ANTIBODIES BINDING TO PLASMODIUM CIRCUMSPOROZOITE PROTEIN AND USES THEREOF

Abstract

The present invention provides antibodies targeting Plasmodium sporozoites, in particular plasmodium circumsporozoite protein. The invention also provides nucleic acids that encode such antibodies. In addition, the invention provides the use of the antibodies of the invention in prophylaxis and treatment malaria.

Claims

1. An antibody, or an antigen-binding fragment thereof, comprising (i) the heavy chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 12, respectively, and the light chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively; or (ii) the heavy chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and the light chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 14, respectively; or (iii) the heavy chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 12, respectively, and the light chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 14, respectively; or (iv) the heavy chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19, respectively, and the light chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 28, respectively; or (v) the heavy chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19, respectively, and the light chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 20, SEQ ID NO: 22, and SEQ ID NO: 28, respectively wherein the antibody, or antigen-binding fragment thereof binds to Plasmodium falciparum sporozoites.

2. The antibody, or an antigen-binding fragment thereof, of claim 1, wherein the antibody, or the antigen-binding fragment thereof, comprises: (i) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 13 or an amino acid sequence having at least 70% identity to SEQ ID NO: 13 and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 8 or an amino acid sequence having at least 70% identity to SEQ ID NO: 8; or (ii) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 7 or an amino acid sequence having at least 70% identity to SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 15 or an amino acid sequence having at least 70% identity to SEQ ID NO: 15; or (iii) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 16 or an amino acid sequence having at least 70% identity to SEQ ID NO: 16 and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 8 or the amino acid sequence having at least 70% identity to SEQ ID NO: 8; or (iv) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 11 or an amino acid sequence having at least 70% identity to SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 15 or the amino acid sequence having at least 70% identity to SEQ ID NO: 15; or (v) a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 13 or the amino acid sequence having at least 70% identity to SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 15 or the amino acid sequence having at least 70% identity to SEQ ID NO: 15; or (vi) a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 16 or the amino acid sequence having at least 70% identity to SEQ ID NO: 16 and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 15 or the amino acid sequence having at least 70% identity to SEQ ID NO: 15; or (vii) a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 24 or the amino acid sequence having at least 70% identity to SEQ ID NO: 24 and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 29 or the amino acid sequence having at least 70% identity to SEQ ID NO: 29; or (viii) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 104 or an amino acid sequence having at least 70% identity to SEQ ID NO: 104 and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 8 or the amino acid sequence having at least 70% identity to SEQ ID NO: 8; or (ix) a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 104 or the amino acid sequence having at least 70% identity to SEQ ID NO: 104 and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 15 or the amino acid sequence having at least 70% identity to SEQ ID NO: 15.

3-8. (canceled)

9. The antibody, or the antigen-binding fragment thereof, of claim 1, wherein the antibody, or the antigen-binding fragment thereof, comprises the heavy chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 12, respectively, and the light chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively.

10. The antibody, or the antigen-binding fragment thereof, of claim 9, wherein the antibody, or the antigen-binding fragment thereof, comprises (A) (i) a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 13 or an amino acid sequence having at least 70% identity to SEQ ID NO: 13 and (ii) a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 8 or an amino acid sequence having at least 70% identity to SEQ ID NO: 8, (B) (i) a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 16 or an amino acid sequence having at least 70% identity to SEQ ID NO: 16 and (ii) a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 8 or an amino acid sequence having at least 70% identity to SEQ ID NO: 8, or (C) (i) a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 104 or an amino acid sequence having at least 70% identity to SEQ ID NO: 104 and (ii) a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 8 or an amino acid sequence having at least 70%-identity to SEQ ID NO: 8.

11-12. (canceled)

13. The antibody, or the antigen-binding fragment thereof, of claim 1, wherein the antibody, or the antigen-binding fragment thereof, comprises the heavy chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and the light chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 14, respectively.

14. The antibody, or the antigen-binding fragment thereof, of claim 13, wherein the antibody, or the antigen-binding fragment thereof, comprises (A) (i) a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 7 or an amino acid sequence having at least 70% identity to SEQ ID NO: 7 and (ii) a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 15 or an amino acid sequence having at least 70% identity to SEQ ID NO: 15, or (B) (i) a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 11 or an amino acid sequence having at least 70% identity to SEQ ID NO: 11 and (ii) a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 15 or an amino acid sequence having at least 70% identity to SEQ ID NO: 15.

15. (canceled)

16. The antibody, or the antigen-binding fragment thereof, of claim 1, wherein the antibody, or the antigen-binding fragment thereof, comprises the heavy chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 12, respectively, and the light chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 14, respectively.

17. The antibody, or the antigen-binding fragment thereof, of claim 16, wherein the antibody, or the antigen-binding fragment thereof, comprises (A) (i) a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 13 or an amino acid sequence having at least 70% identity to SEQ ID NO: 13 and (ii) a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 15 or an amino acid sequence having at least 70% identity to SEQ ID NO: 15, (B) (i) a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 16 or an amino acid sequence having at least 70% identity to SEQ ID NO: 16 and (ii) a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 15 or an amino acid sequence having at least 70% identity to SEQ ID NO: 15, or (C) (i) a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 104 or an amino acid sequence having at least 70% identity to SEQ ID NO: 104 and (ii) a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 15 or an amino acid sequence having at least 70% identity to SEQ ID NO: 15.

18-19. (canceled)

20. The antibody, or the antigen-binding fragment thereof, of claim 1, wherein the antibody, or the antigen-binding fragment thereof, comprises the heavy chain CDR1, CDR2, and CDR3 sequences (i) as set forth in SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19, respectively, and the light chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 28, respectively or (ii) as set forth in SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19, respectively, and the light chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NO: 20, SEQ ID NO: 22, and SEQ ID NO: 28, respectively.

21. (canceled)

22. The antibody, or the antigen-binding fragment thereof, of claim 20, wherein the antibody, or the antigen-binding fragment thereof, comprises (i) a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 24 or an amino acid sequence having at least 70% identity to SEQ ID NO: 24 and (ii) a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 29 or an amino acid sequence having at least 70% identity to SEQ ID NO: 29.

23. An antibody, or an antigen-binding fragment thereof, comprising (i) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 8; or (ii) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 24 and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 29.

24-36. (canceled)

37. The antibody, or an antigen-binding fragment thereof, of claim 1, wherein the antibody, or the antigen-binding fragment thereof, is a human antibody and/or a monoclonal antibody.

38. (canceled)

39. The antibody of claim 1, wherein the antibody comprises an Fc moiety.

40. The antibody, or an antigen-binding fragment thereof, of claim 39, wherein the antibody, or the antigen-binding fragment thereof, comprises the mutations M428L and/or N434S in the heavy chain constant region.

41. The antibody of claim 1, wherein the antibody is of the IgG type.

42. (canceled)

43. The antibody, or an antigen-binding fragment thereof, of claim 1, wherein the antibody, or the antigen-binding fragment thereof, is purified, a single-chain antibody, a Fab, a Fab′, a F(ab′)2, a Fv, or a scFv.

44-45. (canceled)

46. The antibody, or an antigen-binding fragment thereof, of claim 1, 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.

47-48. (canceled)

49. A composition comprising (i) a nucleic acid molecule comprising a polynucleotide encoding the antibody, or an antigen-binding fragment thereof, of claim 1 or (ii) a first nucleic acid molecule comprising a polynucleotide encoding the heavy chain of the antibody, or antigen-binding fragment thereof, of claim 1, and a second nucleic acid molecule comprising a polynucleotide encoding the light chain of the same antibody, or antigen-binding fragment thereof.

50-64. (canceled)

65. A vector or combination of vectors comprising the nucleic acid molecule or molecules of claim 49.

66. (canceled)

67. A cell expressing the antibody, or an antigen-binding fragment thereof, of claim 1, or comprising the vector or combination of vectors of claim 65.

68. A pharmaceutical composition comprising the antibody, or an antigen-binding fragment thereof, of claim 1, the nucleic acid or combination of nucleic acids of claim 49, or the vector or combination of vectors of claim 65.

69-70. (canceled)

71. A method of reducing malaria, or lowering the risk of Plasmodium falciparum infection, comprising: administering to a subject in need thereof, a therapeutically effective amount of the antibody, or an antigen-binding fragment thereof, of claim 1, the nucleic acid or combination of nucleic acids of claim 49, the vector or combination of vectors of claim 65, or the pharmaceutical composition of claim 68.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0223] 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.

[0224] FIG. 1 shows for Example 3 the results of the sporozoite invasion/maturation assay for a control antibody (A) and for antibodies MGU10 (B), MGU10v2 (C) and MGU10v2_LS (D) with five dilutions tested for each antibody.

[0225] FIG. 2 shows for Example 4 the results of the sporozoite gliding assay for a control antibody (A) and for antibodies MGU10 (B) and MGU10v2_LS (C) with five dilutions tested for each antibody.

[0226] FIG. 3 shows for Example 5 the results of the sporozoite traversal assay for a control antibody (A) and for antibodies MGU10 (B) and MGU10v2_LS (C) with five dilutions tested for each antibody.

[0227] FIG. 4 shows for Example 6 the dimerization (Dimers) and aggregation (HMWs) of antibodies MGU10v2_LS (upper panel) and MGU10_LS (lower panel) at 40° C. in two distinct buffers as indicated.

[0228] FIG. 5 shows for Example 7 the results of the in vivo protection conferred by MGU10 antibodies in a challenge study; with bioluminescence (A) and percent inhibition (B).

[0229] FIG. 6 shows for Example 8 the results of the in vivo protection conferred by MGH2 antibodies in a challenge study; with bioluminescence (A) and percent inhibition (B).

[0230] FIG. 7 shows for Example 9 the binding of MGU10v2 and MGU10v8 to peptides NANP (A) and NPDP19 (B).

EXAMPLES

[0231] 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: Design of Variants of Antibodies MGU10 and MGH2

[0232] Recently, very potent anti-malaria antibodies were described, which are specific for Plasmodium falciparum circumsporozoite protein (CSP) (Tan J, Sack B K, Oyen D, et al. A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein. Nat Med. 2018; 24(4):401-407. doi:10.1038/nm.4513). The most potent dual-specific antibodies described in this study include antibodies “MGU10” and “MGH2”.

[0233] Based thereon, the present inventors designed the following variants of MGU10 (SEQ ID NOs: 1-8) and MGH2 (SEQ ID NOs: 17-27), which exhibit amino acid mutations in the heavy and/or light chain of said reference antibodies: [0234] 1. MGU10variant1 (MGU10v1), which differs from MGU10 in the framework regions (FR) of the heavy chain variable region (VH; SEQ ID NO: 11); [0235] 2. MGU10variant2 (MGU10v2), which differs from MGU10 in the heavy chain CDR3 (CDRH3: SEQ ID NO: 12; VH: SEQ ID NO: 13); [0236] 3. MGU10variant3 (MGU10v3), which differs from MGU10 in the light chain CDR3 (CDRL3: SEQ ID NO: 14; light chain variable region (VL): SEQ ID NO: 15); [0237] 4. MGU10variant4 (MGU10v4), which represents a combination of MGU10v1 and MGU10v2 and, therefore, differs from MGU10 in the heavy chain CDR3 (CDRH3; SEQ ID NO: 12) and in the heavy chain FR (VH; SEQ ID NO: 16); [0238] 5. MGU10variant5 (MGU10v5), which represents a combination of MGU10v1 and MGU10v3 (including the VH of MGU10v1 and the VL of MGU10v3) and, therefore, differs from MGU10 in the heavy chain FR (VH; SEQ ID NO: 11) and in the CDRL3 (CDRL3: SEQ ID NO: 14; VL: SEQ ID NO: 15); [0239] 6. MGU10variant6 (MGU10v6), which represents a combination of MGU10v2 and MGU10v3 (including the VH of MGU10v2 and the VL of MGU10v3) and, therefore, differs from MGU10 in the CDRH3 (CDRH3: SEQ ID NO: 12; VH: SEQ ID NO: 13) and in the CDRL3 (CDRL3: SEQ ID NO: 14; VL: SEQ ID NO: 15); [0240] 7. MGU10variant7 (MGU10v7), which represents a combination of MGU10v1, MGU10v2 and MGU10v3 (including the VH of MGU10v4 and the VL of MGU10v3) and, therefore, differs from MGU10 in the CDRH3 (SEQ ID NO: 12) and heavy chain FR (VH; SEQ ID NO: 16) and in the CDRL3 (CDRL3: SEQ ID NO: 14; VL: SEQ ID NO: 15); and [0241] 8. MGH2variant1 (MGH2v1), which differs from MGH2 in the light chain CDR3 (CDRL3: SEQ ID NO: 28; VL: SEQ ID NO: 29).

[0242] An overview over the SEQ ID NOs of CDR and VH/VL sequences of the variants in comparison with MGU10 and MGH2, respectively, is provide in Table 2:

TABLE-US-00002 TABLE 2 Antibody Heavy chain Light chain name CDR1 CDR2 CDR3 VH CDR1 CDR2 CDR3 VL MGU10 1 2 3 7 4 5 6 8 MGU10v1 1 2 3 11 4 5 6 8 MGU10v2 1 2 12 13 4 5 6 8 MGU10v3 1 2 3 7 4 5 14 15 MGU10v4 1 2 12 16 4 5 6 8 MGU10v5 1 2 3 11 4 5 14 15 MGU10v6 1 2 12 13 4 5 14 15 MGU10v7 1 2 12 16 4 5 14 15 MGH2 17 18 19 24 20 21/22 23 25 MGH2v1 17 18 19 24 20 21/22 28 29

Example 2: Antibodies of the Invention Show Dual Specificity

[0243] Tan et al., 2018 showed that the most potent antibodies of their study—including MGU10 and MGH2— simultaneously target epitopes in (i) the NANP-repeat region of CSP and (ii) an N-terminal region of CSP covering the junction between the N-terminal domain and the NANP-repeats (Tan), Sack B K, Oyen D, et al. A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein. Nat Med. 2018; 24(4):401-407. doi:10.1038/nm.4513). Moreover, this study showed that the extreme potency of those antibodies was due to their dual specificity, while antibodies targeting only one of the CSP epitopes were typically less potent.

[0244] Accordingly, antibodies of the present invention were produced and tested for their capacity to bind to both of the epitopes described by Tan et al., 2018: (i) the NANP-repeat region of CSP and (ii) the N-terminal region of CSP covering the junction between the N-terminal domain and the NANP-repeats.

[0245] To this end, antibodies MGU10v1, MGU10v2, MGU10v3 and MGH2v1 were produced. Namely, the antibodies were synthetized by Genscript and subcloned in vectors for the expression of IgG1 and kappa or lambda chains. The purified plasmids of heavy and light chains were combined and used to transfect Expi293F cells (ThermoFisher Scientific) using polyethylenimine (micro-scale transfection (600 μl) in a 96-well plate). The transfected cells were harvested on day 6 and supernatants were collected by centrifugation and filtration.

[0246] Total IgGs present in the supernatants were quantified using 96-well MaxiSorp plates (Nunc) coated with 10 μg/ml goat anti-human IgG (SouthernBiotech). Plates were then blocked with PBS with 1% BSA and incubated with titrated monoclonal antibodies, using Certified Reference Material 470 (ERMs-DA470, Sigma-Aldrich) as a standard. Plates were then washed and incubated with 1/500 alkaline phosphatase (AP)-conjugated goat anti-human IgG (Southern Biotech). Substrate (para-nitrophenyl phosphate (p-NPP), Sigma) was added and plates were read at wavelength of 405 nm to determine optical density (OD) values.

[0247] To test specific antibody binding to (i) the NANP-repeat region of CSP and (ii) the N-terminal region of CSP covering the junction between the N-terminal domain and the NANP-repeats, ELISA plates were coated with 10 μg/ml of avidin (Sigma). Plates were blocked with PBS with 1% BSA and incubated with 1 μg/ml biotinylated NANP-peptide (SEQ ID NO: 34) or with 1 μg/ml biotinylated NPDP-peptide (SEQ ID NO: 35). The plates were washed and incubated with titrated monoclonal antibodies, followed by 1/500 AP-conjugated goat anti-human IgG (Southern Biotech) and pNPP substrate. EC50 (ng/ml) values were calculated for every sample tested by nonlinear regression analysis using the Graph Pad Prism 7 software.

[0248] The results are shown in Table 3 for MGU10 and its variants MGU10v1, MGU10v2 and MGU10v3 and in Table 4 for MGH2 and its variant MGH2v1:

TABLE-US-00003 TABLE 3 Antibody NANP EC.sub.50 (ng/ml) NPDP EC.sub.50 (ng/ml) MGU10 34.3 26.1 MGU10v1 28.51 22.54 MGU10v2 26.79 20.45 MGU10v3 26.28 25.08

TABLE-US-00004 TABLE 4 Antibody NANP EC.sub.50 (ng/ml) NPDP EC.sub.50 (ng/ml) MGH2 27.88 48.8 MGH2v1 22.32 65.82

[0249] Surprisingly, all variants tested for MGU10 show an increased binding affinity for both CSP epitopes, while MGH2v1 only shows an increased binding affinity for the NANP-repeat region in comparison to MGH2.

Example 3: Sporozoite Invasion/Maturation Assay

[0250] Variant antibody MGU10v2 was selected for further characterization in functional assays. The sporozoite invasion/maturation assay is a functional assay for testing the antibodies' effects on the infectivity of sporozoites. Sporozoite invasion of hepatocytes and subsequent maturation into exoerythrocytic forms is an essential step in the establishment of malaria infection.

[0251] Cryopreserved human primary hepatocytes were seeded in a microtiter plate and incubated for 2 days. Salivary gland Plasmodium falciparum NF54 sporozoites were isolated from An. stephensi mosquitoes infected with P. falciparum. For each well, sporozoites were pre-incubated with serially diluted antibody sample for 30 minutes and thereafter transferred onto the hepatocytes. After 3 hours, non-invaded sporozoites were washed off and the cells were incubated for 4 days. Cells were fixed and stained with anti-HSP70 and DAPI. The number of hepatocyte nuclei and HSP70 positive forms were quantified by automated high content imaging.

[0252] In this assay, variant antibody MGU10v2 was compared to the parental antibody MGU10. In addition, Fc variant “MGU10v2_LS” of MGU10v2 was tested, which differs from variant antibody MGU10v2 only in that it comprises the mutations M428L and N434S (EU numbering) in the heavy chain constant region (amino acid sequence of MGU10v2_LS heavy chain: SEQ ID NO: 100). Accordingly, the variable regions of MGU10v2_LS are identical to those of MGU10v2. An irrelevant antibody was used as control. Five dilutions were tested per antibody sample with two replicates per dilution. 3SP2/Atovaquone treated sporozoites were used as MIN control and vehicle treated sporozoites as MAX control.

[0253] Data are expressed as total number of hepatocyte nuclei, total number of HSP70 positive forms, % infected hepatocytes. IC50 values were estimated using a four parameter non-linear regression model using least squares to find the best fit. The resulting values (expressed in μg/ml) are presented in Table 5 below:

TABLE-US-00005 TABLE 5 Antibody IC50 (μg/ml) MGU10 0.418 MGU10v2 0.302 MGU10v2_LS 0.179 control >10

[0254] Graphical representations of the results are shown in FIG. 1. All antibodies, with the exception of the control antibody, functionally blocked the development of liver stage schizonts in human primary hepatocytes. Interestingly, variant antibody MGU10v2 was more effective than parental antibody MGU10 and the additional Fc variant MGU10v2_LS was most efficient.

Example 4: Sporozoite Gliding Assay

[0255] The sporozoite gliding assay is a functional assay, wherein the effects of compounds on the sporozoites' gliding motility can be assessed. Plasmodium sporozoites are transmitted into the skin of their vertebrate host through the bite of an infectious mosquito. Sporozoite motility is a key prerequisite for parasite transmission and successful infection of the vertebrate host. Motility constitutes the first parasite mechanism that can be inhibited and is, therefore, of interest for intervention strategies.

[0256] Plates were coated with anti-CSP mAb 3SP2 to capture shed CSP (circumsporozoite protein). Fresh salivary gland sporozoites were isolated from An. stephensi mosquitoes infected with P. falciparum and pre-incubated with serially diluted sample (5 dilutions/sample) for 30 min and then transferred into the 3SP2 coated wells. After 90 minutes sporozoites were washed off and gliding trails were fixed and stained with biotinylated-anti-CSP-antibody followed by streptavidin-AF555. Gliding trails were captured by automated high content imaging and total gliding trail length was analyzed using machine learning algorithms.

[0257] In this assay, variant antibody MGU10v2_LS was compared to the parental antibody MGU10. An irrelevant antibody was used as control. Five dilutions were tested per antibody sample with two replicates per dilution. 3SP2/Gramicidin treated sporozoites were used as MIN control and vehicle treated sporozoites as MAX control.

[0258] Total gliding trails were quantified by image analysis and reported as relative fluorescence counts. IC50 values were estimated using a four parameter non-linear regression model using least squares to find the best fit. The resulting values (expressed in μg/ml) are presented in Table 6 below:

TABLE-US-00006 TABLE 6 Antibody IC50 (μg/ml) MGU10 0.975 MGU10v2_LS 0.748 control >10

[0259] Graphical representations of the results are shown in FIG. 2. Antibodies MGU10 and MGU10v2_LS, but not the control antibody, functionally blocked gliding motility of P. falciparum sporozoites. Variant antibody MGU10v2_LS was more effective than parental antibody MGU10.

Example 5: Sporozoite Traversal Assay

[0260] Plasmodium sporozoites are deposited in the skin of the vertebrate host. As sporozoites move towards the liver, they can enter and exit host cells within transient vacuoles, a process known as cell traversal. Traversal allows the sporozoites to cross cellular barriers and evade the host immune response, thereby representing a key prerequisite for successful infection of the vertebrate host. The sporozoite traversal assay is a functional assay, wherein the effects of compounds on the sporozoites' cell traversal can be assessed.

[0261] Human hepatoma (HC-04) cells were seeded in microtiter plates and grown to near confluence. Fresh P. falciparum salivary gland sporozoites were isolated from An. stephensi mosquitoes and pre-incubated with diluted IgG for 30 minutes before adding rhodamin-dextran. Following incubation for 1 hour at 37° C., cell nuclei were stained with DAPI. Fluorescence levels of traversed cells were quantified using a high content automated imager.

[0262] In this assay, variant antibody MGU10v2_LS was compared to the parental antibody MGU10. An irrelevant antibody was used as control. Five dilutions were tested per antibody sample with two replicates per dilution. 3SP2/Cytochalasin D treated sporozoites were used as MIN control and vehicle treated sporozoites as MAX control.

[0263] Data were expressed as % traversed cells relative to the MIN and MAX controls of the assay plate. IC50 values were estimated using a four parameter non-linear regression model using least squares to find the best fit. The resulting values (expressed in μg/ml) are presented in Table 7 below:

TABLE-US-00007 TABLE 7 Antibody IC50 (μg/ml) MGU10 1.928 MGU10v2_LS 1.356 control >10

[0264] Graphical representations of the results are shown in FIG. 3. Antibodies MGU10 and MGU10v2_LS, but not the control antibody, functionally blocked traversal of P. falciparum sporozoites. Variant antibody MGU10v2_LS was more effective than parental antibody MGU10.

Example 6: Stability of Antibodies

[0265] To test their stability, variant antibody MGU10v2_LS was compared to its parental version MGU10_LS. MGU10_LS differs from parental antibody MGU10 only in that it comprises the mutations M428L and N434S (EU numbering) in the heavy chain constant region (amino acid sequence of MGU10_LS heavy chain: SEQ ID NO: 101) Accordingly, the variable regions of MGU10_LS are identical to those of MGU10. Variant antibody MGU10v2_LS and its parental version MGU10_LS were exposed to heat stress under different conditions.

[0266] To this end, variant antibody MGU10v2_LS and its parental version MGU10_LS were incubated at 40° C. in sodium acetate buffer at pH 5.6 for two weeks. The formation of aggregates and dimers (high and low molecular weight species) was assessed by size exclusion chromatography. Results are shown in Table 8 below:

TABLE-US-00008 TABLE 8 MGU10_LS MGU10v2_LS % HMWS % monomer % LMWS % HMWS % monomer % LMWS unstressed 0.63 99 0.37 0.22 99.38 0.4 40° C. 4.65 92.83 2.52 4.29 93.09 2.62 HMWS: high molecular weight species, indicating aggregation; LMWS: low molecular weight species, representing dimer formation; % monomer indicates antibodies which do not dimerize or aggregate.

[0267] To further assess stability and aggregation of mAb MGU10, parental and developed mAbs were tested in two different buffers with different pH. To compare mAb dimerization and aggregation in different buffers, mAbs batches were buffer-exchanged to 50 mM Na-Acetate, 50 mM NaCl, pH 5.5 or to 20 mM Na-Citrate, 50 mM NaCl, pH 6.0 upon purification. Size exclusion chromatography was used to assess the molecular weight of the mAb species after 4 and 15 days at 40° C., using a BEH450 SEC Protein Standard Mix 5 component protein mixture (Thyroglobulin, IgG, BSA, Myoglobin, Uracil) for size calculation.

[0268] Results are shown in FIG. 4. Variant antibody MGU10v2_LS formed less high molecular weight species (less aggregates) when kept at 40° C. in 50 mM Na-Acetate/50 mM NaCl buffer, pH 5.5, for two weeks as compared to its parental version MGU10_LS. Accordingly, variant antibody MGU10v2_LS shows increased stability compared to the parental antibody.

Example 7: In Vivo Protection Conferred by Variant Antibody MGU10v2— Challenge Study

[0269] To assess in vivo protection against P. berghei chimeric parasite expressing full-length P. falciparum CSP, C57BL/6 mice (n=5 per group) were injected i.v. with 54.5 μg/mouse of variant antibody MGU10v2_LS or with 100 μg/mouse of the respective parental antibody MGU10_LS. As negative control, unrelated antibody AB-1245 (100 μg/mouse) was used. Forty-eight hours after antibody injection, antibody-treated mice as well as an additional group of naive mice (n=5) were challenged with 2×10.sup.3 chimeric P. berghei sporozoites expressing full-length P. falciparum CSP injected i.v. Forty-two hours after challenge, mice were injected with 100 μl of D-Luciferin (30 mg/mL), anesthetized with isoflurane and imaged with the IVIS spectrum to measure the bioluminescence expressed by the chimeric parasites. % inhibition was calculated in comparison to the naive group (representing 100% infection).

[0270] Results are shown in FIG. 5. In contrast to unrelated control antibody AB-1245, both variant antibody MGU10v2_LS and the respective parental antibody MGU10_LS significantly inhibited infection with the parasite in vivo with 80.76 (MGU10v2_LS) and 69.60% inhibition (MGU10_LS), respectively. Accordingly, a stronger inhibition of infection was achieved with variant antibody MGU10v2_LS as compared to its parental antibody MGU10_LS.

Example 8: In Vivo Protection Conferred by Variant Antibody MGH2v1— Challenge Study

[0271] To assess in vivo protection against P. berghei chimeric parasite expressing full-length P. falciparum CSP, C57BL/6 mice (n=5 per group) were injected i.v. with 100 μg/mouse of variant antibody MGH2v1_LS or with the respective parental antibody MGH2_LS. Fc variants MGH2v1_LS and MGH2_LS differ from MGH2v1 and MGH2, respectively, only in two mutations in the Fc region, i.e. the respective variable regions are maintained. Namely, variant antibody MGH2v1_LS differs from variant antibody MGH2v1 only in that it comprises the mutations M428L and N434S (EU numbering) in the heavy chain constant region (amino acid sequence of MGH2v1_LS heavy chain: SEQ ID NO: 102). Accordingly, antibody MGH2_LS differs from antibody MGH2 only in that it comprises the mutations M428L and N434S (EU numbering) in the heavy chain constant region (amino acid sequence of MGH2_LS heavy chain: SEQ ID NO: 102). As variant antibody MGH2v1 differs from parental antibody MGH2 only in the light chain CDR3 (VL), the heavy chain amino acid sequences of MGH2LS and MGH2v1_LS are identical.

[0272] As negative control, unrelated antibody AB-1245 (100 μg/mouse) was used. Forty-eight hours after antibody injection, antibody-treated mice as well as an additional group of naive mice (n=5) were challenged with 2×10.sup.3 chimeric P. berghei sporozoites expressing full-length P. falciparum CSP injected i.v. as described in Example 7. Forty-two hours after challenge, mice were injected with 100 μl of D-Luciferin (30 mg/mL), anesthetized with isoflurane and imaged with the IVIS spectrum to measure the bioluminescence expressed by the chimeric parasites. % inhibition was calculated in comparison to the naive group (representing 100% infection).

[0273] Results are shown in FIG. 6. In contrast to unrelated control antibody AB-1245, both variant antibody MGH2v1_LS and the respective parental antibody MGH2_LS inhibited infection with the parasite in vivo with 38.62% (MGH2v1_LS) and 25.23% inhibition (MGH2_LS), respectively. Accordingly, a stronger inhibition of infection was achieved with variant antibody MGH2v1_LS as compared to its parental antibody MGH2v1_LS.

Example 9: Design and Testing of a Further Variant of MGU10/MGU10v2

[0274] As shown above in Example 6, MGU10v2, which differs from MGU10 in mutation D106E, shows increased stability. Without being bound to any theory, the present inventors believe that mutation D106E removes an isomerization motif and thereby increases the stability of antibody MGU10v2 as shown in Example 6.

[0275] In view thereof, a further variant of MGU10 was designed, wherein—in comparison to MGU10v2— the additional mutation D97E was introduced in the framework region of the heavy chain (VH) of MGU10v2 in order to remove a further isomerization motif (to further increase the antibody's stability and manufacturability). Accordingly, MGU10v8 comprises the same CDR sequences as MGU10v2; and the same VL sequence as MGU10v2 and its parental antibody MGU10. The VH of MGU10v8 comprises an amino acid sequence as set forth in SEQ ID NO: 104. SEQ ID NO: 106 provides an exemplary nucleotide sequence encoding the MGHv8 VH.

[0276] New variant antibody MGU10v8 was expressed essentially as described in Example 2 using ExpiCHO cells (in higher volume, e.g. 25 ml or 100 ml or more), and binding to (i) the NANP-repeat region of CSP (“NANP”-peptide) and (ii) the N-terminal region of CSP covering the junction between the N-terminal domain and the NANP-repeats (“NPDP”-peptide) were tested in ELISA. To this end, Pierce™ Streptavidin coated plates (Life Technologies) were used to coat either biotinylated NANP-peptide (N-term biotinylation; SEQ ID NO: 34) or biotinylated NPDP19-peptide (N-term biotinylation; SEQ ID NO: 105), each at 5 μg/ml in blocking buffer (PBS, 1% BSA). Plates were washed (PBS, 0.05% Tween 20) before addition of titrated antibodies MGU10v2 or MGU10v8 for 90 min at RT. After another wash step, secondary antibody goat anti-human IgG HRP F(ab′)2 fragment Fcg specific (Jackson ImmunoResearch) was added at 0.8 μg/ml. Sure Blue TMB (Bioconcept) was used for color development that was stopped with 1% HCl in water. Optical density at 450 nm was detected using an ELISA Reader ELx808IU (Biotek).

[0277] Results are shown in FIG. 7. As shown in FIG. 7, binding to both peptides, NANP and NPDP19, is very similar in variant antibodies MGU10v2 and MGU10v8.

TABLE-US-00009 TABLE OF SEQUENCES AND SEQ ID NUMBERS (SEQUENCE LISTING): SEQ ID NO Sequence Remarks Amino acid sequences MGU10 SEQ ID NO: 1 GFAFSNYG CDRH1 SEQ ID NO: 2 IWHDGSLK CDRH2 SEQ ID NO: 3 TVWYLETPDDGFDI CDRH3 SEQ ID NO: 4 HGHTSKA CDRL1 SEQ ID NO: 5 VNSDGSH CDRL2 SEQ ID NO: 6 QAWDSGIWV CDRL3 SEQ ID NO: 7 QVQLVESGGGVVQPGRSLRLSCAASGFAFSNY VH GMNWVRQAPGKGLEWVAVIWHDGSLKYYTQ SVKGRFTISRDNAKNTLFLQMDSLSADDTAMYY CTVWYLETPDDGFDIWGRGTMVTVSS SEQ ID NO: 8 QLVLTQPPSASASLGVSVTLTCTLSHGHTSKAIA VL WHQQQPGKGPRYLMKVNSDGSHTKGAAVPD RFSGSTSGAERHFTISNLQSDDEADYYCQAWDS GIWVFGGGTKLTVL SEQ ID NO: 9 QVQLVESGGGVVQPGRSLRLSCAASGFAFSNY Heavy chain GMNWVRQAPGKGLEWVAVIWHDGSLKYYTQ SVKGRFTISRDNAKNTLFLQMDSLSADDTAMYY CTVWYLETPDDGFDIWGRGTMVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VLHEALHSHYTQKSLSLSPGK SEQ ID NO: 10 QLVLTQPPSASASLGVSVTLTCTLSHGHTSKAIA Light chain WHQQQPGKGPRYLMKVNSDGSHTKGAAVPD RFSGSTSGAERHFTISNLQSDDEADYYCQAWDS GIWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQ ANKATLVCLISDFYPGAVTVAWKADSSPVKAGV ETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSC QVTHEGSTVEKTVAPTECS MGU10variant1 (MGU10v1) SEQ ID NO: 11 QVQLVESGGGVVQPGRSLRLSCAASGFAFSNY VH GMHWVRQAPGKGLEWVAVIWHDGSLKYYTQ SVKGRFTISRDNAKNTLFLQMDSLSADDTAMYY CTVWYLETPDDGFDIWGQGTMVTVSS MGU10variant2 (MGU10v2) SEQ ID NO: 12 TVWYLETPDEGFDI CDRH3 SEQ ID NO: 13 QVQLVESGGGVVQPGRSLRLSCAASGFAFSNY VH GMNWVRQAPGKGLEWVAVIWHDGSLKYYTQ SVKGRFTISRDNAKNTLFLQMDSLSADDTAMYY CTVWYLETPDEGFDIWGRGTMVTVSS MGU10variant3 (MGU10v3) SEQ ID NO: 14 QAWESGIWV CDRL3 SEQ ID NO: 15 QLVLTQPPSASASLGVSVTLTCTLSHGHTSKAIA VL WHQQQPGKGPRYLMKVNSDGSHTKGAAVPD RFSGSTSGAERHFTISNLQSDDEADYYCQAWES GIWVFGGGTKLTVL MGU10variant4 (MGU10v4) SEQ ID NO: 16 QVQLVESGGGVVQPGRSLRLSCAASGFAFSNY VH GMHWVRQAPGKGLEWVAVIWHDGSLKYYTQ SVKGRFTISRDNAKNTLFLQMDSLSADDTAMYY CTVWYLETPDEGFDIWGQGTMVTVSS MGH2 SEQ ID NO: 17 GFSFSSYA CDRH1 SEQ ID NO: 18 TRYDGSNK CDRH2 SEQ ID NO: 19 AKVGDGTVAGTIDY CDRH3 SEQ ID NO: 20 QSLVYSDGNTY CDRL1 SEQ ID NO: 21 KVS CDRL2 SEQ ID NO: 22 LIYKVSNRD CDRL2 long SEQ ID NO: 23 MQGTHWWT CDRL3 SEQ ID NO: 24 QVQLVESGGGVVQPGGSLRLSCTASGFSFSSYA VH MHWVRQAPGKGLEWVAYTRYDGSNKFYLDSV QGRFTISRDNSKNTLYLEMDSLRLEDTAVYFCAK VGDGTVAGTIDYWGQGTLVTVSS SEQ ID NO: 25 YIVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGN VL TYLNWYQQRPGQSPRRLIYKVSNRDSGVPDRFS GSGSGTDFTLKISRVEAEDVGVYYCMQGTHW WTFGQGTKVEIK SEQ ID NO: 26 QVQLVESGGGVVQPGGSLRLSCTASGFSFSSYA Heavy chain MHWVRQAPGKGLEWVAYTRYDGSNKFYLDSV QGRFTISRDNSKNTLYLEMDSLRLEDTAVYFCAK VGDGTVAGTIDYWGQGTLVTVSSASTKGPSVF PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLH EALHSHYTQKSLSLSPGK SEQ ID NO: 27 YIVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGN Light chain TYLNWYQQRPGQSPRRLIYKVSNRDSGVPDRFS GSGSGTDFTLK1SRVEAEDVGVYYCMQGTHW WTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGT ASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC MGH2variant1 (MGH2v1) SEQ ID NO: 28 MQGTHFWT CDRL3 SEQ ID NO: 29 YIVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGN VL TYLNWYQQRPGQSPRRLIYKVSNRDSGVPDRFS GSGSGTDFTLKISRVEAEDVGVYYCMQGTHFW TFGQGTKVEIK Constant regions SEQ ID NO: 30 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE heavy chain constant PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV region TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVLHEALHSHYTQKSLSLSPGK SEQ ID NO: 31 GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYP lambda light chain GAVTVAWKADSSPVKAGVETTTPSKQSNNKYA ASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVA PTECS SEQ ID NO: 32 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR kappa light chain EAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 33 MMRKLAILSVSSFLFVEALFQEYQCYGSSSNTRVL PfCSP NELNYDNAGTNLYNELEMNYYGKQENWYSLK KNSRSLGENDDGNNEDNEKLRKPKHKKLKQPA DGNPDPNANPNVDPNANPNVDPNANPNVDP NANPNANPNANPNANPNANPNANPNANPNA NPNANPNANPNANPNANPNANPNANPNANP NANPNANPNVDPNANPNANPNANPNANPNA NPNANPNANPNANPNANPNANPNANPNANP NANPNANPNANPNANPNANPNANPNKNNQ GNGQGHNMPNDPNRNVDENANANSAVKNN NNEEPSDKHIKEYLNKIQNSLSTEWSPCSVTCGN GIQVRIKPGSANKPKDELDYANDIEKKICKMEKC SSVFNVVNSSIGLIMVLSFLFLN SEQ ID NO: 34 NANPNANPNANPNANPNA NANP-peptide SEQ ID NO: 35 KQPADGNPDPNANPN NPDP-peptide Nucleic acid sequences SEQ ID NO: 36 CAGGTGCAGCTGGTGGAGAGCGGAGGAGG MGU10v1 VH AGTGGTGCAGCCAGGCCGGTCCCTGAGACT GTCTTGCGCCGCCAGCGGCTTCGCCTTTTCC AACTACGGAATGCACTGGGTGCGGCAGGCA CCTGGCAAGGGACTGGAGTGGGTGGCCGTG ATCTGGCACGACGGATCCCTGAAGTACTATA CACAGTCTGTGAAGGGCAGGTTCACCATCTC TCGCGACAACGCCAAGAATACACTGTTTCTG CAGATGGATTCTCTGAGCGCCGACGATACCG CCATGTACTATTGTACAGTGTGGTATCTGGAG ACCCCCGACGATGGCTTCGATATCTGGGGCC AGGGCACCATGGTGACAGTGAGCTCC SEQ ID NO: 37 CAGGTGCAGCTGGTGGAGAGCGGAGGAGG MGU10v2 VH AGTGGTGCAGCCAGGCCGGTCCCTGAGACT GTCTTGCGCCGCCAGCGGCTTCGCCTTTTCC AACTACGGCATGAATTGGGTGCGGCAGGCA CCTGGCAAGGGACTGGAGTGGGTGGCCGT GATCTGGCACGACGGATCCCTGAAGTACTAT ACACAGTCTGTGAAGGGCAGGTTCACCATCT CTCGCGACAACGCCAAGAATACACTGTTTCT GCAGATGGATTCTCTGAGCGCCGACGATACC GCCATGTACTATTGTACAGTGTGGTATCTGG AGACCCCCGACGAGGGCTTCGATATCTGGG GCAGGGGCACCATGGTGACAGTGAGCTCC SEQ ID NO: 38 CAGCTGGTGCTGACACAGCCACCTAGCGCCT MGU10v3 VL CCGCCTCTCTGGGCGTGAGCGTGACCCTGA CATGCACCCTGTCCCACGGCCACACCTCTAA GGCAATCGCATGGCACCAGCAGCAGCCAGG CAAGGGACCACGGTACCTGATGAAGGTGAA CAGCGACGGATCCCACACAAAGGGAGCAGC AGTGCCAGATCGGTTCAGCGGCTCCACATCT GGCGCCGAGAGACACTTTACCATCTCTAATC TGCAGAGCGACGATGAGGCCGACTACTATT GTCAGGCCTGGGAGTCCGGAATCTGGGTGT TCGGAGGAGGAACAAAGCTGACCGTGCTG SEQ ID NO: 39 TACATCGTGATGACCCAGTCCCCCCTGTCTCT MGH2v1 VL GCCTGTGACACTGGGCCAGCCTGCCTCTATC AGCTGCCGGAGCTCCCAGAGCCTGGTGTAC TCCGACGGCAACACCTACCTGAATTGGTATC AGCAGAGGCCAGGACAGTCCCCACGGAGAC TGATCTATAAGGTGTCTAACAGGGACAGCGG AGTGCCAGATCGCTTCTCCGGATCTGGAAGC GGAACCGACTTTACACTGAAGATCTCTCGGG TGGAGGCCGAGGATGTGGGCGTGTACTATT GTATGCAGGGCACCCACTTCTGGACATTTGG CCAGGGCACAAAGGTGGAGATCAAG SEQ ID NO: 40 CAGGTGCAGCTGGTGGAGAGCGGCGGCGG MGU10 VHv1 CGTGGTGCAGCCCGGCAGAAGCCTGAGACT GAGCTGCGCCGCCAGCGGCTTCGCCTTCAG CAACTACGGCATGAACTGGGTGAGACAGGC CCCCGGCAAGGGCCTGGAGTGGGTGGCCG TGATCTGGCACGACGGCAGCCTGAAGTACTA CACCCAGAGCGTGAAGGGCAGATTCACCAT CAGCAGAGACAACGCCAAGAACACCCTGTTC CTGCAGATGGACAGCCTGAGCGCCGACGAC ACCGCCATGTACTACTGCACCGTGTGGTACC TGGAGACCCCCGACGACGGCTTCGACATCT GGGGCAGAGGCACCATGGTGACCGTGAGC AGC SEQ ID NO: 41 CAGCTTCAGTTAGTCGAGAGTGGGGGCGGG MGU10 VHv2 GTTGTGCAACCAGGGAGATCGTTGAGGCTC AGCTGCGCAGCCAGTGGCTTCGCCTTCAGTA ATTACGGCATGAACTGGGTTAGGCAGGCTCC TGGCAAAGGTTTGGAGTGGGTAGCAGTGAT TTGGCATGACGGCTCTTTGAAATATTACACAC AGAGTGTGAAAGGAAGATTCACAATCAGCA GAGACAACGCCAAGAATACTCTGTTCCTGCA GATGGATTCCCTGTCAGCCGACGACACGGC CATGTATTACTGTACCGTGTGGTATCTCGAGA CACCCGATGATGGCTTCGACATCTGGGGGA GAGGCACCATGGTTACCGTGAGCAGC SEQ ID NO: 42 CAGGTCCAGCTGGTCGAGTCAGGCGGGGG MGU10 VHv3 CGTTGTCCAACCGGGACGCTCTTTGCGATTA TCTTGCGCAGCGTCCGGCTTTGCGTTCAGTA ATTATGGCATGAACTGGGTCCGACAAGCTCC CGGAAAAGGGCTGGAATGGGTTGCGGTGAT TTGGCATGACGGAAGCTTGAAGTACTATACG CAGTCAGTGAAAGGAAGGTTCACAATTTCAC GGGATAATGCGAAGAACACTCTATTCCTACA GATGGACTCACTTTCCGCTGACGACACCGCC ATGTATTACTGCACCGTTTGGTACTTGGAAAC GCCGGACGACGGGTTTGATATCTGGGGCAG AGGGACAATGGTTACCGTTTCCTCA SEQ ID NO: 43 CAGGTGCAGCTGGTGGAGAGCGGCGGCGG MGU10 heavy chain CGTGGTGCAGCCCGGCAGAAGCCTGAGACT variant 1 GAGCTGCGCCGCCAGCGGCTTCGCCTTCAG CAACTACGGCATGAACTGGGTGAGACAGGC CCCCGGCAAGGGCCTGGAGTGGGTGGCCG TGATCTGGCACGACGGCAGCCTGAAGTACTA CACCCAGAGCGTGAAGGGCAGATTCACCAT CAGCAGAGACAACGCCAAGAACACCCTGTTC CTGCAGATGGACAGCCTGAGCGCCGACGAC ACCGCCATGTACTACTGCACCGTGTGGTACC TGGAGACCCCCGACGACGGCTTCGACATCT GGGGCAGAGGCACCATGGTGACCGTGAGC AGCGCCAGCACCAAGGGCCCCAGCGTGTTC CCCCTGGCCCCCAGCAGCAAGAGCACCAGC GGCGGCACCGCCGCCCTGGGCTGCCTGGTG AAGGACTACTTCCCCGAGCCCGTGACCGTGA GCTGGAACAGCGGCGCCCTGACCAGCGGC GTGCACACCTTCCCCGCCGTGCTGCAGAGCA GCGGCCTGTACAGCCTGAGCAGCGTGGTGA CCGTGCCCAGCAGCAGCCTGGGCACCCAGA CCTACATCTGCAACGTGAACCACAAGCCCAG CAACACCAAGGTGGACAAGAAGGTGGAGCC CAAGAGCTGCGACAAGACCCACACCTGCCC CCCCTGCCCCGCCCCCGAGCTGCTGGGCGG CCCCAGCGTGTTCCTGTTCCCCCCCAAGCCC AAGGACACCCTGATGATCAGCAGAACCCCC GAGGTGACCTGCGTGGTGGTGGACGTGAGC CACGAGGACCCCGAGGTGAAGTTCAACTGG TACGTGGACGGCGTGGAGGTGCACAACGCC AAGACCAAGCCCAGAGAGGAGCAGTACAAC AGCACCTACAGAGTGGTGAGCGTGCTGACC GTGCTGCACCAGGACTGGCTGAACGGCAAG GAGTACAAGTGCAAGGTGAGCAACAAGGCC CTGCCCGCCCCCATCGAGAAGACCATCAGCA AGGCCAAGGGCCAGCCCAGAGAGCCCCAG GTGTACACCCTGCCCCCCAGCAGAGACGAG CTGACCAAGAACCAGGTGAGCCTGACCTGC CTGGTGAAGGGCTTCTACCCCAGCGACATCG CCGTGGAGTGGGAGAGCAACGGCCAGCCC GAGAACAACTACAAGACCACCCCCCCCGTGC TGGACAGCGACGGCAGCTTCTTCCTGTACAG CAAGCTGACCGTGGACAAGAGCAGATGGCA GCAGGGCAACGTGTTCAGCTGCAGCGTGCT GCACGAGGCCCTGCACAGCCACTACACCCA GAAGAGCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 44 CAGGTTCAGTTAGTCGAGAGTGGGGGCGGG MGU10 heavy chain GTTGTGCAACCAGGGAGATCGTTGAGGCTC variant 2 AGCTGCGCAGCCAGTGGCTTCGCCTTCAGTA ATTACGGCATGAACTGGGTTAGGCAGGCTCC TGGCAAAGGTTTGGAGTGGGTAGCAGTGAT TTGGCATGACGGCTCTTTGAAATATTACACAC AGAGTGTGAAAGGAAGATTCACAATCAGCA GAGACAACGCCAAGAATACTCTGTTCCTGCA GATGGATTCCCTGTCAGCCGACGACACGGC CATGTATTACTGTACCGTGTGGTATCTCGAGA CACCCGATGATGGCTTCGACATCTGGGGGA GAGGCACCATGGTTACCGTGAGCAGCGCTT CCACCAAAGGCCCATCCGTCTTCCCACTGGC CCCCTCCTCAAAAAGTACCTCAGGAGGGACC GCCGCCTTGGGCTGCCTTGTAAAAGACTACT TCCCTGAGCCCGTTACTGTCTCTTGGAACTCC GGCGCTCTGACCTCCGGCGTTCATACGTTTC CTGCCGTGCTTCAGTCCAGTGGCTTGTATTCC CTGAGCTCTGTAGTCACCGTGCCGAGCAGTA GCCTCGGCACACAGACGTACATATGTAACGT GAATCACAAGCCATCTAACACTAAAGTCGAT AAAAAAGTAGAGCCTAAAAGCTGTGATAAAA CCCACACATGTCCGCCATGTCCCGCGCCCGA ACTGTTGGGCGGGCCCAGTGTGTTCCTATTC CCACCAAAACCGAAAGACACCTTGATGATCA GTCGCACACCTGAGGTAACCTGCGTGGTCGT CGACGTCTCCCACGAAGACCCCGAGGTCAA GTTTAACTGGTATGTTGATGGCGTCGAGGTA CACAATGCAAAAACCAAACCAAGGGAAGAA CAATATAATAGTACATATCGCGTGGTGAGTG TCCTCACCGTGCTCCACCAGGACTGGCTAAA TGGGAAGGAGTATAAATGCAAGGTGAGCAA CAAGGCACTCCCGGCCCCAATTGAGAAAACC ATTTCCAAAGCCAAGGGCCAACCACGAGAAC CACAGGTCTACACCCTCCCACCTTCACGCGA CGAGTTGACAAAGAATCAAGTGTCTCTCACC TGTCTTGTGAAGGGGTTTTATCCCAGTGATAT CGCGGTGGAATGGGAGAGCAATGGACAACC AGAGAACAACTATAAGACCACCCCGCCTGTC CTGGATTCCGACGGATCTTTCTTCCTTTATTCA AAGTTGACCGTGGACAAGTCCCGGTGGCAG CAAGGGAATGTGTTCAGCTGCTCGGTGCTCC ATGAGGCCCTTCACAGCCACTATACGCAGAA GAGCTTATCTCTGAGCCCTGGGAAG SEQ ID NO: 45 CAGGTCCAGCTGGTCGAGTCAGGCCGGGG MGU10 heavy chain CGTTGTCCAACCGGGACGCTCTTTGCGATTA variant 3 TCTTGCGCAGCGTCCGGCTTTGCGTTCAGTA ATTATGGCATGAACTGGGTCCGACAAGCTCC CGGAAAAGGGCTGGAATGGGTTGCGGTGAT TTGGCATGACGGAAGCTTGAAGTACTATACG CAGTCAGTGAAAGGAAGGTTCACAATTTCAC GGGATAATGCGAAGAACACTCTATTCCTACA GATGGACTCACTTTCCGCTGACGACACCGCC ATGTATTACTGCACCGTTTGGTACTTGGAAAC GCCGGACGACGGGTTTGATATCTGGGGCAG AGGGACAATGGTTACCGTTTCCTCAGCCAGT ACGAAGGGGCCCTCAGTATTTCCGCTAGCGC CGAGCTCAAAGTCGACATCTGGGGGCACAG CAGCACTGGGATGTCTGGTCAAAGATTACTT CCCCGAGCCTGTAACCGTTAGTTGGAATAGT GGTGCCTTAACGAGTGGGGTTCATACATTTC CAGCGGTACTCCAGTCCTCAGGGCTCTACTC CTTATCAAGCGTCGTTACAGTCCCAAGTTCAT CGCTAGGTACTCAAACTTACATCTGCAATGTT AACCATAAGCCCAGCAATACCAAAGTCGACA AAAAAGTCGAACCGAAGTCCTGCGACAAGA CGCACACGTGTCCACCTTGTCCTGCCCCGGA GTTATTGGGCGGCCCGTCGGTGTTCTTGTTT CCTCCCAAACCGAAGGATACCCTAATGATTTC GAGGACGCCAGAAGTAACATGTGTTGTGGT CGATGTATCTCATGAAGACCCAGAGGTTAAG TTCAACTGGTATGTCGATGGCGTCGAAGTAC ACAACGCAAAGACCAAACCCAGGGAAGAAC AGTACAATAGTACTTATAGGGTTGTATCAGTA CTTACGGTCCTGCATCAGGACTGGCTTAACG GTAAAGAGTACAAATGTAAGGTGTCTAATAA GGCACTGCCCGCGCCAATTGAAAAAACCATC TCGAAAGCTAAGGGCCAGCCCAGAGAACCT CAAGTGTACACGCTTCCGCCGAGTCGCGAC GAACTGACTAAGAACCAGGTTTCTCTGACTT GCCTAGTTAAAGGTTTCTACCCGTCGGACAT AGCAGTCGAATGGGAAAGCAACGGCCAGCC GGAGAACAACTACAAGACCACGCCTCCGGT GCTCGATTCGGATGGGTCTTTCTTTTTATATTC GAAATTAACCGTGGATAAAAGTCGGTGGCAA CAAGGTAATGTTTTCAGTTGTTCTGTCCTTCA CGAAGCCCTACATTCGCACTACACGCAAAAG AGTTTAAGTTTGTCACCGGGGAAG SEQ ID NO: 46 CAGCTGGTGCTGACCCAGCCCCCCAGCGCC MGU10 VLv1 AGCGCCAGCCTGGGCGTGAGCGTGACCCTG ACCTGCACCCTGAGCCACGGCCACACCAGC AAGGCCATCGCCTGGCACCAGCAGCAGCCC GGCAAGGGCCCCAGATACCTGATGAAGGTG AACAGCGACGGCAGCCACACCAAGGGCGCC GCCGTGCCCGACAGATTCAGCGGCAGCACC AGCGGCGCCGAGAGACACTTCACCATCAGC AACCTGCAGAGCGACGACGAGGCCGACTAC TACTGCCAGGCCTGGGACAGCGGCATCTGG GTGTTCGGCGGCGGCACCAAGCTGACCGTG CTG SEQ ID NO: 47 CAGTTGGTGTTGACCCAACCACCGTCTGCCT MGU10 VLv2 CTGCAAGTCTGGGGGTGTCTGTGACACTTAC TTGCACGCTGTCTCACGGGCACACAAGCAAG GCCATTGCTTGGCACCAACAGCAGCCTGGCA AGGGACCTCGGTACTTGATGAAGGTCAACTC CGACGGCAGTCATACCAAAGGTGCAGCAGT GCCGGATAGATTTTCCGGCTCCACAAGTGGC GCGGAGCGCCACTTTACCATCTCCAACCTTC AGAGCGATGACGAAGCTGATTATTATTGTCA GGCCTGGGACTCAGGCATATGGGTATTCGG GGGGGGGACCAAGCTCACCGTGTTA SEQ ID NO: 48 CAACTCGTTCTCACCCAACCGCCTTCAGCCA MGU10 VLv3 GCGCCAGTCTCGGAGTATCGGTGACCCTTAC GTGCACACTCTCACACGGCCACACGTCGAAG GCTATAGCCTGGCATCAGCAACAACCGGGC AAAGGACCGCGTTATCTAATGAAGGTCAATT CCGACGGATCTCATACAAAAGGCGCCGCCG TACCTGACCGCTTTAGCGGGAGTACGTCCGG GGCAGAGCGTCATTTCACGATAAGTAATCTC CAGTCGGATGACGAGGCTGACTATTATTGTC AGGCCTGGGACTCAGGTATTTGGGTATTTGG AGGGGGGACCAAGTTGACGGTCTTA SEQ ID NO: 49 CAGCTGGTGCTGACCCAGCCCCCCAGCCCC MGU10 light chain AGCGCCAGCCTGGGCGTGAGCGTGACCCTG variant 1 ACCTGCACCCTGAGCCACGGCCACACCAGC AAGGCCATCGCCTGGCACCAGCAGCAGCCC GGCAAGGGCCCCAGATACCTGATGAAGGTG AACAGCGACGGCAGCCACACCAAGGGCGCC GCCGTGCCCGACAGATTCAGCGGCAGCACC AGCGGCGCCGAGAGACACTTCACCATCAGC AACCTGCAGAGCGACGACGAGGCCGACTAC TACTGCCAGGCCTGGGACAGCGGCATCTGG GTGTTCGGCGGCGGCACCAAGCTGACCGTG CTGGGCCAGCCCAAGGCCGCCCCCAGCGTG ACCCTGTTCCCCCCCAGCAGCGAGGAGCTG CAGGCCAACAAGGCCACCCTGGTGTGCCTG ATCAGCGACTTCTACCCCGGCGCCGTGACCG TGGCCTGGAAGGCCGACAGCAGCCCCGTGA AGGCCGGCGTGGAGACCACCACCCCCAGCA AGCAGAGCAACAACAAGTACGCCGCCAGCA GCTACCTGAGCCTGACCCCCGAGCAGTGGA AGAGCCACAGAAGCTACAGCTGCCAGGTGA CCCACGAGGGCAGCACCGTGGAGAAGACC GTGGCCCCCACCGAGTGCAGC SEQ ID NO: 50 CAGTTGGTGTTGACCCAACCACCGTCTGCCT MGU10 light chain CTGCAAGTCTGGGGGTGTCTGTGACACTTAC variant 2 TTGCACGCTGTCTCACGGGCACACAAGCAAG GCCATTGCTTGGCACCAACAGCAGCCTGGCA AGGGACCTCGGTACTTGATGAAGGTCAACTC CGACGGCAGTCATACCAAAGGTGCAGCAGT GCCGGATAGATTTTCCGGCTCCACAAGTGGC GCGGAGCGCCACTTTACCATCTCCAACCTTC AGAGCGATGACGAAGCTGATTATTATTGTCA GGCCTGGGACTCAGGCATATGGGTATTCGG GGGGGGGACCAAGCTCACCGTGTTAGGGCA ACCGAAAGCGGCACCCAGTGTGACCCTGTTT CCCCCCAGCAGTGAGGAACTCCAGGCAAAT AAGGCCACTTTGGTCTGTCTGATTAGTGATTT TTATCCCGGGGCAGTCACCGTGGCTTGGAAA GCGGACTCTTCTCCCGTAAAAGCCGGAGTCG AGACCACTACACCGTCTAAGCAGAGTAATAA CAAATATGCTGCTAGCTCTTACCTGTCCCTGA CACCAGAACAGTGGAAGTCCCATAGGAGTTA TAGCTGCCAGGTCACACACGAGGGGAGCAC CGTGGAGAAGACAGTTGCACCCACTGAGTG CTCC SEQ ID NO: 51 CAACTCCTTCTCACCCAACCGCCTTCAGCCA MGU10 light chain GCGCCAGTCTCGGAGTATCGGTGACCCTTAC variant 3 GTGCACACTCTCACACGGCCACACGTCGAAG GCTATAGCCTGGCATCAGCAACAACCGGGC AAAGGACCGCGTTATCTAATGAAGGTCAATT CCGACGGATCTCATACAAAAGGCGCCGCCG TACCTGACCGCTTTAGCGGGAGTACGTCCGG GGCAGAGCGTCATTTCACGATAAGTAATCTC CAGTCGGATGACGAGGCTGACTATTATTGTC AGGCCTGGGACTCAGGTATTTGGGTATTTGG AGGGGGGACCAAGTTGACGGTCTTAGGCCA GCCTAAGGCGGCGCCGTCTGTTACTTTATTC CCTCCTTCTTCGGAGGAGCTTCAGGCCAACA AGGCCACCCTTGTATGTCTTATATCCGACTTT TATCCTGGAGCCGTTACTGTTGCGTGGAAGG CCGACTCGTCGCCTGTCAAGGCCGGGGTCG AGACTACGACCCCTTCAAAGCAAAGTAACAA TAAGTACGCTGCAAGCTCTTATCTGTCACTAA CGCCTGAGCAGTGGAAGTCGCACAGATCAT ATAGCTGCCAGGTTACCCATGAAGGGAGCA CTGTGGAAAAAACCGTTGCACCAACTGAATG CAGC SEQ ID NO: 52 CAGGTGCAGCTGGTGGAGAGCGGCGGCGG MGH2 VHv1 CGTGGTGCAGCCCGGCGGCAGCCTGAGACT GAGCTGCACCGCCAGCGGCTTCAGCTTCAG CAGCTACGCCATGCACTGGGTGAGACAGGC CCCCGGCAAGGGCCTGGAGTGGGTGGCCTA CACCAGATACGACGGCAGCAACAAGTTCTAC CTGGACAGCGTGCAGGGCAGATTCACCATC AGCAGAGACAACAGCAAGAACACCCTGTAC CTGGAGATGGACAGCCTGAGACTGGAGGAC ACCGCCGTGTACTTCTGCGCCAAGGTGGGC GACGGCACCGTGGCCGGCACCATCGACTAC TGGGGCCAGGGCACCCTGGTGACCGTGAGC AGC SEQ ID NO: 53 CAGGTGCAGCTGGTGGAAAGCGGGGGGGG MGH2 VHv2 AGTCGTGCAGCCTGGCGGCTCTTTGCGGCT GTCTTGTACGGCTTCTGGATTCTCATTCTCTTC CTACGCCATGCACTGGGTCCGCCAGGCGCC CGGGAAGGGGCTGGAATGGGTTGCCTACAC AAGGTATGATGGTTCAAACAAGTTCTACTTAG ATTCAGTGCAGGGTAGATTCACTATAAGCCG GGACAATAGTAAGAACACTCTCTACCTAGAA ATGGACTCTCTCAGACTGGAAGATACCGCTG TGTACTTCTGTGCTAAGGTTGGGGACGGCAC CGTTGCCGGCACAATCGACTATTGGGGACAA GGGACCCTCGTCACAGTCAGCTCG SEQ ID NO: 54 CAAGTCCAGCTTGTCGAGTCGGGGGGAGGG MGH2 VHv3 GTTGTCCAGCCTGGTGGTAGCTTACGCCTGA GTTGTACAGCATCGGGGTTTAGCTTCTCTTCC TATGCGATGCACTGGGTGAGACAGGCTCCC GGAAAGGGCTTAGAGTGGGTGGCCTACACT CGGTATGACGGTTCGAATAAGTTTTACTTAGA CAGCGTTCAGGGTAGGTTCACCATCTCACGT GATAATAGTAAGAATACATTATATCTTGAGAT GGACAGCCTTCGGTTGGAGGATACTGCCGT CTACTTTTGTGCTAAGGTAGGCGATGGTACG GTAGCAGGCACGATAGATTACTGGGGCCAA GGAACGTTGGTCACTGTCTCTTCA SEQ ID NO: 55 CAGGTGCAGCTGGTGGAGAGCGGCGGCGG MGH2 heavy chain CGTGGTGCAGCCCGGCGGCAGCCTGAGACT variant 1 GAGCTGCACCGCCAGCGGCTTCAGCTTCAG CAGCTACGCCATGCACTGGGTGAGACAGGC CCCCGGCAAGGGCCTGGAGTGGGTGGCCTA CACCAGATACGACGGCAGCAACAAGTTCTAC CTGGACAGCGTGCAGGGCAGATTCACCATC AGCAGAGACAACAGCAAGAACACCCTGTAC CTGGAGATGGACAGCCTGAGACTGGAGGAC ACCGCCGTGTACTTCTGCGCCAAGGTGGGC GACGGCACCGTGGCCGGCACCATCGACTAC TGGGGCCAGGGCACCCTGGTGACCGTGAGC AGCGCCAGCACCAAGGGCCCCAGCGTGTTC CCCCTGGCCCCCAGCAGCAAGAGCACCAGC GGCGGCACCGCCGCCCTGGGCTGCCTGGTG AAGGACTACTTCCCCGAGCCCGTGACCGTGA GCTGGAACAGCGGCGCCCTGACCAGCGGC GTGCACACCTTCCCCGCCGTGCTGCAGAGCA GCGGCCTGTACAGCCTGAGCAGCGTGGTGA CCGTGCCCAGCAGCAGCCTGGGCACCCAGA CCTACATCTGCAACGTGAACCACAAGCCCAG CAACACCAAGGTGGACAAGAAGGTGGAGCC CAAGAGCTGCGACAAGACCCACACCTGCCC CCCCTGCCCCGCCCCCGAGCTGCTGGGCGG CCCCAGCGTGTTCCTGTTCCCCCCCAAGCCC AAGGACACCCTGATGATCAGCAGAACCCCC GAGGTGACCTGCGTGGTGGTGGACGTGAGC CACGAGGACCCCGAGGTGAAGTTCAACTGG TACGTGGACGGCGTGGAGGTGCACAACGCC AAGACCAAGCCCAGAGAGGAGCAGTACAAC AGCACCTACAGAGTGGTGAGCGTGCTGACC GTGCTGCACCAGGACTGGCTGAACGGCAAG GAGTACAAGTGCAAGGTGAGCAACAAGGCC CTGCCCGCCCCCATCGAGAAGACCATCAGCA AGGCCAAGGGCCAGCCCAGAGAGCCCCAG GTGTACACCCTGCCCCCCAGCAGAGACGAG CTGACCAAGAACCAGGTGAGCCTGACCTGC CTGGTGAAGGGCTTCTACCCCAGCGACATCG CCGTGGAGTGGGAGAGCAACGGCCAGCCC GAGAACAACTACAAGACCACCCCCCCCGTGC TGGACAGCGACGGCAGCTTCTTCCTGTACAG CAAGCTGACCGTGGACAAGAGCAGATGGCA GCAGGGCAACGTGTTCAGCTGCAGCGTGCT GCACGAGGCCCTGCACAGCCACTACACCCA GAAGAGCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 56 CAGGTGCAGCTGGTGGAAAGCGGGGGGGG MGH2 heavy chain AGTCGTGCAGCCTGGCGGCTCTTTGCGGCT variant 2 GTCTTGTACGGCTTCTGGATTCTCATTCTCTTC CTACGCCATGCACTGGGTCCGCCAGGCGCC CGGGAAGGGGCTGGAATGGGTTGCCTACAC AAGGTATGATGGTTCAAACAAGTTCTACTTAG ATTCAGTGCAGGGTAGATTCACTATAAGCCG GGACAATAGTAAGAACACTCTCTACCTAGAA ATGGACTCTCTCAGACTGGAAGATACCGCTG TGTACTTCTGTGCTAAGGTTGGGGACGGCAC CGTTGCCGGCACAATCGACTATTGGGGACAA GGGACCCTCGTCACAGTCAGCTCGGCCAGT ACCAAGGGCCCCAGTGTGTTCCCTTTGGCCC CTTCTAGCAAATCAACGTCAGGGGGGACAG CCGCCCTTGGGTGTCTTGTGAAAGATTATTTT CCTGAGCCGGTGACCGTTTCCTGGAATAGTG GAGCACTGACAAGCGGCGTACATACCTTCCC AGCAGTGCTCCAATCAAGTGGGCTATACAGT CTGAGTAGCGTGGTCACCGTGCCATCTTCCT CTCTGGGAACTCAAACCTATATTTGCAACGTT AATCACAAACCTTCTAATACGAAAGTCGATAA GAAGGTAGAACCGAAGTCCTGCGACAAAAC CCACACATGCCCTCCGTGCCCAGCCCCTGAG CTACTGGGCGGCCCCTCTGTGTTTTTGTTTCC CCCAAAACCTAAGGATACCTTAATGATCTCAA GAACACCCGAGGTGACCTGCGTCGTGGTAG ATGTTTCTCACGAGGACCCTGAGGTTAAATTT AATTGGTACGTGGACGGCGTGGAGGTCCAT AACGCCAAGACTAAACCAAGAGAAGAGCAG TACAACTCCACATACAGGGTTGTGTCTGTGCT GACGGTCTTACACCAAGACTGGCTTAACGGC AAAGAGTATAAATGCAAGGTGAGTAATAAAG CGCTTCCTGCCCCAATCGAAAAGACCATCAG TAAAGCCAAAGGACAGCCCAGGGAGCCTCA AGTCTACACGTTACCTCCCTCAAGGGATGAG CTCACCAAAAACCAGGTGTCTCTGACCTGCC TGGTTAAGGGCTTTTATCCTTCAGACATCGCT GTTGAGTGGGAATCAAATGGGCAGCCAGAA AATAACTATAAAACTACCCCTCCTGTGCTGGA CAGTGACGGTTCGTTCTTCCTCTATAGTAAGT TGACCGTGGATAAAAGCCGATGGCAGCAGG GAAATGTGTTCAGCTGCTCTGTACTACATGA GGCCCTCCACAGTCACTATACGCAGAAGTCA CTGAGTCTAAGTCCAGGGAAG SEQ ID NO: 57 CAAGTCCAGCTTGTCGAGTCGGGGGGAGGG MGH2 heavy chain GTTGTCCAGCCTGGTGGTAGCTTACGCCTGA variant 3 GTTGTACAGCATCGGGGTTTAGCTTCTCTTCC TATGCGATGCACTGGGTGAGACAGGCTCCC GGAAAGGGCTTAGAGTGGGTGGCCTACACT CGGTATGACGGTTCGAATAAGTTTTACTTAGA CAGCGTTCAGGGTAGGTTCACCATCTCACGT GATAATAGTAAGAATACATTATATCTTGAGAT GGACAGCCTTCGGTTGGAGGATACTGCCGT CTACTTTTGTGCTAAGGTAGGCGATGGTACG GTAGCAGGCACGATAGATTACTGGGGCCAA GGAACGTTGGTCACTGTCTCTTCAGCATCTAC CAAGGGTCCATCTGTCTTCCCACTGGCCCCA TCCTCCAAAAGCACGAGCGGAGGCACCGCT GCTCTAGGGTGTCTCGTCAAGGACTACTTTC CCGAGCCAGTGACAGTTAGTTGGAATTCCGG TGCACTTACGTCGGGGGTTCACACATTCCCA GCAGTGCTGCAGTCGAGCGGCCTCTACAGC TTGTCCTCAGTCGTAACTGTTCCATCCAGTTC GCTCGGGACTCAGACTTACATCTGCAATGTA AACCACAAACCATCCAATACGAAGGTGGATA AAAAGGTTGAGCCTAAGTCATGCGACAAGAC ACATACGTGCCCACCATGTCCCGCGCCAGAG TTGCTTGGCGGACCCAGCGTCTTTCTGTTCCC ACCTAAACCCAAGGACACGTTGATGATTAGC AGGACCCCCGAAGTTACTTGTGTCGTGGTGG ATGTAAGCCATGAAGACCCAGAGGTGAAATT TAACTGGTATGTGGATGGAGTTGAAGTCCAT AATGCGAAGACAAAACCTCGAGAGGAACAA TATAACTCCACGTATCGAGTCGTGTCCGTACT CACAGTGTTACATCAAGATTGGTTAAATGGTA AAGAGTACAAATGCAAGGTTTCGAATAAAGC ACTGCCAGCGCCGATCGAAAAGACTATCTCA AAGGCAAAAGGCCAGCCCCGGGAGCCTCAA GTATATACGCTGCCGCCATCGCGCGACGAGT TAACAAAAAACCAAGTATCGTTGACGTGTTTG GTGAAAGGTTTTTACCCTTCGGATATAGCCGT GGAGTGGGAATCCAACGGTCAACCAGAGAA CAACTATAAGACAACCCCACCAGTCTTAGATA GTGATGGCTCTTTCTTCCTCTATAGTAAACTA ACGGTCGATAAATCTCGCTGGCAGCAGGGC AACGTCTTTTCGTGTTCGGTTTTACATGAAGC TCTACATAGTCACTATACCCAGAAGAGTCTAT CTCTAAGCCCCGGCAAG SEQ ID NO: 58 TACATCGTGATGACCCAGAGCCCCCTGAGCC MGH2 VLv1 TGCCCGTGACCCTGGGCCAGCCCGCCAGCA TCAGCTGCAGAAGCAGCCAGAGCCTGGTGT ACAGCGACGGCAACACCTACCTGAACTGGTA CCAGCAGAGACCCGGCCAGAGCCCCAGAAG ACTGATCTACAAGGTGAGCAACAGAGACAG CGGCGTGCCCGACAGATTCAGCGGCAGCGG CAGCGGCACCGACTTCACCCTGAAGATCAGC AGAGTGGAGGCCGAGGACGTGGGCGTGTA CTACTGCATGCAGGGCACCCACTGGTGGAC CTTCGGCCAGGGCACCAAGGTGGAGATCAA G SEQ ID NO: 59 TACATTGTTATGACCCAGAGTCCTCTTTCACT MGH2 VLv2 GCCTGTGACCCTTGGCCAGCCTGCCTCCATC AGCTGCCGGTCCAGCCAATCTCTCGTGTACT CCGACGGCAATACCTACCTGAACTGGTATCA ACAACGACCCGGCCAGTCACCCAGACGCCT GATCTATAAGGTCAGCAATCGGGACAGCGG CGTCCCGGATAGGTTCTCAGGTTCAGGTTCA GGCACCGATTTCACGCTGAAAATTAGTAGAG TTGAGGCAGAAGATGTCGGCGTGTACTACTG TATGCAGGGTACCCATTGGTGGACCTTTGGG CAGGGCACAAAAGTAGAGATTAAG SEQ ID NO: 60 TACATAGTAATGACGCAGAGTCCTCTGTCCTT MGH2 VLv3 ACCAGTTACACTGGGCCAACCTGCATCTATAT CGTGTCGATCATCTCAGTCCCTCGTGTACTCA GATGGAAATACGTATTTGAACTGGTATCAAC AGCGTCCGGGACAGAGCCCTCGCCGTTTAAT CTACAAAGTTAGTAACCGAGACAGTGGCGTT CCTGACCGTTTCTCAGGATCAGGTTCCGGGA CAGATTTCACCTTAAAAATAAGCAGGGTTGA AGCTGAGGACGTGGGGGTTTATTATTGCATG CAGGGTACCCACTGGTGGACTTTTGGACAG GGTACGAAGGTTGAGATCAAG SEQ ID NO: 61 TACATCGTGATGACCCAGAGCCCCCTGAGCC MGH2 light chain TGCCCGTGACCCTGGGCCAGCCCGCCAGCA variant 1 TCAGCTGCAGAAGCAGCCAGAGCCTGGTGT ACAGCGACGGCAACACCTACCTGAACTGGTA CCAGCAGAGACCCGGCCAGAGCCCCAGAAG ACTGATCTACAAGGTGAGCAACAGAGACAGC GGCGTGCCCGACAGATTCAGCGGCAGCGGC AGCGGCACCGACTTCACCCTGAAGATCAGCA GAGTGGAGGCCGAGGACGTGGGCGTGTACT ACTGCATGCAGGGCACCCACTGGTGGACCTT CGGCCAGGGCACCAAGGTGGAGATCAAGAG AACCGTGGCCGCCCCCAGCGTGTTCATCTTC CCCCCCAGCGACGAGCAGCTGAAGAGCGGC ACCGCCAGCGTGGTGTGCCTGCTGAACAACT TCTACCCCAGAGAGGCCAAGGTGCAGTGGA AGGTGGACAACGCCCTGCAGAGCGGCAACA GCCAGGAGAGCGTGACCGAGCAGGACAGC AAGGACAGCACCTACAGCCTGAGCAGCACC CTGACCCTGAGCAAGGCCGACTACGAGAAG CACAAGGTGTACGCCTGCGAGGTGACCCAC CAGGGCCTGAGCAGCCCCGTGACCAAGAGC TTCAACAGAGGCGAGTGC SEQ ID NO: 62 TACATTGTTATGACCCAGAGTCCTCTTTCACT MGH2 light chain GCCTGTGACCCTTGGCCAGCCTGCCTCCATC variant 2 AGCTGCCGGTCCAGCCAATCTCTCGTGTACT CCGACGGCAATACCTACCTGAACTGGTATCA ACAACGACCCGGCCAGTCACCCAGACGCCT GATCTATAAGGTCAGCAATCGGGACAGCGG CGTCCCGGATAGGTTCTCAGGTTCAGGTTCA GGCACCGATTTCACGCTGAAAATTAGTAGAG TTGAGGCAGAAGATGTCGGCGTGTACTACTG TATGCAGGGTACCCATTGGTGGACCTTTGGG CAGGGCACAAAAGTAGAGATTAAGCGGACT GTGGCAGCTCCCTCAGTCTTTATATTTCCCCC ATCCGATGAGCAGTTGAAAAGCGGGACCGC ATCAGTTGTGTGTCTGTTGAACAAGTTTTACC CTCGGGAGGCCAAGGTGCAGTGGAAGGTTG ATAACGCTTTACAGTCAGGCAATTCTCAGGA AAGTGTAACAGAACAGGATTCTAAGGACTCA ACTTATAGCCTCTCCAGCACCCTCACATTGTC AAAGGCCGACTATGAGAAGCACAAAGTGTAT GCGTGTGAGGTTACACATCAGGGCCTGAGC TCTCCGGTAACAAAGTCTTTTAACAGGGGAG AGTGC SEQ ID NO: 63 TACATAGTAATCACGCAGAGTCCTCTGTCCTT MGH2 light chain ACCAGTTACACTGGGCCAACCTGCATCTATAT variant 3 CGTGTCGATCATCTCAGTCCCTCGTGTACTCA GATGGAAATACGTATTTGAACTGGTATCAAC AGCGTCCGGGACAGAGCCCTCGCCGTTTAAT CTACAAAGTTAGTAACCGAGACAGTGGCGTT CCTGACCGTTTCTCAGGATCAGGTTCCGGGA CAGATTTCACCTTAAAAATAAGCAGGGTTGA AGCTGAGGACGTGGGGGTTTATTATTGCATG CAGGGTACCCACTGGTGGACTTTTGGACAG GGTACGAAGGTTGAGATCAAGCGGACCGTT GCAGCCCCGTCCGTCTTTATTTTCCCCCCGTC CGATGAACAATTGAAATCCGGTACAGCGTCA GTAGTATGCCTCCTGAACAATTTTTATCCTCG GGAAGCCAAGGTTCAGTGGAAAGTGGATAA CGCACTTCAGTCCGGCAACAGTCAGGAGTCT GTGACCGAGCAAGACTCTAAAGACTCAACCT ACTCTCTTTCCTCGACCCTGACTCTTTCAAAG GCGGATTATGAGAAGCACAAAGTTTATGCCT GTGAAGTAACACATCAAGGCTTGTCGTCACC GGTTACCAAATCGTTCAACAGAGGGGAGTG C SEQ ID NO: 64 GGCTTCGCCTTCAGCAACTACGGC MGU10 CDRH1v1 SEQ ID NO: 65 GGCTTCGCCTTCAGTAATTACGGC MGU10 CDRH1v2 SEQ ID NO: 66 GGGTTTGCGTTCAGTAATTATGGC MGU10 CDRH1v3 SEQ ID NO: 67 ATCTGGCACGACGGCAGCCTGAAG MGU10 CDRH2v1 SEQ ID NO: 68 ATTTGGCATGACGGCTCTTTGAAA MGU10 CDRH2v2 SEQ ID NO: 69 ATTTGGCATGACGGAAGCTTGAAG MGU10 CDRH2v3 SEQ ID NO: 70 ACCGTGTGGTACCTGGAGACCCCCGACGAC MGU10 CDRH3v1 GGCTTCGACATC SEQ ID NO: 71 ACCGTGTGGTATCTCGAGACACCCGATGATG MGU10 CDRH3v2 GCTTCGACATC SEQ ID NO: 72 ACCGTTTGGTACTTGGAAACGCCGGACGAC MGU10 CDRH3v3 GGGTTTGATATC SEQ ID NO: 73 CACGGCCACACCAGCAAGGCC MGU10 CDRL1v1 SEQ ID NO: 74 CACGGGCACACAAGCAAGGCC MGU10 CDRL1v2 SEQ ID NO: 75 CACGGCCACACGTCGAAGGCT MGU10 CDRL1v3 SEQ ID NO: 76 GTCAATTCCGACGGATCTCAT MGU10 CDRL2v1 SEQ ID NO: 77 GTCAACTCCGACGGCAGTCAT MGU10 CDRL2v2 SEQ ID NO: 78 GTGAACAGCGACGGCAGCCAC MGU10 CDRL2v3 SEQ ID NO: 79 CAGGCCTGGGACAGCGGCATCTGGGTG MGU10 CDRL3v1 SEQ ID NO: 80 CAGGCCTGGGACTCAGGCATATGGGTA MGU10 CDRL3v2 SEQ ID NO: 81 CAGGCCTGGGACTCAGGTATTTGGGTA MGU10 CDRL3v3 SEQ ID NO: 82 GGCTTCAGCTTCAGCAGCTACGCC MGH2 CDRH1v1 SEQ ID NO: 83 GGATTCTCATTCTCTTCCTACGCC MGH2 CDRH1v2 SEQ ID NO: 84 GGGTTTAGCTTCTCTTCCTATGCG MGH2 CDRH1v3 SEQ ID NO: 85 ACTCGGTATGACGGTTCGAATAAG MGH2 CDRH2v1 SEQ ID NO: 86 ACAAGGTATGATGGTTCAAACAAG MGH2 CDRH2v2 SEQ ID NO: 87 ACCAGATACGACGGCAGCAACAAG MGH2 CDRH2v3 SEQ ID NO: 88 GCCAAGGTGGGCGACGGCACCGTGGCCGG MGH2 CDRH3v1 CACCATCGACTAC SEQ ID NO: 89 GCTAAGGTTGGGGACGGCACCGTTGCCGGC MGH2 CDRH3v2 ACAATCGACTAT SEQ ID NO: 90 GCTAAGGTAGGCGATGGTACGGTAGCAGGC MGH2 CDRH3v3 ACGATAGATTAC SEQ ID NO: 91 CAGAGCCTGGTGTACAGCGACGGCAACACC MGH2 CDRL1v1 TAC SEQ ID NO: 92 CAATCTCTCGTGTACTCCGACGGCAATACCTA MGH2 CDRL1v2 C SEQ ID NO: 93 CAGTCCCTCGTGTACTCAGATGGAAATACGT MGH2 CDRL1v3 AT SEQ ID NO: 94 AAAGTTAGT MGH2 CDRL2v1 SEQ ID NO: 95 AAGGTCAGC MGH2 CDRL2v2 SEQ ID NO: 96 AAGGTGAGC MGH2 CDRL2v3 SEQ ID NO: 97 ATGCAGGGCACCCACTGGTGGACC MGH2 CDRL3v1 SEQ ID NO: 98 ATGCAGGGTACCCATTGGTGGACC MGH2 CDRL3v2 SEQ ID NO: 99 ATGCAGGGTACCCACTGGTGGACT MGH2 CDRL3v3 Amino acid sequences SEQ ID NO: 100 QVQLVESGGGVVQPGRSLRLSCAASGFAFSNY MGU10v2_LS heavy GMNWVRQAPGKGLEWVAVIWHDGSLKYYTQ chain SVKGRFTISRDNAKNTLFLQMDSLSADDTAMYY CTVWYLETPDEGFDIWGRGTMVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYTCNVNHKPSNTKVDKRVEPKSCDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV LHEALHSHYTQKSLSLSPGK SEQ ID NO: 101 QVQLVESGGGVVQPGRSLRLSCAASGFAFSNY MGU10_LS heavy GMNWVRQAPGKGLEWVAVTWHDGSLKYYTQ chain SVKGRFTISRDNAKNTLFLQMDSLSADDTAMYY CTVWYLETPDDGFDIWGRGTMVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPTEKTISKAKGQPREPQVYTLPPSREEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVLHEALHSHYTQKSLSLSPGK SEQ ID NO: 102 QVQLVESGGGVVQPGGSLRLSCTASGFSFSSYA MGH2/MGH2v1_LS MHWVRQAPGKGLEWVAYTRYDGSNKFYLDSV heavy chain QGRFTISRDNSKNTLYLEMDSLRLEDTAVYFCAK VGDGTVAGTIDYWGQGTLVTVSSASTKGPSVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEA LHSHYTQKSLSLSPGK SEQ ID NO: 103 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE heavy chain constant PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV region LS TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTTSKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVLHEALHSHYTQKSLSLSPGK SEQ ID NO: 104 QVQLVESGGGVVQPGRSLRLSCAASGFAFSNY MGU10v8 VH GMNWVRQAPGKGLEWVAVIWHDGSLKYYTQ SVKGRFTISRDNAKNTLFLQMDSLSAEDTAMYY CTVWYLETPDEGFDIWGRGTMVTVSS SEQ ID NO: 105 KQPADGNPDPNANPNVDPN NPDP19-peptide Nucleic acid sequences SEQ ID NO: 106 ACCGGTGTACATTCTCAGGTGCAGCTGGTGG MGU10v8 VH AGTCCGGAGGAGGAGTGGTGCAGCCAGGC AGGAGCCTGAGGCTGTCTTGCGCTGCTTCCG GATTCGCCTTTAGCAACTACGGCATGAATTG GGTGAGGCAGGCTCCTGGCAAGGGACTGG AGTGGGTGGCTGTGATCTGGCACGACGGCA GCCTGAAGTACTATACACAGTCTGTGAAGGG CAGATTCACCATCTCTCGCGATAACGCTAAG AATACACTGTTTCTGCAGATGGACTCTCTGTC CGCCGAGGATACCGCTATGTACTATTGTACA GTGTGGTATCTGGAGACCCCAGACGAGGGC TTCGATATCTGGGGCAGAGGCACCATGGTG ACAGTGTCCAGCGCGTCGAC