPD-peptide, such as MGG1 or MGU3. In summary, the data suggest that antibodies binding to the NDPD-peptide, such as MGG4 and MGU5, have potent functional activity due to their ability to bind closer to the N-terminus.

    [0528] As a note, unlabelled MGV3 could not inhibit binding as overall this antibody bound with low affinity to sporozoites and the concentration of biotinylated MGV3 used was much below its saturation point.

    Example 6: Identification of Antibodies Binding to a C-Terminal Binding Site in CSP

    [0529] Since the data of Example 3 (FIG. 5) suggest that of all antibodies tested only antibody MGU3 binds to a C-terminal binding site in CSP, different antibodies were tested for their ability to bind to the C-terminus of CSP.

    [0530] To this end, essentially the same experiment as described in Example 3 was performed with the antibodies shown in Table 1. However, instead of the CSP-test-peptides described in Example 3 (i.e., 22-110-peptide, NPDP-peptide, NANP-peptide) in the present experiment C-terminal peptide 282-383 (SEQ ID NO: 312) was used. Briefly, the C-terminal peptide 282-383 was coated at a concentration of 1 g/ml, and the B cell supernatants were tested from a 1/3 dilution to a 1/648 dilution.

    [0531] Results for selected antibodies MGU1, MGU3, MGU5 and MGU8 are shown in FIG. 8 (data of the other antibodies of Table 1 not shown). As expected from the results of Examples 3 and 5, only antibody MGU3 bound to C-terminal peptide 282-383, whereas all other antibodies tested did not bind to the C-terminus of CSP. These results confirm that antibody MGU3 binds to the C-terminus of CSP, whereas the other antibodies do not bind to that region of CSP.

    TABLE-US-00043 TABLE OF SEQUENCES AND SEQ ID NUMBERS (SEQUENCE LISTING): SEQ ID NO Sequence Remarks SEQ ID NO: 1 NPDP CSP epitope SEQ ID NO: 2 NPDPN CSP epitope SEQ ID NO: 3 NPDPNA CSP epitope SEQ ID NO: 4 NPDPNAN CSP epitope SEQ ID NO: 5 NPDPNANP CSP epitope SEQ ID NO: 6 NPDPNANPN CSP epitope SEQ ID NO: 7 GNPDPNANP CSP epitope SEQ ID NO: 8 GNPDPNANPN CSP epitope SEQ ID NO: 9 DGNPDPNANP CSP epitope SEQ ID NO: 10 NPDPNANPNK CSP epitope SEQ ID NO: 11 DGNPDPNANPN CSP epitope SEQ ID NO: 12 GNPDPNANPNK CSP epitope SEQ ID NO: 13 DGNPDPNANPNK CSP epitope SEQ ID NO: 14 ADGNPDPNANPN CSP epitope SEQ ID NO: 15 QPADGNPDPNANPNK CSP epitope SEQ ID NO: 16 ADGNPDPNANPNK CSP epitope SEQ ID NO: 17 PADGNPDPNANPNK CSP epitope SEQ ID NO: 18 ADGNPDPNANPNKN CSP epitope SEQ ID NO: 19 PADGNPDPNANPNKN CSP epitope SEQ ID NO: 20 QPADGNPDPNANPNKN CSP epitope SEQ ID NO: 21 PADGNPDPNANPNKNN CSP epitope SEQ ID NO: 22 QPADGNPDPNANPNKNN CSP epitope SEQ ID NO: 23 KQPADGNPDPNANPNKNN NPDP-peptide SEQ ID NO: 24 MMRKLAILSVSSFLFVEALFQEYQCYGSSSNTRVL PfCSP NELNYDNAGTNLYNELEMNYYGKQENWYSLK KNSRSLGENDDGNNEDNEKLRKPKHKKLKQPA DGNPDPNANPNVDPNANPNVDPNANPNVDP NANPNANPNANPNANPNANPNANPNANPNA NPNANPNANPNANPNANPNANPNANPNANP NANPNANPNVDPNANPNANPNANPNANPNA NPNANPNANPNANPNANPNANPNANPNANP NANPNANPNANPNANPNANPNANPNKNNQ GNGQGHNMPNDPNRNVDENANANSAVKNN NNEEPSDKHIKEYLNKIQNSLSTEWSPCSVTCGN GIQVRIKPGSANKPKDELDYANDIEKKICKMEKC SSVFNVVNSSIGLIMVLSFLFLN SEQ ID NO: 25 KLKQP CSP region I SEQ ID NO: 26 NANPNANPNANPNANPNANPNANPNANPNA NANP-peptide NPNANPNANP SEQ ID NO: 27 EYQCYGSSSNTRVLNELNYDNAGTNLYNELEM 22-110-peptide NYYGKQENWYSLKKNSRSLGENDDGNNEDNE KLRKPKHKKLKQPADGNPDPNANPNV MGG1 SEQ ID NO: 28 GFTFDDYA CDRH1 aa SEQ ID NO: 29 INWNGGST CDRH2 aa SEQ ID NO: 30 ARLGRAAREYYYYYMDV CDRH3 aa SEQ ID NO: 31 SSNIGNNY CDRL1 aa SEQ ID NO: 32 DNN CDRL2 aa SEQ ID NO: 33 LIYDNNKRP CDRL2 long aa SEQ ID NO: 34 GTWDSSLSAGV CDRL3 aa SEQ ID NO: 35 EVQLVESGGGVVRPGGSLRLSCAASGFTFDDYA VH aa MSWVRQAPGKGLEWVSGINWNGGSTGYADS VKGRFTISRDNAKNSLYLQMNSLRAEDTALYHC ARLGRAAREYYYYYMDVWGKGTTVTVSS SEQ ID NO: 36 QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYV VL aa SWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKS GTSATLGITGLQTGDEADYYCGTWDSSLSAGVF GGGTKLTVLGQ SEQ ID NO: 37 ggattcacctttgatgattatgcc CDRH1 nuc SEQ ID NO: 38 attaattggaatggtggtagcaca CDRH2 nuc SEQ ID NO: 39 gcgagacttgggagagcagcccgtgagtactactactactacatg CDRH3 nuc gacgtc SEQ ID NO: 40 agctccaacattgggaataattat CDRL1 nuc SEQ ID NO: 41 gacaataat CDRL2 nuc SEQ ID NO: 42 ctcatttatgacaataataagcgaccc CDRL2 long nuc SEQ ID NO: 43 ggcacatgggatagcagcctgagtgctggagtg CDRL3 nuc SEQ ID NO: 44 gaggtgcagctggtggagtctgggggaggtgtggtacggcctgggg VH nuc ggtccctgagactctcctgtgcagcctctggattcacctttgatgatta tgccatgagctgggtccgccaagctccagggaaggggctggagtg ggtctctggtattaattggaatggtggtagcacaggttatgcagactct gtgaagggccgattcaccatctccagagacaacgccaagaactc cctgtatctgcaaatgaacagtctgagagccgaggacacggccttg tatcactgtgcgagacttgggagagcagcccgtgagtactactacta ctacatggacgtctggggcaaagggaccacggtcaccgtctcctca SEQ ID NO: 45 cagtctgtgttgacgcagccgccctcagtgtctgcggccccaggac VL nuc agaaggtcaccatctcctgctctggaagcagctccaacattgggaa taattatgtatcctggtaccagcagctcccaggaacagcccccaaa ctcctcatttatgacaataataagcgaccctcagggattcctgaccg attctctggctccaagtctggcacgtcagccaccctgggcatcacc ggactccagactggggacgaggccgattattactgcggcacatgg gatagcagcctgagtgctggagtgttcggcggagggaccaagctg accgtcctaggtcag MGG2 SEQ ID NO: 46 GFTLNNYW CDRH1 aa SEQ ID NO: 47 INIDGSTT CDRH2 aa SEQ ID NO: 48 AKGSIKAGGFWSGYSNWFDP CDRH3 aa SEQ ID NO: 49 PGPVTSGHY CDRL1 aa SEQ ID NO: 50 DTS CDRL2 aa SEQ ID NO: 51 LIYDTSNKH CDRL2 long aa SEQ ID NO: 52 LLSYGGAPV CDRL3 aa SEQ ID NO: 53 EVQLVESGGGLVQPGGSLRLSCAASGFTLNNY VH aa WMHWVRQAPGKGLVWVAHINIDGSTTTYADS VKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYC AKGSIKAGGFWSGYSNWFDPWGQGTLVTVSS SEQ ID NO: 54 QAVVTQEPSLTVSPGGTVTLTCDSDPGPVTSGH VL aa YPYWFQQKPGQVPRTLIYDTSNKHSWTPARFS GSLLGGKAALTLSGAQPEDEADYYCLLSYGGAP VFGGGTKLTVL SEQ ID NO: 55 ggattcaccctcaataactactgg CDRH1 nuc SEQ ID NO: 56 attaatatcgatggcagtactaca CDRH2 nuc SEQ ID NO: 57 gcaaagggaagtattaaggccggaggtttttggagtggttactccaa CDRH3 nuc ctggttcgacccc SEQ ID NO: 58 cctggacctgtcaccagtggtcattat CDRL1 nuc SEQ ID NO: 59 gataccagc CDRL2 nuc SEQ ID NO: 60 ctgatttatgataccagcaacaaacac CDRL2 long nuc SEQ ID NO: 61 ctgctctcgtatggtggtgcccctgta CDRL3 nuc SEQ ID NO: 62 gaggtgcagctggtggagtccgggggaggcttagttcagccgggg VH nuc gggtccctgagactctcctgtgcagcctctggattcaccctcaataa ctactggatgcactgggtccgccaagctccagggaaggggctggt ctgggtcgcacatattaatatcgatggcagtactacaacctacgcgg actccgtgaagggccgattcaccatctccagagacaacgccaag aacacgctgtatctgcaaatgaacagtctgagagccgaggacacg gctgtctattactgtgcaaagggaagtattaaggccggaggtttttgg agtggttactccaactggttcgacccctggggccagggaaccctgg tcaccgtctcctcag SEQ ID NO: 63 caggctgtggtgactcaggagccctcactgactgtgtccccaggag VL nuc ggacagtcactctcacctgtgactccgaccctggacctgtcaccag tggtcattatccctactggttccagcagaagcctggccaagtcccc aggacactgatttatgataccagcaacaaacactcctggacacctg cccggttttcaggctccctccttgggggcaaagctgccctgaccctt tcgggtgcgcagcctgaggatgaggctgactattactgcctgctctc gtatggtggtgcccctgtattcggcggagggaccaaactgaccgtc ctaa MGG3 SEQ ID NO: 64 GFTFSTFG CDRH1 aa SEQ ID NO: 65 IWYDGSSK CDRH2 aa SEQ ID NO: 66 VKVGANWGWRYFDL CDRH3 aa SEQ ID NO: 67 QSLLHSDGNTY CDRL1 aa SEQ ID NO: 68 EVS CDRL2 aa SEQ ID NO: 69 LIYEVSSRF CDRL2 long aa SEQ ID NO: 70 MQGIHSWT CDRL3 aa SEQ ID NO: 71 QEQLVESGGGVVQPGKSLRLSCAASGFTFSTFG VH aa MHWVRQAPGKGLEWVAVIWYDGSSKYHADS VKGRFTISRDNSKSTLYLQMNSLRAEDTAMYYC VKVGANWGWRYFDLWGRGTLVTVSS SEQ ID NO: 72 DIVMTQTPLSLSVTPGQPASISCKSSQSLLHSDG VL aa NTYLSWYLQKPGQSPQLLIYEVSSRFSGVPDRFS GSGSGTDFTLKISRVEADDVGVYYCMQGIHSW TFGQGTKVEIK SEQ ID NO: 73 gattcaccttcagtacctttggc CDRH1 nuc SEQ ID NO: 74 atctggtatgatggaagtagtaaa CDRH2 nuc SEQ ID NO: 75 gtgaaagtcggagctaactggggatggaggtacttcgatctc CDRH3 nuc SEQ ID NO: 76 cagagcctcctacatagtgatggaaacacctat CDRL1 nuc SEQ ID NO: 77 gaagtttcc CDRL2 nuc SEQ ID NO: 78 ctgatctatgaagtttccagccggttc CDRL2 long nuc SEQ ID NO: 79 atgcaaggcatacactcgtggacg CDRL3 nuc SEQ ID NO: 80 caggagcaactggtggagtctgggggaggcgtggtccagcctggg VH nuc aagtccctgagactctcctgtgcagcctctggattcaccttcagtacc tttggcatgcactgggtccgccaggctccaggcaaggggctggagt gggtggcagtcatctggtatgatggaagtagtaaataccatgcagac tccgtgaagggccgattcaccatctccagagacaattccaagagc acgctgtatctgcaaatgaacagcctgagagctgaggacacggct atgtattactgtgtgaaagtcggagctaactggggatggaggtacttc gatctctggggccgtggcaccctggtcaccgtctcctcag SEQ ID NO: 81 gatattgtgatgacccagactccactctctctgtccgtcacccctgg VL nuc acagccggcctccatctcctgcaagtctagtcagagcctcctacat agtgatggaaacacctatttgtcttggtacctgcagaagccaggcc agtctccacagctcctgatctatgaagtttccagccggttctctggag tgccagataggttcagcggcagcgggtcagggacagatttcacact gaaaatcagccgggtggaggctgacgatgttggggtttactactgc atgcaaggcatacactcgtggacgttcggccaagggaccaaggtg gaaatcaaac MGG4 SEQ ID NO: 82 GFRFSDYG CDRH1 aa SEQ ID NO: 83 IWYDGSNE CDRH2 aa SEQ ID NO: 84 AKLLVGITTDVFDV CDRH3 aa SEQ ID NO: 85 QSVLSSSNNKNY CDRL1 aa SEQ ID NO: 86 WAS CDRL2 aa SEQ ID NO: 87 LIYWASTRE CDRL2 long aa SEQ ID NO: 88 QQYYTASPF CDRL3 aa SEQ ID NO: 89 QVQLVESGGGVVQPGRSLRLSCAASGFRFSDYG VH aa MHWVRQAPGKGLEWVALIWYDGSNESYLDSV KGRFTISRDNSKNTLYLQMNNLRTEDTAVYYCA KLLVGITTDVFDVWGOGTVVTVSS SEQ ID NO: 90 DIVMTQSPDSLAVSLGERATINCRSSQSVLSSSN VL aa NKNYLAWYQHKPRQPPKLLIYWASTRESGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTA SPFFGGGTKVEIK SEQ ID NO: 91 ggattcaggttcagtgactatggc CDRH1 nuc SEQ ID NO: 92 atatggtatgatggaagtaatgaa CDRH2 nuc SEQ ID NO: 93 gcgaaactactagtgggaattactactgatgtttttgatgtc CDRH3 nuc SEQ ID NO: 94 cagagtgttttatccagctccaacaataagaactac CDRL1 nuc SEQ ID NO: 95 tgggcatct CDRL2 nuc SEQ ID NO: 96 ctcatttactgggcatctacccgggaa CDRL2 long nuc SEQ ID NO: 97 cagcaatattatactgcttccccatt CDRL3 nuc SEQ ID NO: 98 caggtgcagctggtggagtctgggggaggcgtggtccagcctggg VH nuc aggtccctgagactctcctgtgcagcctctggattcaggttcagtgac tatggcatgcactgggtccgccaggctccgggcaaggggctggag tgggtggcacttatatggtatgatggaagtaatgaatcctatttagact ccgtgaagggccgattcaccatctccagagacaattccaagaaca cactgtatctgcaaatgaacaacctgagaactgaggacacggctgt gtattactgtgcgaaactactagtgggaattactactgatgtttttgatgt ctggggccaagggacagtggtcaccgtctcttcag SEQ ID NO: 99 gacatcgtgatgacccagtctccagactccctggctgtgtctctggg VL nuc cgagagggccaccatcaactgcaggtccagccagagtgttttatcc agctccaacaataagaactacttagcttggtaccagcacaaacca cgacagcctcctaaactgctcatttactgggcatctacccgggaatc cggggtccctgaccgattcagtggcagcgggtctgggacagatttc actctcaccatcagcagcctgcaggctgaagatgtggcagtttatta ctgtcagcaatattatactgcttccccatttttcggcggagggaccaa ggtagagatcaaac MGG8 SEQ ID NO: 100 GFMISGSV CDRH1 aa SEQ ID NO: 101 IRDKANNEAT CDRH2 aa SEQ ID NO: 102 TRGIIVGDTWHFDP CDRH3 aa SEQ ID NO: 103 ESLLRSDGKTY CDRL1 aa SEQ ID NO: 104 EVS CDRL2 aa SEQ ID NO: 105 LMYEVSKRF CDRL2 long aa SEQ ID NO: 106 MQSIQLVT CDRL3 aa SEQ ID NO: 107 EVQLVESGGGLVQPGGSLKLSCAASGFMISGSVL VH aa HWVRQASGKGLEWLGRIRDKANNEATAYAASV KGRFTISRDDSKDTTYLQMNSLRIEDTAVYYCTR GIIVGDTWHFDPWGQGTLVTVSS SEQ ID NO: 108 DIVMTQTPLSLSVTPGQTASISCKSSESLLRSDGK VL aa TYLYWYLQKPGQSPQLLMYEVSKRFSGVPDRFS GSGSGTDFTLKISRVETDDVGIYYCMQSIQLVTF GQGTKVEIK SEQ ID NO: 109 gggttcatgatcagtggctctgtt CDRH1 nuc SEQ ID NO: 110 attagagacaaagctaacaatgaggcgaca CDRH2 nuc SEQ ID NO: 111 acgaggggtatcatagtaggtgacacctggcacttcgacccc CDRH3 nuc SEQ ID NO: 112 gagagcctcctgagaagcgatggaaagaccta CDRL1 nuc SEQ ID NO: 113 gaagtttcc CDRL2 nuc SEQ ID NO: 114 ctgatgtatgaagtttccaagcgcttc CDRL2 long nuc SEQ ID NO: 115 atgcaaagtatacagcttgtgact CDRL3 nuc SEQ ID NO: 116 gaagtgcagctggtggagtccgggggaggcctggtccagcctggg VH nuc gggtccctgaaactctcctgtgcagcctctgggttcatgatcagtggc tctgttctacactgggtccgccaggcctccgggaaagggctggagt ggcttggccgtattagagacaaagctaacaatgaggcgacagcat atgcagcgtcggtgaaaggcaggttcaccatctccagagatgattc aaaggacacgacatatctgcaaatgaacagcctgagaatcgagg acacggccgtgtattactgtacgaggggtatcatagtaggtgacacc tggcacttcgacccctggggccagggaaccctggtcaccgtctcct cag SEQ ID NO: 117 gatattgtgatgacccagactccactctctctgtccgtcacccctgg VL nuc acagacggcctccatctcctgcaagtctagtgagagcctcctgaga agcgatggaaagacctacttgtattggtatctgcagaagccaggcc agtctccacagctcctgatgtatgaagtttccaagcgcttctctggag tgccagataggttcagtggcagcgggtcaggaacagattttacact gaaaatcagccgggtggagactgatgatgttggcatttattactgcat gcaaagtatacagcttgtgactttcggccaagggaccaaggtggaa atcaaac MGH1 SEQ ID NO: 118 GYTFTDYY CDRH1 aa SEQ ID NO: 119 INPYIGVS CDRH2 aa SEQ ID NO: 120 AACSNVGCYVY CDRH3 aa SEQ ID NO: 121 QSLVYSDGNTY CDRL1 aa SEQ ID NO: 122 KVS CDRL2 aa SEQ ID NO: 123 LIYKVSNRD CDRL2 long aa SEQ ID NO: 124 MQGTHWPDT CDRL3 aa SEQ ID NO: 125 QVQLVQSGAEVKKPGASVRVSCKTSGYTFTDYY VH aa VHWVRQAPGHGLECMGWINPYIGVSKYAQKF QGRVTLTRDTSISTAYMEISRLTSDDTAVYYCAA CSNVGCYVYWGQGSLVTVSS SEQ ID NO: 126 DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDG VL aa NTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDR FSGSGSGTDFTLKISRVEAEDVAIYFCMQGTHW PDTFGQGTKLEIK SEQ ID NO: 127 ggatacacgttcaccgactactat CDRH1 nuc SEQ ID NO: 128 atcaatccttacattggtgtctca CDRH2 nuc SEQ ID NO: 129 gcggcttgtagtaacgttggctgctacgtctat CDRH3 nuc SEQ ID NO: 130 caaagtctcgtgtacagtgatggaaacacctac CDRL1 nuc SEQ ID NO: 131 aaggtttct CDRL2 nuc SEQ ID NO: 132 ctaatttataaggtttctaatcgggac CDRL2 long nuc SEQ ID NO: 133 atgcaaggtacacactggcctgacact CDRL3 nuc SEQ ID NO: 134 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggg VH nuc gcctcagtgagagtctcctgcaagacatctggatacacgttcaccg actactatgtccactgggtgcgacaggccccaggacacgggcttg agtgcatgggctggatcaatccttacattggtgtctcaaagtatgcac agaagtttcagggcagggtcaccttgaccagggacacgtccatca gcacagcctacatggaaattagcaggctaacatctgacgacacgg ccgtctattactgtgcggcttgtagtaacgttggctgctacgtctattgg ggccagggatcgctggtcaccgtctcctcag SEQ ID NO: 135 gatgttgtgatgactcagtctccactctccctgcccgtcacccttgga VL nuc cagccggcctccatctcctgcaggtctagtcaaagtctcgtgtaca gtgatggaaacacctacttgaattggtttcagcagaggccaggcca atctccaaggcgcctaatttataaggtttctaatcgggactctggggt cccagacagattcagcggcagtgggtcaggcactgatttcacactg aaaatcagcagggtggaggctgaggatgttgcgatttatttctgcatg caaggtacacactggcctgacacttttggccaggggaccaaactg gagatcaaac MGH2 SEQ ID NO: 136 GFSFSSYA CDRH1 aa SEQ ID NO: 137 TRYDGSNK CDRH2 aa SEQ ID NO: 138 AKVGDGTVAGTIDY CDRH3 aa SEQ ID NO: 139 QSLVYSDGNTY CDRL1 aa SEQ ID NO: 140 KVS CDRL2 aa SEQ ID NO: 141 LIYKVSNRD CDRL2 long aa SEQ ID NO: 142 MQGTHWWT CDRL3 aa SEQ ID NO: 143 QVQLVESGGGVVQPGGSLRLSCTASGFSFSSYA VH aa MHWVRQAPGKGLEWVAYTRYDGSNKFYLDSV QGRFTISRDNSKNTLYLEMDSLRLEDTAVYFCAK VGDGTVAGTIDYWGQGTLVTVSS SEQ ID NO: 144 YIVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGN VL aa TYLNWYQQRPGQSPRRLIYKVSNRDSGVPDRFS GSGSGTDFTLKISRVEAEDVGVYYCMQGTHW WTFGQGTKVEIK SEQ ID NO: 145 ggtttcagcttcagtagttatgcc CDRH1 nuc SEQ ID NO: 146 acacggtatgatggaagtaataag CDRH2 nuc SEQ ID NO: 147 gcgaaagtgggggacgggacagtggctggtactattgacta CDRH3 nuc SEQ ID NO: 148 caaagcctcgtatatagtgatggaaacacctac CDRL1 nuc SEQ ID NO: 149 aaggtttct CDRL2 nuc SEQ ID NO: 150 ctaatttataaggtttctaatcgggac CDRL2 long nuc SEQ ID NO: 151 atgcaaggtacacactggtggacg CDRL3 nuc SEQ ID NO: 152 caggtgcagctggtggagtctgggggaggcgtggtccagcctggg VH nuc gggtccctgagactctcctgtacagcgtctggtttcagcttcagtagtt atgccatgcactgggtccgccaggctccaggcaagggactggagt gggtggcatatacacggtatgatggaagtaataagttctacctagact ccgtgcagggccgattcaccatctccagagacaattccaagaaca cgctgtatctggaaatggacagcctgagacttgaggacacggctgt ctatttctgtgcgaaagtgggggacgggacagtggctggtactattga ctactggggccagggaacgctggtcaccgtctcctcag SEQ ID NO: 153 tatattgtgatgactcagtctccactctccctgcccgtcacccttgga VL nuc cagccggcctccatctcctgcaggtctagtcaaagcctcgtatata gtgatggaaacacctacttgaattggtatcagcagaggccaggcca atctccaaggcgcctaatttataaggtttctaatcgggactctggggt cccagacagatttagcggcagtgggtcaggcactgatttcacactg aaaatcagcagggtggaggctgaggatgttggggtttattactgcat gcaaggtacacactggtggacgttcggccaagggaccaaggtgg aaatcaaac MGH3 SEQ ID NO: 154 GFTFSSYT CDRH1 aa SEQ ID NO: 155 ISSSGSYI CDRH2 aa SEQ ID NO: 156 ARNVLDSSGYPTYFDY CDRH3 aa SEQ ID NO: 157 QSLLYSNGYNY CDRL1 aa SEQ ID NO: 158 LGS CDRL2 aa SEQ ID NO: 159 LIYLGSNRA CDRL2 long aa SEQ ID NO: 160 MQAVQTPLT CDRL3 aa SEQ ID NO: 161 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYTM VH aa NWVRQAPGKGLEWVSSISSSGSYIYYADSVKGR CTISRDNAKNSLDLQMNSLRAEDAAVYYCARN VLDSSGYPTYFDYWGOGTLVTVSS SEQ ID NO: 162 DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSNGY VL aa NYLDWYVQKPGQSPRLLIYLGSNRASGVPDRFS GSGSGTDFTLRISRVEAEDVGFYYCMQAVQTPL TFGGGTKVEIK SEQ ID NO: 163 ggattcaccttcagtagttatacc CDRH1 nuc SEQ ID NO: 164 attagtagtagtggtagttacata CDRH2 nuc SEQ ID NO: 165 gcaagaaatgtcttggacagtagtggttaccccacgtactttgactat CDRH3 nuc SEQ ID NO: 166 agagcctcctatatagtaatggatacaactat CDRL1 nuc SEQ ID NO: 167 ttgggttct CDRL2 nuc SEQ ID NO: 168 ctgatctatttgggttctaatcgggcc CDRL2 long nuc SEQ ID NO: 169 atgcaagctgtacaaactcccctcact CDRL3 nuc SEQ ID NO: 170 gaggtgcagctggtggagtctgggggaggcctggtcaagcctggg VH nuc gggtccctgagactctcctgtgcagcctctggattcaccttcagtagt tataccatgaactgggtccgccaggctccagggaaggggctggag tgggtctcatccattagtagtagtggtagttacatatattacgcagact cagtgaagggccgatgcaccatctccagagacaacgccaagaac tcactggatctgcaaatgaacagcctgagagccgaggacgcggct gtgtattactgtgcaagaaatgtcttggacagtagtggttaccccacg tactttgactattggggccagggaacgctggtcaccgtctcctcag SEQ ID NO: 171 gatattgtgatgactcagtctccactctccctgcccgtcacccctgg VL nuc agagccggcctccatctcctgcaggtctagtcagagcctcctatat agtaatggatacaactatctggattggtacgtgcagaagccagggc agtctccacgcctcctgatctatttgggttctaatcgggcctccgggg tccctgacaggttcagtggcagtggatcaggcacagattttacactg agaatcagcagagtggaggctgaggatgttgggttttattactgcatg caagctgtacaaactcccctcactttcggcggagggaccaaggtg gagatcaaac MGU1 SEQ ID NO: 172 GFAFSSYG CDRH1 aa SEQ ID NO: 173 IWHDGTNK CDRH2 aa SEQ ID NO: 174 AIWYLDSPDHGFDI CDRH3 aa SEQ ID NO: 175 NGHSSNA CDRL1 aa SEQ ID NO: 176 VNSDGSH CDRL2 aa SEQ ID NO: 177 QAWDSGIWV CDRL3 aa SEQ ID NO: 178 QVQLVESGGGVVQPGRSLRLSCAASGFAFSSYG VH aa MNWVRQAPGKGLEWVAVIWHDGTNKYYRDS VKGRFIISRDNAKNTLYLQMDSLSAEDTAMYYC AIWYLDSPDHGFDIWGRGTMVTVSS SEQ ID NO: 179 QLVLTQSPSASASLGVSVTLTCTLNNGHSSNAIA VL aa WHQQQPGKGPRYLMKVNSDGSHNKGAAVP DRFSGSSSGTERHLTISSLQSDDEADYYCQAWD SGIWVFGGGTKLTVL SEQ ID NO: 180 ggattcgctttcagtagttatggc CDRH1 nuc SEQ ID NO: 181 atttggcatgatggcaccaataaa CDRH2 nuc SEQ ID NO: 182 gccatttggtatcttgatagtcctgatcatggtttcgatatc CDRH3 nuc SEQ ID NO: 183 aatggccacagttccaatgcc CDRL1 nuc SEQ ID NO: 184 gttaatagtgatggcagcca CDRL2 nuc SEQ ID NO: 185 caggcctgggacagtggcatttgggtt CDRL3 nuc SEQ ID NO: 186 caggtgcagctggtggagtctgggggaggcgtggtccagcctggg VH nuc aggtccctgagactctcatgtgcagcctccggattcgctttcagtagt tatggcatgaactgggtccgccaggctccaggcaagggactggag tgggtggcagttatttggcatgatggcaccaataaatactatagagac tccgtgaagggccgattcatcatctccagagacaatgccaagaac accttgtatctgcaaatggacagcctgagcgctgaggacacggcta tgtattactgtgccatttggtatcttgatagtcctgatcatggtttcgatat ctggggccgagggacaatggtcaccgtctcttcag SEQ ID NO: 187 cagcttgtcctgactcaatcgccctctgcctctgcctccctgggagt VL nuc ctcggtcaccctcacctgtactctgaacaatggccacagttccaat gccatcgcatggcatcaacagcagccagggaagggccctcgttat ttgatgaaggttaatagtgatggcagccacaataagggggccgctg tccctgatcgcttctcaggctctagttctgggactgagcgccacctc accatctccagcctccagtctgacgatgaggctgactattattgtca ggcctgggacagtggcatttgggttttcggcggagggaccaagttg accgtcctag MGU3 SEQ ID NO: 188 GFTFSDYN CDRH1 aa SEQ ID NO: 189 ISHSSSTT CDRH2 aa SEQ ID NO: 190 ARLRPLSYSGRYRDY CDRH3 aa SEQ ID NO: 191 QDVSNY CDRL1 aa SEQ ID NO: 192 DAS CDRL2 aa SEQ ID NO: 193 LIYDASTLQ CDRL2 long aa SEQ ID NO: 194 QQYDSLPLT CDRL3 aa SEQ ID NO: 195 EVLLVESGGGLVQPGGSLRLSCAASGFTFSDYN VH aa MHWVRQAPGKGLEWLSYISHSSSTTYYADSVR GRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR LRPLSYSGRYRDYWGQGTLVTVSS SEQ ID NO: 196 DIQMTQSPSSLSASVGDRVTITCQASQDVSNYV VL aa NWYQQKPGKAPKVLIYDASTLQTGVPSRFSGSG SGTDFTFSISSLQPEDIATYYCQQYDSLPLTFGGG TKVEIK SEQ ID NO: 197 ggattcaccttcagtgactataac CDRH1 nuc SEQ ID NO: 198 attagtcatagtagtagtaccaca CDRH2 nuc SEQ ID NO: 199 gcgagacttcgtcccttatcgtatagtggcaggtaccgcgactac CDRH3 nuc SEQ ID NO: 200 caggacgttagtaattat CDRL1 nuc SEQ ID NO: 201 gatgcatcc CDRL2 nuc SEQ ID NO: 202 ctgatctacgatgcatccactttgcaa CDRL2 long nuc SEQ ID NO: 203 cagcagtatgatagcctcccactcact CDRL3 nuc SEQ ID NO: 204 gaggtgctactagtggagtctgggggaggcttggtacaacctgggg VH nuc ggtccctgagactctcctgtgcagcctctggattcaccttcagtgact ataacatgcactgggtccgccaggctccagggaaggggctggagt ggctttcatacattagtcatagtagtagtaccacatactacgcagact ctgtgaggggccgattcaccatctccagagacaatgccaagaact cactgtatctgcaaatgaacagcctgagagccgaggacacggctg tgtattactgtgcgagacttcgtcccttatcgtatagtggcaggtaccg cgactactggggccagggaacgctggtcaccgtctcctcag SEQ ID NO: 205 gacatccagatgacccagtctccatcctccctgtctgcatctgtagg VL nuc agacagagtcaccatcacttgccaggcgagtcaggacgttagtaat tatgtaaattggtatcagcagaaaccagggaaagcccctaaggtcc tgatctacgatgcatccactttgcaaacaggggtcccatcaaggttc agtggaagtggatcggggacagattttactttcagcatcagcagcct gcagcctgaagatattgcaacatattactgtcagcagtatgatagcc tcccactcactttcggcggagggaccaaggtggagatcaaac MGU5 SEQ ID NO: 206 GFSFSSYG CDRH1 aa SEQ ID NO: 207 IWHDGTNK CDRH2 aa SEQ ID NO: 208 TKRAGWGDALDI CDRH3 aa SEQ ID NO: 209 QDISNY CDRL1 aa SEQ ID NO: 210 DAS CDRL2 aa SEQ ID NO: 211 LIYDASNLE CDRL2 long aa SEQ ID NO: 212 QQQRI CDRL3 aa SEQ ID NO: 213 QVQLVESGGGVVQPGRSLRLSCAASGFSFSSYG VH aa MHWVRQAPGKGLDWVALIWHDGTNKFYTDS VKGRFTISRDNSKDTLFLQMNSLRVEDTAVYYCT KRAGWGDALDIWGQGTMVTVSS SEQ ID NO: 214 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLN VL aa WYQQKPGKAPKLLIYDASNLETGVPSRFSGSGS ATDFTLTISSLQSEDIATYYCQQQRIFGGGTKVEIK SEQ ID NO: 215 ggattcagcttcagtagttatggc CDRH1 nuc SEQ ID NO: 216 atatggcatgatggaactaataaa CDRH2 nuc SEQ ID NO: 217 acgaagcgggctggctggggtgatgctcttgatatc CDRH3 nuc SEQ ID NO: 218 caggacattagcaactat CDRL1 nuc SEQ ID NO: 219 gatgcatcc CDRL2 nuc SEQ ID NO: 220 ctgatctacgatgcatccaatttggaa CDRL2 long nuc SEQ ID NO: 221 caacaacaaaggatt CDRL3 nuc SEQ ID NO: 222 caggtgcagttggtggagtctgggggaggcgtggtccagcctggga VH nuc ggtccctgagactctcctgtgcagcctctggattcagcttcagtagtt atggcatgcactgggtccgccaggctccaggcaaggggctggatt gggtggctcttatatggcatgatggaactaataaattttacacagact ccgtgaagggccgattcaccatctccagagacaattccaaggaca cactgtttctgcaaatgaacagtctgagagttgaggacacggctgtgt attactgtacgaagcgggctggctggggtgatgctcttgatatctggg gccaagggacaatggtcaccgtctcttcag SEQ ID NO: 223 gacatccagatgacccagtctccatcctccctgtctgcatctgtagg VL nuc agacagagtcaccatcacttgccaggcgagtcaggacattagcaa ctatttaaattggtatcagcagaaaccagggaaagcccctaaactc ctgatctacgatgcatccaatttggaaacaggggtcccatcaaggtt cagtggaagtggatctgcgacagattttactctcaccatcagcagc ctgcagtctgaagacattgcaacatattactgtcaacaacaaagga ttttcggcggagggaccaaggtggagatcaaac MGU8 SEQ ID NO: 224 GFTFSNYG CDRH1 aa SEQ ID NO: 225 IWHDGTNK CDRH2 aa SEQ ID NO: 226 TKRGGWGDGSDI CDRH3 aa SEQ ID NO: 227 QDVDNY CDRL1 aa SEQ ID NO: 228 DAS CDRL2 aa SEQ ID NO: 229 LIYDASNLA CDRL2 long aa SEQ ID NO: 230 QQQRI CDRL3 aa SEQ ID NO: 231 QVQLVESGGGVVQPGRSLRLSCAAGGFTFSNY VH aa GMHWVRQAPGKGLEWVALIWHDGTNKFYAD SVKGRFTISRDNSKNTLSLQMDSLTTEDTAIYFCT KRGGWGDGSDIWGQGTMVTVSS SEQ ID NO: 232 DIQMTQSPSSLSASVGDRVTITCQASQDVDNYL VL aa NWYQHKPGKAPKLLIYDASNLATGVPSRFSGSG SSTDFTLTISSLQSDDFATYYCQQQRIFGGGTRV EIK SEQ ID NO: 233 ggatttaccttcagtaactatggc CDRH1 nuc SEQ ID NO: 234 atatggcatgatggaactaataaa CDRH2 nuc SEQ ID NO: 235 acgaagcgaggtggctggggtgatggttctgatatc CDRH3 nuc SEQ ID NO: 236 caggacgttgacaactat CDRL1 nuc SEQ ID NO: 237 gatgcatcc CDRL2 nuc SEQ ID NO: 238 ctgatctacgatgcatccaatttggcg CDRL2 long nuc SEQ ID NO: 239 caacaacaaaggatt CDRL3 nuc SEQ ID NO: 240 caggtgcagctggtggagtctgggggaggcgtggtccagcctggg VH nuc aggtccctaagactctcctgtgcagccggtggatttaccttcagtaac tatggcatgcactgggtccgccaggctccaggcaaggggctggag tgggtggcacttatatggcatgatggaactaataaattctatgcagac tccgtgaagggccgattcaccatctccagagacaattccaagaac acgctgtctctgcaaatggacagcctgacaactgaggacacggct atatatttctgtacgaagcgaggtggctggggtgatggttctgatatct ggggccaagggacaatggtcaccgtctcttcag SEQ ID NO: 241 gacatccagatgacccagtctccatcctccctgtctgcatctgtagg VL nuc agacagagtcaccatcacttgccaggcgagtcaggacgttgacaa ctatttaaattggtatcagcataaaccagggaaagcccctaagctcc tgatctacgatgcatccaatttggcgacaggggtcccatcaaggttc agtggaagtggatcttcgacagattttactctcaccatcagcagcctg cagtctgatgactttgcaacatattactgtcaacaacaaaggattttc ggcggagggaccagggtggaaatcaaac MGU10 SEQ ID NO: 242 GFAFSNYG CDRH1 aa SEQ ID NO: 243 IWHDGSLK CDRH2 aa SEQ ID NO: 244 TVWYLETPDDGFDI CDRH3 aa SEQ ID NO: 245 HGHTSKA CDRL1 aa SEQ ID NO: 246 VNSDGSH CDRL2 aa SEQ ID NO: 247 QAWDSGIWV CDRL3 aa SEQ ID NO: 248 QVQLVESGGGVVQPGRSLRLSCAASGFAFSNY VH aa GMNWVRQAPGKGLEWVAVIWHDGSLKYYTQ SVKGRFTISRDNAKNTLFLQMDSLSADDTAMYY CTVWYLETPDDGFDIWGRGTMVTVSS SEQ ID NO: 249 QLVLTQPPSASASLGVSVTLTCTLSHGHTSKAIA VL aa WHQQQPGKGPRYLMKVNSDGSHTKGAAVPD RFSGSTSGAERHFTISNLQSDDEADYYCQAWDS GIWVFGGGTKLTVL SEQ ID NO: 250 ggattcgctttcagcaattatggc CDRH1 nuc SEQ ID NO: 251 atttggcatgacggcagtcttaaa CDRH2 nuc SEQ ID NO: 252 accgtttggtaccttgaaactcctgatgatggtttcgatatt CDRH3 nuc SEQ ID NO: 253 catggccacacctccaaagcc CDRL1 nuc SEQ ID NO: 254 gttaatagtgatggcagccac CDRL2 nuc SEQ ID NO: 255 caggcctgggacagtggcatttgggtt CDRL3 nuc SEQ ID NO: 256 caggtgcagctggtggagtctgggggaggcgtggtccagcctggg VH nuc aggtccctgagactctcatgtgcagcctccggattcgctttcagcaat tatggcatgaactgggtccgccaggctccaggcaagggactggaa tgggtggcagttatttggcatgacggcagtcttaaatattatacacagt ccgtgaagggccgattcaccatctccagagacaatgccaagaac acgttgtttctccaaatggacagcctgagcgctgacgacacggctat gtattattgtaccgtttggtaccttgaaactcctgatgatggtttcgatatt tggggccgagggacaatggtcaccgtctcgtcag SEQ ID NO: 257 cagcttgtcctgactcaaccgccctctgcctctgcctccctgggagt VL nuc ctcggtcaccctcacctgtactctgagtcatggccacacctccaaa gccatcgcgtggcatcaacagcagccagggaagggccctcgttat ttgatgaaagttaatagtgatggcagccacactaagggggccgctg tccctgatcgcttctcaggctctacttctggggctgagcgccacttca ccatctccaacctccagtctgacgatgaggctgattattattgtcagg cctgggacagtggcatttgggttttcggcggagggaccaagttgac cgtcctag MGU11 SEQ ID NO: 258 GFSFSSYG CDRH1 aa SEQ ID NO: 259 IWYDGTNK CDRH2 aa SEQ ID NO: 260 ANDIAGWGYDGSNA CDRH3 aa SEQ ID NO: 261 QSLVYSDGNTY CDRL1 aa SEQ ID NO: 262 KVS CDRL2 aa SEQ ID NO: 263 LIYKVSNRD CDRL2 long aa SEQ ID NO: 264 MQGTVGFT CDRL3 aa SEQ ID NO: 265 QVQLVESGGGVVQPGRSLRLSCVASGFSFSSYG VH aa MHWVRQAPGKGLEWVAVIVVYDGTNKYYADS VKGRFTISRDNTKNTLYLQMNSLRADDTAMYYC ANDIAGWGYDGSNAWGQGTLVTVSS SEQ ID NO: 266 LSLPVTPGQPASISCKSSQSLVYSDGNTYLNWFQ VL aa QRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTD FTLKISRVEAEDVGVYYCMQGTVGFTFGPGTTV DIK SEQ ID NO: 267 ggattcagcttcagtagctatggc CDRH1 nuc SEQ ID NO: 268 atatggtatgatggaaccaataaa CDRH2 nuc SEQ ID NO: 269 gcgaatgatattgcggggtggggctatgatggtagtaatgcc CDRH3 nuc SEQ ID NO: 270 caaagcctcgtatatagtgatggaaacacctac CDRL1 nuc SEQ ID NO: 271 aaggtttct CDRL2 nuc SEQ ID NO: 272 ctaatttataaggtttctaaccgggac CDRL2 long nuc SEQ ID NO: 273 atgcaaggtacagtggggttcact CDRL3 nuc SEQ ID NO: 274 caggtgcagctggtggagtctgggggaggcgtagtccagcctggg VH nuc aggtccctgagactctcctgcgtagcctctggattcagcttcagtagc tatggcatgcactgggtccgccaggctccaggcaaggggctggag tgggtggcagttatatggtatgatggaaccaataaatactatgcagat tccgtgaagggccgattcaccatctccagagacaataccaagaac acgttgtacctgcaaatgaacagcctgagagcggacgacacggct atgtattactgtgcgaatgatattgcggggtggggctatgatggtagta atgcctggggccagggaaccctggtcaccgtctcctcag SEQ ID NO: 275 ctctccctgcccgtcacccctggacagccggcctccatctcctgca VL nuc agtctagtcaaagcctcgtatatagtgatggaaacacctacttgaatt ggtttcagcagaggccaggccaatctccaaggcgcctaatttataa ggtttctaaccgggactctggggtcccagacagattcagcggcagt gggtcaggcactgatttcacactgaaaatcagcagggtggaggctg aggatgttggggtttattactgcatgcaaggtacagtggggttcacttt cggccctgggaccacagtggatatcaaac MGU12 SEQ ID NO: 276 GFSFSSYG CDRH1 aa SEQ ID NO: 277 IWHDGSYS CDRH2 aa SEQ ID NO: 278 VKVEDYVRGSSHGGAFHI CDRH3 aa SEQ ID NO: 279 QTINNW CDRL1 aa SEQ ID NO: 280 KAS CDRL2 aa SEQ ID NO: 281 LIYKASSLE CDRL2 long aa SEQ ID NO: 282 QQYSSYWT CDRL3 aa SEQ ID NO: 283 QVQLVESGGGVVQPGRSLRLSCAASGFSFSSYG VH aa MHWVRQAPGKGPEWVAVIWHDGSYSYYADS VRGRFTISRDNSKNTLYLQMNSLRPEDTGMYHC VKVEDYVRGSSHGGAFHIWGQGTMVTVSS SEQ ID NO: 284 DIQMTQSPSTLSASVGDRVTITCRASQTINNWL VL aa AWYQWKPGKAPELLIYKASSLESGVPSRFSGSGS GTEFTLTISSLQPDDFATYYCQQYSSYWTFGQG TKVDIK SEQ ID NO: 285 ggattcagcttcagtagttatggc CDRH1 nuc SEQ ID NO: 286 atttggcatgatggaagttacagt CDRH2 nuc SEQ ID NO: 287 gtgaaagttgaggattacgttagggggagttcacatgggggtgctttt CDRH3 nuc catatc SEQ ID NO: 288 cagactattaataactgg CDRL1 nuc SEQ ID NO: 289 taaggcgtct CDRL2 nuc SEQ ID NO: 290 ctgatctataaggcgtctagtttagaa CDRL2 long nuc SEQ ID NO: 291 caacagtatagtagttattggacg CDRL3 nuc SEQ ID NO: 292 caggtacaactggtggaatctgggggaggcgtggtccagcctggg VH nuc aggtccctgagactctcctgtgcagcctccggattcagcttcagtagt tatggcatgcactgggtccgccaggctccaggcaaggggccgga gtgggtggcagtgatttggcatgatggaagttacagttactatgcaga ctccgtgaggggccgattcaccatctccagagacaattccaagaa cacgctgtatctgcaaatgaacagcctgagacctgaggacacggg gatgtatcactgtgtgaaagttgaggattacgttagggggagttcaca tgggggtgcttttcatatctggggccaagggacaatggtcaccgtctc ttcag SEQ ID NO: 293 gacatccagatgacccagtctccttccaccctgtctgcatctgtagg VL nuc ggacagagtcaccatcacttgccgggccagtcagactattaataac tggttggcctggtatcagtggaaaccggggaaagcccctgagctcc tgatctataaggcgtctagtttagaaagtggggtcccatcaaggttca gcggcagtggatctgggacagaattcactctcaccatcagcagcct gcagcctgatgattttgcaacttattactgccaacagtatagtagttatt ggacgttcggccaagggaccaaggtggacatcaaac MGV3 SEQ ID NO: 294 GFTVSDSY CDRH1 aa SEQ ID NO: 295 IYSGSST CDRH2 aa SEQ ID NO: 296 ARGPNDYRNRKYYYYMDV CDRH3 aa SEQ ID NO: 297 QSVDSPY CDRL1 aa SEQ ID NO: 298 GAS CDRL2 aa SEQ ID NO: 299 LIFGASIRA CDRL2 long aa SEQ ID NO: 300 HQYGNAPYI CDRL3 aa SEQ ID NO: 301 EVQVVESGGDLVQPGGSLRLSCAVYGFTVSDSY VH aa MSWVRQAPGKGLEWVSVIYSGSSTYYIDSVKGR FTISRDRSKNTLYLQMNTLRVEDTALYYCARGPN DYRNRKYYYYMDVWGKGTAVTVSS SEQ ID NO: 302 EIVLTQSPDTLSLSAGERVTLSCRASQSVDSPYLA VL aa WYQQRPGQTPRLLIFGASIRATDIPDRFSGGGS GTDFTLTISRLEPEDSGVYYCHQYGNAPYIFGQG TKLEIK SEQ ID NO: 303 ggattcaccgtcagtgacagctac CDRH1 nuc SEQ ID NO: 304 atctatagtggtagtagtaca CDRH2 nuc SEQ ID NO: 305 gcgagaggccctaatgactacagaaatcgcaaatattactactac CDRH3 nuc atggacgtc SEQ ID NO: 306 cagagtgttgacagtccctac CDRL1 nuc SEQ ID NO: 307 ggtgcctct CDRL2 nuc SEQ ID NO: 308 ctcatttttggtgcctctattagggcc CDRL2 long nuc SEQ ID NO: 309 caccagtatggtaacgcaccctacatt CDRL3 nuc SEQ ID NO: 310 gaggtgcaggtggtggagtctgggggagacttggtccagccgggg VH nuc gggtccctgagactctcctgtgcagtctatggattcaccgtcagtgac agctacatgagctgggtccgccaggctccggggaaggggctgga gtgggtctcagttatctatagtggtagtagtacatactacatagactcc gtgaagggccgattcaccatctccagagacaggtccaagaacac cttgtatcttcaaatgaacaccctgagagttgaggacacggctcttta ttactgcgcgagaggccctaatgactacagaaatcgcaaatattact actacatggacgtctggggcaaagggaccgcggtcaccgtctcct cag SEQ ID NO: 311 gaaattgtgttgacacagtctccagacaccctgtccttgtctgcagg VL nuc ggaaagagtcaccctctcttgcagggccagtcagagtgttgacagt ccctacttagcctggtatcagcaaagacctggccagactcccagg ctcctcatttttggtgcctctattagggccactgacatcccagacagg ttcagtggcggtgggtctgggacagacttcactctcaccatcagca gactggaacctgaagattctggagtgtattactgtcaccagtatggta acgcaccctacatttttggccaggggaccaagctggagatcaaac SEQ ID NO: 312 KNNQGNGQGHNMPNDPNRNVDENANANSA CSP C-terminal VKNNNNEEPSDKHIKEYLNKIQNSLSTEWSPCSV peptide 282-383 TCGNGIQVRIKPGSANKPKDELDYANDIEKKICK MEKCS SEQ ID NO: 313 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE IgG1 CH1CH2CH3 PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV aa TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 314 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR IgG CK aa EAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 315 GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYP IgG CL aa GAVTVAWKADSSPVKAGVETTTPSKQSNNKYA ASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVA PTECS SEQ ID NO: 316 gcgtcgaccaagggcccatcggtcttccccctggcaccctcctcc IgG1 CH1CH2CH3 aagagcacctctgggggcacagcggccctgggctgcctggtcaa nuc ggactacttccccgaacctgtgacggtctcgtggaactcaggcgcc ctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcag gactctactccctcagcagcgtggtgaccgtgccctccagcagctt gggcacccagacctacatctgcaacgtgaatcacaagcccagca acaccaaggtggacaagagagttgagcccaaatcttgtgacaaaa ctcacacatgcccaccgtgcccagcacctgaactcctgggggga ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatga tctcccggacccctgaggtcacatgcgtggtggtggacgtgagcca cgaAgaCcctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactg gctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcag ccccgagaaccacaggtgtacaccctgcccccatcccgggagga gatgaccaagaaccaggtcagcctgacctgcctggtcaaaggctt ctatcccagcgacatcgccgtggagtgggagagcaatgggcagc cggagaacaactacaagaccacgcctcccgtgctggactccgac ggctccttcttcctctatagcaagctcaccgtggacaagagcaggtg gcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgc acaaccactacacgcagaagagcctctccctgtccccgggtaaa SEQ ID NO: 317 cgTacGgtggctgcaccatctgtcttcatcttcccgccatctgatga IgG CK nuc gcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttc tatcccagagaggccaaagtacagtggaaggtggataacgccctc caatcgggtaactcccaggagagtgtcacagagcaggacagcaa ggacagcacctacagcctcagcagcaccctgacgctgagcaaag cagactacgagaaacacaaagtctacgcctgcgaagtcacccat cagggcctgagctcgcccgtcacaaagagcttcaacaggggaga gtgt SEQ ID NO: 318 ggtcagcccaaggctgccccctcggtcactctgttcccgccctcct IgG CL nuc ctgaggagcttcaagccaacaaggccacactggtgtgtctcataag tgacttctacccgggagccgtgacagtggcttggaaagcagatagc agccccgtcaaggcgggagtggagaccaccacaccctccaaac aaagcaacaacaagtacgcggccagcagctatctgagcctgacg cctgagcagtggaagtcccacagaagctacagctgccaggtcac gcatgaagggagcaccgtggagaagacagtggcccctacagaat gttca SEQ ID NO: 319 MENITSGFLGPLLVLQAGFFLLTRILTIPQSLDSW HBsAg S domain WTSLNFLGGTTVCLGQNSQSPTSNHSPTSCPPT CPGYRWMCLRRFIIFLFILLLCLIFLLVLLDYQGML PVCPLIPGSSTTSTGPCRTCMTTAQGTSMYPSCC CTKPSDGNCTCIPIPSSWAFGKFLWEWASARFS WLSLLVPFVQWFVGLSPTVWLSVIWMMWYWG PSLYSILSPFLPLLPIFFCLWVYI SEQ ID NO: 320 MMRKLAILSVSSFLFVEALFQEYQCYGSSSNTRVL N-terminus of CSP NELNYDNAGTNLYNELEMNYYGKQENWYSLKK NSRSLGENDDGNNEDNEKLRKPKHKKLKQPAD GNPDP SEQ ID NO: 321 KKLKQPA N-terminal region of CSP SEQ ID NO: 322 HKKLKQPAD N-terminal region of CSP SEQ ID NO: 323 KHKKLKQPADG N-terminal region of CSP SEQ ID NO: 324 KHKKLKQP N-terminal region of CSP SEQ ID NO: 325 RKPKHKKLKQP N-terminal region of CSP SEQ ID NO: 326 PKHKKLKQPADGN N-terminal region of CSP SEQ ID NO: 327 KPKHKKLKQPADGNP N-terminal region of CSP SEQ ID NO: 328 RKPKHKKLKQPADGNPD N-terminal region of CSP SEQ ID NO: 329 NEKLRKPKHKKLKQP N-terminal region of CSP SEQ ID NO: 330 NEKLRKPKHKKLKQPADG N-terminal region of CSP SEQ ID NO: 331 MLSKDIIKLLNEQVNKEMNSSNLYMSMSSWCYT ferritin polypeptide HSLDGAGLFLFDHAAEEYEHAKKLIVFLNENNVP VQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINN IVDHAIKGKDHATFNFLQWYVAEQHEEEVLFKD ILDKIELIGNENHGLYLADQYVKGIAKSRKS SEQ ID NO: 332 MEFLKRSFAPLTEKQWQEIDNRAREIFKTQLYGR encapsulin KFVDVEGPYGWEYAAHPLGEVEVLSDENEVVK polypeptide: WGLRKSLPLIELRATFTLDLWELDNLERGKPNVD LSSLEETVRKVAEFEDEVIFRGCEKSGVKGLLSFEER KIECGSTPKDLLEAIVRALSIFSKDGIEGPYTLVINT DRWINFLKEEAGHYPLEKRVEECLRGGKIITTPRIE DALVVSERGGDFKLILGQDLSIGYEDREKDAVRL FITETFTFQVVNPEALILLKF

    [0532] In the VH/VL sequences the three sequences in bold show the CDR1, CDR2 and CDR3 in this order.