RU2793755C2 - Antibody molecules against april and applications thereof - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: molecule of antibody against a ligand A inducing proliferation (APRIL), method of preparation thereof and also the composition containing the said molecule and the panel. Nucleic acid molecule encoding the variable region of H chain (VH) and the variable region of the L chain of the said antibody molecule and also the containing cell and vector thereof are also disclosed.

EFFECT: treatment of diabetic nephropathy in a subject.

42 cl, 41 dwg, 8 tbl, 13 ex

Description

Cross-references to related applications

This application claims priority of U.S. Provisional Application No. 62/259897 filed November 25, 2015, U.S. Provisional Application No. 62/313684 filed March 25, 2016, U.S. Provisional Application No. 62/399087 filed September 23, 2016, Provisional Application US 62/422848, filed November 16, 2016. The content of the above applications is incorporated into the present description by reference in its entirety.

SEQUENCE LIST

This application contains a sequence listing, which is presented in electronic form in ASCII format and is fully incorporated into the present description by reference. The specified ASCII copy, created on November 21, 2016, is named P2029-7004WO_SL.txt and is 259298 bytes in size.

State of the art

IgA nephropathy is one of the most common chronic glomerular diseases worldwide. Conservative epidemiological estimates indicate a global incidence of approximately 5-50 cases/million (children) and 10-40 cases/million (adults). This incidence has a regional bias with higher prevalence in Asia and the Americas, with a particularly high disease burden in Japan and regions of China. Biopsy-confirmed cases of IgA nephropathy in Japan are predicted to affect approximately 350,000 people. In the US, this prognosis is approximately 100,000, and as such, this disease is the most commonly diagnosed glomerular disease in adults. Despite the relatively slow course of the disease, IgA nephropathy leads to end-stage renal disease (ESRD), i.e. kidney failure in 20-50% of patients within 20-30 years. These figures are probably grossly underestimated given the need to confirm the disease with kidney biopsy, a protocol that can be applied in a variety of clinical settings. The disease has a complex pathogenesis with genetic, epidemiological, and potentially environmental components for the etiology, pathology, and progression of the disease. It also has a variable clinical presentation, ranging from asymptomatic to end-stage renal disease (ESRD). IgG nephropathy is caused by the deposition of IgA, usually in the form of immune complexes, in the mesangium of the kidney. Currently, there are no specific treatments for the disease directed at the primary disease or progression.

There is a need to develop new approaches to the treatment, prevention and diagnosis of IgA nephropathy and other disorders that share similar disease mechanisms.

The essence of the invention

The present disclosure provides, at least in part, antibody molecules that bind to APRIL, eg, human and/or murine APRIL, and that have one or more of the functional and structural properties disclosed herein. In one embodiment, the antibody molecule binds to APRIL and/or reduces (eg, inhibits, blocks or neutralizes) one or more APRIL activities. In one embodiment, the antibody molecule binds to a region in APRIL that interacts with TACI (eg, the CRD2 domain of TACI). In one embodiment, the antibody molecule binds to one or more residues within the human APRIL region as defined in any of Tables 3-4 or 7-8. Without wishing to be bound by theory, it is believed that in one embodiment, improved or optimal inhibition of APRIL activity can be achieved by targeting specific regions on APRIL (eg, region(s) associated with interactions from APRIL and the TACI CDR2 domain). In one embodiment, the antibody molecule is selected from Table 1 or 5 or competes for binding to APRIL with an antibody molecule selected from Table 1 or 5. In one embodiment, the antibody molecule binds to the same or overlapping epitope as the epitope recognized by the antibody molecule selected from Table 1 or 5. In one embodiment, the antibody molecule contains one or more heavy chain variable regions and/or one or more light chain variable regions described in Table 1 or 5. In one embodiment, the antibody molecule contains one or more Heavy chain CDRs and/or one or more light chain CDRs described in Table 1 or 5. In one embodiment, nucleic acid molecules encoding antibody molecules, expression vectors, host cells, compositions (e.g., pharmaceutical compositions), kits are also provided. , containers and methods for obtaining antibody molecules. The antibody molecules disclosed herein may be used (alone or in combination with other agents or therapeutic modalities) for the treatment, prevention and/or diagnosis of disorders associated with APRIL, such as IgA nephropathy.

Accordingly, in some aspects, the present disclosure provides an antibody molecule, e.g., an antibody molecule described herein having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23) of the following properties:

a) Binds to human APRIL with high affinity, e.g., a dissociation constant (KD) of less than about 100 nM, typically about 10 nM, and more typically about 10-0.001 nM, about 10-0.01 nM, about 5- 0.01 nM, about 3-0.05 nM, about 1-0.1 nM or greater, such as less than about 80, 70, 60, 50, 40, 30, 20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005 or 0.001 nM,

b) Binds to murine APRIL with high affinity, e.g., a dissociation constant (KD) of less than about 100 nM, typically about 10 nM and more typically about 10-0.001 nM, about 10-0.01 nM, about 5 -0.01 nM, about 3-0.05 nM, about 1-0.1 nM, or greater, e.g., less than about 80, 70, 60, 50, 40, 30, 20, 10, 8, 6, 4 , 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005 or 0.001 nM,

c) Does not bind to mouse APRIL or binds to mouse APRIL with low affinity, e.g., a dissociation constant (KD) of greater than about 500 nM, e.g., greater than about 1000 nM,

d) Does not bind or binds with low affinity, e.g., a dissociation constant (KD) greater than about 500 nM, e.g., greater than about 1000 nM, to one or more (e.g., 2, 3, 4, 5, 6, 7 , 8 or more) non-APRIL TNF (TNFSF) superfamily cytokines (e.g., TNFα, CD40 (TNFSF4), FasL (TNFSF6), TRAIL (TNFSF10), RANKL (TNFSF11), Tweak (TNFSF12), BAFF (TNFSF13B) or LIGHT (TNFSF14)),

e) Binds to one or more residues (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, or all) within the APRIL region as defined in Table 3, or specifically binds to an epitope on APRIL, e.g., an epitope containing one or more residues (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or all) described in Table 3,

f) Binds to one or more residues (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all) within the APRIL region as defined in Table 4, or binds specifically to an epitope on APRIL , for example, with an epitope containing one or more residues (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all) described in Table 4,

g) Associated with one or more residues (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all) within the APRIL region , as defined in Table 7, or specifically binds to an epitope on APRIL, e.g., an epitope containing one or more residues (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or all) described in Table 7,

h) Binds to one or more residues (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, or all) within the APRIL region as defined in Table 8, or specifically binds to an epitope on APRIL, e.g., an epitope containing one or more residues (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or all) described in Table 8,

i) Specifically binds to an epitope on APRIL, e.g. the same, similar or overlapping epitope as an epitope recognized by the monoclonal antibody described in Table 1 or 5, e.g. any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419 -0205 2419-0206 2419-0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 , 2922 3327 3530 3525 3125 2621 4035 4035-062 3934 3833 3631 3732 4338 4540 4540-063 4540-033 4439

j) Reduces (eg, inhibits, blocks or neutralizes) one or more biological activities of APRIL (eg human APRIL, murine APRIL or both), in vitro , ex vivo or in vivo ,

k) Reduces (e.g., inhibits, blocks, or neutralizes) binding of human APRIL to TACI, e.g., at an IC ₅₀ of about 50 nM or less, typically about 0.01-50 nM, 0.1-25 nM, 0.1 -10 nM, 0.5-5 nM, or 1-5 nM, such as less than about 40, 30, 20, 10, 5, 1, 0.5, 0.2, 0.1, 0.05, or 0 .01 nM, for example, as determined by the method described herein,

l) Reduces (e.g., inhibits, blocks, or neutralizes) binding of murine APRIL to TACI, e.g., at an IC ₅₀ of about 100 nM or less, typically about 0.01-75 nM, 0.1-50 nM, 0.1 -25 nM, 0.1-10 nM, 0.5-5 nM, or 1-5 nM, such as less than about 80, 60, 40, 20, 10, 5, 1, 0.5, 0.2 , 0.1, 0.05, or 0.01 nM, for example, as determined by the method described herein,

m) Reduces (e.g., inhibits, blocks, or neutralizes) binding of human APRIL to BMCA, e.g., at an IC ₅₀ of about 50 nM or less, typically about 0.01-50 nM, 0.1-25 nM, 0.1-10 nM, 0.5-5 nM, or 1-5 nM, such as less than about 40, 30, 20, 10, 5, 1, 0.5, 0.2, 0.1, 0.05, or 0.01 nM, for example, as determined by the method described herein,

n) Reduces (e.g., inhibits, blocks, or neutralizes) binding of murine APRIL to BMCA, e.g., with an IC ₅₀ of about 200 nM or less, typically about 0.01-200 nM, 0.1-150 nM, 0.1 -100 nM, 0.1-50 nM, 0.1-25 nM, 0.1-10 nM, 0.5-5 nM, or 1-5 nM, e.g., less than about 150, 100, 50, 40 , 30, 20, 10, 5, 1, 0.5, 0.2, 0.1, 0.05, or 0.01 nM, for example, as determined by the method described herein,

o) Demonstrates the same or similar binding affinity or specificity, or both, as a monoclonal antibody described in Table 1 or 5, e.g. 0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439 or 4237,

p) Shows the same or similar binding affinity or specificity, or both, as an antibody molecule containing a heavy chain variable region and/or a light chain variable region described in Table 1 or 5, e.g., a heavy chain variable region and/or a variable region light chain region of any of the monoclonal antibodies , 2419-1305 2419-1306 2419-1310 2419-1406 2922 3327 3530 3525 3125 2621 4035 4035-062 , 4540-033, 4439 or 4237,

q) Shows the same or similar binding affinity or specificity, or both, as an antibody molecule containing one or more (e.g., two or three) heavy chain CDRs and/or one or more (e.g., two or three ) light chain CDRs as described in Table 1 or 5, e.g., one or more (e.g., two or three) heavy chain CDRs and/or one or more (two or three) light chain CDRs of any of the monoclonal antibodies 2218, 2419, 2419 -0105 2419-0205 2419-0206 2419-0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 , 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 437.

r) Demonstrates the same or similar binding affinity or specificity, or both, as an antibody molecule containing the amino acid sequence shown in Table 1 or 5,

s) Demonstrates the same or similar binding affinity or specificity, or both, as an antibody molecule containing the amino acid sequence encoded by the nucleotide sequence shown in Table 2,

t) Inhibits, e.g., competitively inhibits, the binding of a second antibody molecule to human APRIL, murine APRIL, or both, where the second antibody molecule is an antibody molecule selected from Table 1 or 5, e.g., any of monoclonal antibodies 2218, 2419, 2419-0105 2419-0205 2419-0206 2419-0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, or 433.

u) Competes for binding with a second antibody molecule to human APRIL, mouse APRIL, or both, where the second antibody molecule is a monoclonal antibody selected from Table 1 or 5, e.g., any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419 - 0205 2419-0206 2419-0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 , 2922 3327 3530 3525 3125 2621 4035 4035-062 3934 3833 3631 3732 4338 4540 4540-063 4540-033 4439

v) Has one or more of the biological properties of a monoclonal antibody selected from Table 1 or 5, such as any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419- 0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 3327 3530 062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439 or 4237,

w) Has one or more of the structural properties of a monoclonal antibody selected from Table 1 or 5, such as any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419- 0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 3327 3530 062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439 or 4237 or

x) Has one or more pharmacokinetic properties of a monoclonal antibody selected from Table 1 or 5, for example, any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419- 0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 3327 3530 062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439 or 4237.

In one aspect, the disclosure provides an anti-APRIL antibody molecule that:

(i) binds or substantially binds to human APRIL;

(ii) binds or substantially binds to murine APRIL;

(iii) inhibits or substantially inhibits the binding of APRIL (eg, human APRIL, mouse APRIL, or both) to TACI (eg, human TACI, mouse TACI, or both); And

(iv) inhibits or substantially inhibits the binding of APRIL (eg, human APRIL, murine APRIL, or both) to BCMA (eg, human BCMA, murine BCMA, or both).

In one embodiment, the antibody molecule is a synthetic antibody molecule. In one embodiment, the antibody molecule is an isolated antibody molecule.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, for example, 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way.

In one embodiment, the antibody molecule binds or substantially binds to murine APRIL at an EC ₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 100 nM, such as 0.001 nM to 50 nM, 0.01 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM or 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM or 0.01 nM to 0.1 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both), with an IC ₅₀ of 50 nM or less, such as 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0 .05 nM or less, 0.02 nM or less, or 0.01 nM or less, such as 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM up to 5 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), e.g., at an IC ₅₀ of 200 nM or less, 150 nM or less 100 nM or less 50 nM or less 40 nM or less 30 nM or less 20 nM or less 10 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less , 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, for example, from 0.01 nM to 50 nM, from 0, 1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0, 5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule is an IgG antibody molecule, e.g., containing an IgG heavy chain constant region, e.g., selected from IgG1, IgG2 (e.g., IgG2a), IgG3, or IgG4, e.g., IgG2 or IgG4. In one embodiment, the antibody molecule is an IgG1 antibody molecule, eg, having the IgG1 constant region described herein. In another embodiment, the antibody molecule is an IgG2 antibody molecule, eg, having the IgG2 constant region described herein. In one embodiment, the antibody molecule comprises a kappa light chain or lambda light chain constant region.

In one embodiment, the antibody molecule contains an Fc region. In one embodiment, the Fc region contains one or more mutations located at the interface between the CH2 and CH3 domains (eg, to increase the binding affinity for the neonatal FcRn receptor and/or the half-life of the antibody molecule). In one embodiment, the Fc region contains one or more mutations, e.g., one or more (e.g., 2, 3, 4, 5, 6, or all) mutations selected from T250Q, M252Y, S254T, T256E, M428L, H433K, N434F, or any combination of them in IgG1. In one embodiment, the Fc region contains one or more mutations at positions 233-236 or 322 of human IgG1 or IgG2, or one or more substitutions at positions 327, 330, or 331 of human IgG4 (e.g., to reduce complement-dependent cytotoxicity (CDC)) . In one embodiment, the Fc region contains one or more (e.g., 2, 3, 4, 5, 6, 7, or all) mutations selected from E233P, L234V, L235A, G236, K322A, A327G, A330S, P331S, or any of them. combinations.

In one embodiment, the antibody molecule is a humanized antibody molecule, for example, containing one or more framework regions derived from a human germline framework sequence. In one embodiment, the antibody molecule contains the heavy chain variable region (VH) described in Table 1 or 5. In one embodiment, the antibody molecule contains the light chain variable region (VL) described in Table 1 or 5. In one embodiment, the antibody molecule contains a heavy chain variable region (VH) and a light chain variable region (VL) described in Table 1 or 5. In one embodiment, the antibody molecule contains one, two or three CDRs of the heavy chain variable region (VH) described in Table 1 or 5. In one embodiment, the antibody molecule contains one, two, or three CDRs of the light chain variable region (VL) described in Table 1 or 5. In one embodiment, the antibody molecule contains one, two, or three CDRs of the heavy chain variable region (VH) described in Table 1 or 5, and one, two or three variable light chain (VL) CDRs described in Table 1 or 5. In one embodiment, the antibody molecule contains two heavy chain variable regions and two light chain variable regions. In one embodiment, the antibody molecule is a Fab, F(ab')2, Fv, Fd, or a single chain Fv fragment (scFv).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of of the following: (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 61); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 62); or (ii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 63).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of of the following: (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 67); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 45); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3530 (for example, SEQ ID NO: 61); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 62 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 63) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the LCDR1 monoclonal antibody 3530 (eg, SEQ ID NO: 67); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains: (i) VH containing: HCDR1 containing the amino acid sequence of HCDR1 monoclonal antibody 3530 (eg, SEQ ID NO: 61); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3530 (for example, SEQ ID NO: 62); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3530 (eg, SEQ ID NO: 63) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3530 (eg, SEQ ID NO: 67); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3530 (eg, SEQ ID NO: 45); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3530 (eg, SEQ ID NO: 46).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of of the following: (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 64); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 65); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR3 monoclonal antibody 3530 (e.g., SEQ ID NO: 63).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of of the following: (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 67); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 45); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3530 (for example, SEQ ID NO: 64); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 65 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 63) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the LCDR1 monoclonal antibody 3530 (eg, SEQ ID NO: 67); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains: (i) VH containing: HCDR1 containing the amino acid sequence of HCDR1 monoclonal antibody 3530 (for example, SEQ ID NO: 64); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3530 (for example, SEQ ID NO: 65); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3530 (eg, SEQ ID NO: 63) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3530 (eg, SEQ ID NO: 67); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3530 (eg, SEQ ID NO: 45); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3530 (eg, SEQ ID NO: 46).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 66). In one embodiment, the antibody molecule comprises a VL containing the amino acid a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology to the VL amino acid sequence of monoclonal antibody 3530 (eg, SEQ ID NO: 70).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 3530 monoclonal antibody (eg, SEQ ID NO: 66); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology to the VL amino acid sequence of a 3530 monoclonal antibody (eg, SEQ ID NO: 70). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 3530 (eg, SEQ ID NO: 66); and (ii) a VL containing the VL amino acid sequence of the monoclonal antibody 3530 (eg, SEQ ID NO: 70).

In one embodiment, the antibody molecule is a 3530 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3530 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 61); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 62); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR3 monoclonal antibody 3525 (e.g., SEQ ID NO: 63).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of of the following: (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 44); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3525 (for example, SEQ ID NO: 61); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 62 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 63) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 44); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule comprises: (i) a VH containing three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises: HCDR1 containing the HCDR1 amino acid sequence of a 3525 monoclonal antibody (e.g. ID NO: 61); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3525 (for example, SEQ ID NO: 62); and HCDR3 comprising the amino acid sequence HCDR3 of monoclonal antibody 3525 (e.g., SEQ ID NO: 63) and (ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), where the variable region of the light chain contains: LCDR1 containing the amino acid sequence of LCDR1 monoclonal antibody 3525 (for example, SEQ ID NO: 44); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 45); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 46).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of of the following: (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 64); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 65); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR3 monoclonal antibody 3525 (e.g., SEQ ID NO: 63).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of of the following: (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 44); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3525 (for example, SEQ ID NO: 64); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 65 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 3525 (e.g., SEQ ID NO: 63) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 44); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains: (i) VH containing: HCDR1 containing the amino acid sequence of HCDR1 monoclonal antibody 3525 (for example, SEQ ID NO: 64); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3525 (for example, SEQ ID NO: 65); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3525 (eg, SEQ ID NO: 63) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3525 (eg, SEQ ID NO: 44); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 45); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 46).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VH amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 66). In one embodiment, the antibody molecule contains a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the VL amino acid sequence of a 3525 monoclonal antibody (eg, SEQ ID NO: 50).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VH amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 66); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 50). In one embodiment, the antibody molecule comprises: (i) a VH comprising the VH amino acid sequence of the monoclonal antibody 3525 (eg, SEQ ID NO: 66); and (ii) a VL containing the VL amino acid sequence of the monoclonal antibody 3525 (eg, SEQ ID NO: 50).

In one embodiment, the antibody molecule is a 3525 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3525 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of of the following: (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3833 monoclonal antibody (e.g., SEQ ID NO: 113); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 114); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 115).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of of the following: (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3833 monoclonal antibody (e.g., SEQ ID NO: 116); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 117); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3833 monoclonal antibody (e.g., SEQ ID NO: 118).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3833 (for example, SEQ ID NO: 113); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 114 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 115) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 116); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 117 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In one embodiment, the antibody molecule comprises: (i) a VH containing three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises: HCDR1 containing the HCDR1 amino acid sequence of the 3833 monoclonal antibody (e.g. ID NO: 113); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3833 (for example, SEQ ID NO: 114); and HCDR3 comprising the HCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 115) and (ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the variable region of the light chain contains: LCDR1 containing the amino acid sequence of LCDR1 monoclonal antibody 3833 (for example, SEQ ID NO: 116); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 117); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 118).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of of the following: (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3833 monoclonal antibody (e.g., SEQ ID NO: 119); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 120); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 115).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of of the following: (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3833 monoclonal antibody (e.g., SEQ ID NO: 116); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 117); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3833 monoclonal antibody (e.g., SEQ ID NO: 118).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3833 (for example, SEQ ID NO: 119); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 120 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 115) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 116); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 117 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In one embodiment, the antibody molecule contains: (i) VH containing: HCDR1 containing the amino acid sequence of HCDR1 monoclonal antibody 3833 (for example, SEQ ID NO: 119); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3833 (for example, SEQ ID NO: 120); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3833 (eg, SEQ ID NO: 115) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3833 (eg, SEQ ID NO: 116); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 117); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 118).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the VH amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 121). In one embodiment, the antibody molecule contains a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the VL amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 122).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 121); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 122). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 3833 (eg, SEQ ID NO: 121); and (ii) a VL containing the VL amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 122).

In one embodiment, the antibody molecule is a 3833 monoclonal antibody. In one embodiment, the 3833 monoclonal antibody is a humanized 3833 monoclonal antibody. In one embodiment, the antibody molecule comprises a VH containing the amino acid sequence of any of SEQ ID NOs: 246-250, VL, containing the amino acid sequence of any of SEQ ID NO: 251-253, or both.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of of the following: (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3631 monoclonal antibody (e.g., SEQ ID NO: 123); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 124); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 125).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of of the following: (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3631 monoclonal antibody (e.g., SEQ ID NO: 126); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3631 monoclonal antibody (e.g., SEQ ID NO: 128).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3631 (for example, SEQ ID NO: 123); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 124 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 125) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 126); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 127 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In one embodiment, the antibody molecule comprises: (i) a VH comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises: HCDR1 comprising the HCDR1 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 123); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3631 (for example, SEQ ID NO: 124); and HCDR3 comprising the HCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 125) and (ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), where the variable region of the light chain contains: LCDR1 containing the amino acid sequence of LCDR1 monoclonal antibody 3631 (for example, SEQ ID NO: 126); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 127); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 128).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of of the following: An HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO : 129); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 130 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 125).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO : 126); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 127 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3631 (for example, SEQ ID NO: 129); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 130 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 125) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 126); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 127 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 129); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3631 (for example, SEQ ID NO: 130); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3631 (eg, SEQ ID NO: 125) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3631 (eg, SEQ ID NO: 126); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 127); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 128).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the VH amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 131). In one embodiment, the antibody molecule contains a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the VL amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 132).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 131); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 132). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 3631 (eg, SEQ ID NO: 131); and (ii) a VL containing the VL amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 132).

In an embodiment, the antibody molecule is a 3631 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3631 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of of the following: (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3732 monoclonal antibody (e.g., SEQ ID NO: 133); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 134); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 135).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3732 monoclonal antibody (e.g., SEQ ID NO: 136); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3732 monoclonal antibody (e.g., SEQ ID NO: 137).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3732 (for example, SEQ ID NO: 133); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 134 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 135) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 136); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 127 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In one embodiment, the antibody molecule contains: (i) a VH containing three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), where the heavy chain variable region contains: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 133); HCDR2 containing the amino acid sequence of the HCDR2 monoclonal antibody 3732 (for example, SEQ ID NO: 134); and HCDR3 comprising the HCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 135) and (ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3 ), where the variable region of the light chain contains: LCDR1 containing the amino acid sequence of LCDR1 monoclonal antibody 3732 (for example, SEQ ID NO: 136); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 127); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 137).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3732 monoclonal antibody (e.g., SEQ ID NO: 138); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 139); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 135).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3732 monoclonal antibody (e.g., SEQ ID NO: 136); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3732 monoclonal antibody (e.g., SEQ ID NO: 137).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3732 (for example, SEQ ID NO: 138); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 139 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 135) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 136); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 127 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In one embodiment, the antibody molecule contains: (i) VH containing: HCDR1 containing the amino acid sequence of HCDR1 monoclonal antibody 3732 (for example, SEQ ID NO: 138); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3732 (for example, SEQ ID NO: 139); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3732 (eg, SEQ ID NO: 135) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3732 (eg, SEQ ID NO: 136); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 127); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 137).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VH amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 140). In one embodiment, the antibody molecule contains a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the VL amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 141).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 140); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 141). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 3732 (eg, SEQ ID NO: 140); and (ii) a VL containing the VL amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 141).

In one embodiment, the antibody molecule is a 3732 monoclonal antibody. In one embodiment, the 3732 monoclonal antibody is a humanized 3732 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibodies 4540, 4540-063 or 4540-033 (eg, SEQ ID NO: 154); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibodies 4540, 4540-063, or 4540-033 (for example, SEQ ID NO: 155); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR3 monoclonal antibodies 4540, 4540-063 or 4540-033 (for example, SEQ ID NO: 156).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 4540 monoclonal antibody (e.g., SEQ ID NO: 116), 4540-063 (eg SEQ ID NO: 274) or 4540-033 (eg SEQ ID NO: 274); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 157), 4540-063 (eg SEQ ID NO: 275) or 4540-033 (eg SEQ ID NO: 275); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibodies 4540, 4540-063 or 4540-033 (for example, SEQ ID NO: 158).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 4540, 4540-063 or 4540-033 (eg, SEQ ID NO: 154); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4540, 4540-063, or 4540-033 (for example, SEQ ID NO: 155); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4540, 4540-063, or 4540- 033 (for example, SEQ ID NO: 156) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with monoclonal antibody LCDR1 amino acid sequence 4540 (eg, SEQ ID NO: 116), 4540-063 (eg, SEQ ID NO: 274) or 4540-033 (eg, SEQ ID NO: 274); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 157 ), 4540-063 (eg SEQ ID NO: 275) or 4540-033 (eg SEQ ID NO: 275); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4540, 4540-063, or 4540- 033 (for example, SEQ ID NO: 158).

In one embodiment, the antibody molecule comprises: (i) a VH containing three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises: HCDR1 containing the amino acid sequence HCDR1 of monoclonal antibody 4540, 4540-063 or 4540-033 (for example, SEQ ID NO: 154); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 4540, 4540-063 or 4540-033 (for example, SEQ ID NO: 155); and HCDR3 comprising the HCDR3 amino acid sequence of monoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 156) and (ii) a light chain variable region (VL), wherein the light chain variable region contains three complementarity-determining regions light chain (LCDR1, LCDR2 and LCDR3), where the light chain variable region contains: LCDR1 containing the LCDR1 amino acid sequence of a monoclonal antibody 4540 (for example, SEQ ID NO: 116), 4540-063 (for example, SEQ ID NO: 274) or 4540 -033 (for example, SEQ ID NO: 274); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 4540 (eg, SEQ ID NO: 157), 4540-063 (eg, SEQ ID NO: 275) or 4540-033 (eg, SEQ ID NO: 275); and an LCDR3 containing the LCDR3 amino acid sequence of the monoclonal antibody 4540, 4540-063, or 4540-033 (eg, SEQ ID NO: 158).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR1 monoclonal antibody 4540 (e.g., SEQ ID NO: 159), 4540-063 (eg SEQ ID NO: 276) or 4540-033 (eg SEQ ID NO: 159); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 160), 4540-063 (eg SEQ ID NO: 277) or 4540-033 (eg SEQ ID NO: 278); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR3 monoclonal antibodies 4540, 4540-063 or 4540-033 (for example, SEQ ID NO: 156).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 4540 monoclonal antibody (e.g., SEQ ID NO: 116), 4540-063 (eg SEQ ID NO: 274) or 4540-033 (eg SEQ ID NO: 274); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 157), 4540-063 (eg SEQ ID NO: 275) or 4540-033 (eg SEQ ID NO: 275); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4540, 4540-063 or 4540-033 (for example, SEQ ID NO: 158).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4540 (eg, SEQ ID NO: 159), 4540-063 (eg, SEQ ID NO: 276) or 4540-033 (eg, SEQ ID NO: 159); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 160 ), 4540-063 (eg SEQ ID NO: 277) or 4540-033 (eg SEQ ID NO: 278); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4540, 4540-063, or 4540- 033 (for example, SEQ ID NO: 156) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with monoclonal antibody LCDR1 amino acid sequence 4540 (eg, SEQ ID NO: 116), 4540-063 (eg, SEQ ID NO: 274) or 4540-033 (eg, SEQ ID NO: 274); LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 157 ), 4540-063 (eg SEQ ID NO: 275) or 4540-033 (eg SEQ ID NO: 275); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4540, 4540-063, or 4540- 033 (for example, SEQ ID NO: 158).

In one embodiment, the antibody molecule contains: (i) a VH containing one, two, or all of the following: HCDR1 containing the amino acid sequence of HCDR1 of a monoclonal antibody 4540 (e.g. SEQ ID NO: 159), 4540 -063 (e.g. SEQ ID NO : 276) or 4540-033 (eg SEQ ID NO: 159); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 4540 (eg, SEQ ID NO: 160), 4540-063 (eg, SEQ ID NO: 277) or 4540-033 (eg, SEQ ID NO: 278); or HCDR3 containing the amino acid sequence of the HCDR3 monoclonal antibody 4540, 4540-063 or 4540-033 (e.g., SEQ ID NO: 156) and (ii) a VL containing one, two or all of the following: LCDR1 containing the amino acid sequence of the LCDR1 monoclonal antibody 4540 (eg, SEQ ID NO: 116), 4540-063 (eg, SEQ ID NO: 274) or 4540-033 (eg, SEQ ID NO: 274); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 4540 (eg, SEQ ID NO: 157), 4540-063 (eg, SEQ ID NO: 275) or 4540-033 (eg, SEQ ID NO: 275); or an LCDR3 containing the LCDR3 amino acid sequence of the monoclonal antibody 4540, 4540-063, or 4540-033 (eg, SEQ ID NO: 158).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 161), 4540-063 (e.g., SEQ ID NO: 258 ) or 4540-033 (for example, SEQ ID NO: 256). In one embodiment, the antibody molecule contains a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VL amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 162), 4540-063 (e.g., SEQ ID NO: 261 ) or 4540-033 (for example, SEQ ID NO: 261).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 161), 4540-063 (e.g., SEQ ID NO: 258) or 4540-033 (eg SEQ ID NO: 256); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or at least at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VL amino acid sequence of a monoclonal antibody 4540 (e.g., SEQ ID NO: 162), 4540-063 (e.g., SEQ ID NO: 261) or 4540- 033 (for example, SEQ ID NO: 261). In one embodiment, the antibody molecule comprises: (i) a VH comprising the amino acid sequence of the VH monoclonal antibody 4540 (e.g., SEQ ID NO: 161), 4540-063 (e.g., SEQ ID NO: 258), or 4540-033 (e.g., SEQ ID NO: 256); and (ii) a VL containing the VL amino acid sequence of the monoclonal antibody 4540 (eg, SEQ ID NO: 162), 4540-063 (eg, SEQ ID NO: 261) or 4540-033 (eg, SEQ ID NO: 261).

In one embodiment, the antibody molecule is a monoclonal antibody 4540, 4540-063, or 4540-033. In one embodiment, monoclonal antibody 4540 is a humanized monoclonal antibody 4540 (eg, antibodies 4540-063 or 4540-033). In one embodiment, the antibody molecule comprises a VH containing the amino acid sequence of any of SEQ ID NOs: 254-258, a VL containing the amino acid sequence of any of SEQ ID NOs: 259-261, or both.

In one embodiment, the antibody molecule binds or substantially binds to one or more residues, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25 or more residues within the region of human APRIL as defined in any of Tables 3-4 or 7-8.

In one embodiment, the antibody molecule binds or substantially binds to one or more residues, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25 or more residues within the human APRIL region as defined in Table 3. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more residues, e.g. 23, 24, 25, or all human APRIL residues from Table 3. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 3. In one embodiment, the molecule The antibody binds or substantially binds to an epitope that contains APRIL residues from two monomers, such as monomer A and monomer B, as shown in Table 3.

In one embodiment, the antibody molecule binds or substantially binds to one or more residues, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more residues within the human APRIL region as defined in Table 4 In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more residues, e.g. Table 4. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all of the human APRIL residues of Table 4. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains APRIL from loop C-D (for example, the loop connecting the β-sheets of C and D), the loop G-H (for example, the loop connecting the β-sheets of G and H), or from both.

In one embodiment, the antibody molecule binds or substantially binds to one or more residues, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or all residues within the human APRIL region as defined in Table 7. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more residues, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all human APRIL residues from Table 7. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope, which contains or consists of all human APRIL residues from Table 7.

In one embodiment, the antibody molecule binds or substantially binds to one or more residues, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, or all residues within the human APRIL region as defined in Table 8. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more residues, e.g. 23, 24, 25, or all human APRIL residues from Table 8. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 8.

In one embodiment, the antibody molecule binds or substantially binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues of human APRIL positions 105-114 and/or one or more residues (eg, 2, 3, 4, 5, 6, 7, 8, 9 or all) of mouse APRIL residues of positions 96-105. In one embodiment, the antibody molecule does not or substantially does not bind to one, two or all of the Asp129, Arg233 or His203 of human APRIL. In an embodiment, the epitope is a conformational epitope.

In one embodiment, binding of the antibody molecule to APRIL (eg, human APRIL) inhibits or substantially inhibits binding of the CRD2 domain of TACI (eg, human TACI) to APRIL (eg, human APRIL). In another embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits the binding of human human TACI to one or more of, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all of the APRIL residues from Table 3. In yet another embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits binding of human TACI with one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the human APRIL residues from Table 4. In yet another embodiment, binding of the antibody molecule to human APRIL inhibits or essentially inhibits the binding of human TACI to one or more, e.g. Tables 7. In yet another embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits the binding of human human TACI to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all of the human APRIL residues from Table 8. In another embodiment, binding of the antibody molecule to human APRIL inhibits or essentially inhibits the binding of human BCMA to one or more, e.g. 21, 22, 23, 24, 25 or with all human APRIL residues from Table 8.

In one aspect, the disclosure is an antibody molecule that binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more residues within the region of human APRIL as defined in any of Tables 3-4 or 7-8.

In one embodiment, the anti-APRIL antibody molecule binds or substantially binds to an epitope that contains or consists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more residues from human APRIL from any of Tables 3-4 or 7-8. In one embodiment, the antibody molecule binds or substantially binds to a conformational epitope.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more residues within the region of human APRIL as defined in Table 3. In one embodiment, an anti-APRIL antibody molecule binds or substantially binds to an epitope that contains or consists of one or more 23, 24, 25, or all) of the human APRIL residues of Table 3. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains APRIL residues from two monomers, such as monomer A and monomer B, as shown in Table 3 .

In one embodiment, the antibody molecule binds or substantially binds to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or all of the residues in the human APRIL region as defined in Table 4. In one embodiment, the epitope consists of one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the APRIL residues from Table 4. In one embodiment, the epitope contains or consists of one or more APRIL residues from the C-D loop (eg, the loop connecting the β-sheets of C and D), the G-H loop (eg, the loop connecting the β-sheets of G and H), or both.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or with all residues within the human APRIL region as defined in Table 7. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all human APRIL residues from Table 7. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 7.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all residues within the human APRIL region as defined in Table 8. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more e.g. 24, 25, or all human APRIL residues from Table 8. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 8.

In one embodiment, the antibody molecule binds or substantially binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues of human APRIL positions 105-114 and/or one or more than (eg, 2, 3, 4, 5, 6, 7, 8, 9 or all) residues of murine APRIL positions 96-105. In one embodiment, the antibody molecule does not or substantially does not bind to one, two or all of the Asp129, Arg233 or His203 of human APRIL.

In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, , 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or all) human APRIL residues from Table 6.

In one embodiment, the antibody molecule binds or substantially binds to one or more (e.g., 2, 3, 4, 5, or all) of human APRIL amino acid residues selected from V174, F176, Q190, R195, R206, or Y208. In one embodiment, the antibody molecule does not bind or substantially does not bind to one or more (eg, 2, 3, or all) of human APRIL amino acid residues selected from V181, S226, I228, or N237. In one embodiment, the antibody molecule binds or substantially binds to one or more (eg, 2, 3, or all) of human APRIL amino acid residues selected from F176, V181, Q190, or I228. In one embodiment, the antibody molecule does not bind or substantially does not bind to one or both of the amino acid residues of human APRIL selected from Y208 or N237. In one embodiment, the antibody molecule binds or substantially binds to one or more (eg, 2 or all) of human APRIL amino acid residues selected from V174, R206, or Y208. In one embodiment, the antibody molecule does not bind or substantially does not bind to one or more (eg, 2, 3, or all) of human APRIL amino acid residues selected from F176, V181, Q190, or N237.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL and mouse APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL but does not bind to mouse APRIL or binds to mouse APRIL with low affinity.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, for example, from 0.001 nM to 20 nM, e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, e.g., 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, e.g. , as determined by the method described herein.

In one embodiment, the antibody molecule binds or substantially binds to murine APRIL at an EC ₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nM or less, 40 nM or less, 20 nM or less, e.g., 10 nM or less e.g. 9 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less 5 nM or less 4 nM or less 3 nM or less 2 nM or less 1 nM or less , 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, e.g., 0.001 nM to 100 nM, e.g., 0.001 nM to 50 nM, 0.1 nM to 20 nM e.g. 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0, 01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., at an EC ₅₀ of 1000 nM or greater, e.g., 2000 nM or greater, e.g., as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL, mouse APRIL, or both) to TACI (eg, human TACI, mouse TACI, or both). In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both), with an IC ₅₀ of 50 nM or less, for example, 40 nM or less 30 nM or less 20 nM or less 10 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less 5 nM or less 4 nM or less 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, such as 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM , 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein.

In one embodiment, binding of the antibody molecule to APRIL (eg, human APRIL) inhibits or substantially inhibits binding of the CRD2 domain of TACI (eg, human TACI) to APRIL (eg, human APRIL). In one embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits the binding of human TACI to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all of the human APRIL residues from Table 3. In one embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits the binding of human TACI with one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all, of the human APRIL residues of Table 4. In one embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits binding of human TACI to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all of the human APRIL residues from the Table 7. In one embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits binding of human TACI to one or more of, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all of the human APRIL residues from Table 8. In another embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits binding human BCMA with one or more, e.g. , 23, 24, 25 or with all human APRIL residues from Table 8.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL (eg, human APRIL, mouse APRIL, or both) to BCMA (eg, human BCMA, mouse BCMA, or both). In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), e.g., with an IC _{50 of} 200 nM or less, 150 nM or less 100 nM or less 50 nM or less 40 nM or less 30 nM or less 20 nM or less 10 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less , 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, for example, from 0.01 nM to 50 nM, from 0, 1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0, 5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule is a synthetic antibody molecule. In one embodiment, the antibody molecule is an isolated antibody molecule. In one embodiment, the antibody molecule is an IgG antibody molecule, e.g., containing an IgG heavy chain constant region, e.g., selected from IgG1, IgG2 (e.g., IgG2a), IgG3, or IgG4, e.g., IgG2 or IgG4. In one embodiment, the antibody molecule is an IgG1 antibody molecule. In one embodiment, the antibody molecule is an IgG2 antibody molecule. In one embodiment, the antibody molecule comprises a kappa or lambda light chain constant region.

In one embodiment, the antibody molecule contains an Fc region. In one embodiment, the Fc region contains one or more mutations at the interface between the CH2 and CH3 domains (eg, FcRn and/or the half-life of the antibody molecule). In one embodiment, the Fc region contains one or more mutations, e.g., one or more (e.g., 2, 3, 4, 6, or all) mutations selected from T250Q, M252Y, S254T, T256E, M428L, H433K, N434F, or any of them. combinations, IgG1. In one embodiment, the Fc region contains one or more mutations at positions 233-236 or 322 of human IgG1 or IgG2, or one or more substitutions at positions 327, 330, or 331 of human IgG4 (e.g., to reduce complement-dependent cytotoxicity (CDC)) . In one embodiment, the Fc region contains one or more (e.g., 2, 3, 4, 6 7 or all) mutations selected from E233P, L234V, L235A, G236, K322A, A327G, A330S, P331S, or any combination thereof.

In one embodiment, the antibody molecule is a humanized antibody molecule, eg, as described in Table 1 or 5, eg, containing one or more framework regions derived from a human germline framework sequence.

In one embodiment, the antibody molecule contains two heavy chain variable regions and two light chain variable regions. In one embodiment, the antibody molecule is a Fab, F(ab')2, Fv, Fd, or a single chain Fv fragment (scFv).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 1); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of the 2218 monoclonal antibody (e.g., SEQ ID NO: 2); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 3).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of the 2218 monoclonal antibody (e.g., SEQ ID NO: 4); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 5); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of the 2218 monoclonal antibody (e.g., SEQ ID NO: 6).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 2218 (for example, SEQ ID NO: 1); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 2 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 2218 (e.g., SEQ ID NO: 3) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 2218 (eg, SEQ ID NO: 4); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 5 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 6).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 2218 (for example, SEQ ID NO: 1); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 2 ); and HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 2218 (e.g., SEQ ID NO: 3) and (ii) a VL containing: an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of an LCDR1 monoclonal antibodies 2218 (eg, SEQ ID NO: 4); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 5 ); and an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 6).

In one embodiment, the antibody molecule contains a VH containing one, two, or all of the following: (i) HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95 , 99 or 100% homology with the amino acid sequence of the HCDR1 monoclonal antibody 2218 (for example, SEQ ID NO: 7); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 8); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 3).

In one embodiment, the antibody molecule contains a VL containing one, two, or all of the following: (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95 , 99 or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 2218 (eg, SEQ ID NO: 4); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 5); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of the 2218 monoclonal antibody (e.g., SEQ ID NO: 6).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 2218 (for example, SEQ ID NO: 7); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 8 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 2218 (e.g., SEQ ID NO: 3) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 2218 (eg, SEQ ID NO: 4); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 5 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 6).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 2218 (for example, SEQ ID NO: 7); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 8 ); and HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 2218 (e.g., SEQ ID NO: 3) and (ii) a VL containing: an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of an LCDR1 monoclonal antibodies 2218 (eg, SEQ ID NO: 4); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homologues with the LCDR2 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 5 ); and an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 6).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the VH amino acid sequence of monoclonal antibody 2218 (eg, SEQ ID NO: 9). In one embodiment, the antibody molecule contains a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the VL amino acid sequence of monoclonal antibody 2218 (eg, SEQ ID NO: 10).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 2218 (eg, SEQ ID NO: 9); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 2218 (eg, SEQ ID NO: 10). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 2218 (eg, SEQ ID NO: 9); and (ii) a VL containing the VL amino acid sequence of monoclonal antibody 2218 (eg, SEQ ID NO: 10).

In an embodiment, the antibody molecule is a 2218 monoclonal antibody. In one embodiment, the 2218 monoclonal antibody is a humanized 2218 monoclonal antibody. the amino acid sequence of any one of SEQ ID NOs: 202-208, or both.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 11) or associated with 2419 antibodies; (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 12); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 13).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of the 2419 monoclonal antibody (e.g., SEQ ID NO: 14); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 15); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 16).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 2419 (for example, SEQ ID NO: 11); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 12 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 13), and one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence HCDR1 monoclonal antibody 2419 (eg, SEQ ID NO: 11); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 12 ) or associated with 2419 antibodies; or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 13) or associated with 2419 antibodies, and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 2419 (eg, SEQ ID NO: 14); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 15 ) or associated with 2419 antibodies; or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 16) or associated with 2419 antibodies.

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 11) or a 2419-linked antibody; HCDR2 containing the HCDR2 amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 12) or a 2419-linked antibody; or HCDR3 containing the HCDR3 amino acid sequence of a 2419 monoclonal antibody (e.g., SEQ ID NO: 13) or a 2419-linked antibody, and (ii) a VL containing: LCDR1 containing the LCDR1 amino acid sequence of a 2419 monoclonal antibody (e.g., SEQ ID NO: 14 ) or associated with 2419 antibodies; an LCDR2 containing the LCDR2 amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 15) or a 2419-linked antibody; and an LCDR3 containing the LCDR3 amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 16) or a 2419-linked antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR1 monoclonal antibody 2419 (e.g., SEQ ID NO: 17) or associated with 2419 antibodies; (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 18); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 13).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of the 2419 monoclonal antibody (e.g., SEQ ID NO: 14) or associated with 2419 antibodies; (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 15); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 16).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 2419 (for example, SEQ ID NO: 17); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 18 ) or associated with 2419 antibodies; or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 13) or associated with 2419 antibodies, and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 2419 (eg, SEQ ID NO: 14); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 15 ) or associated with 2419 antibodies; or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 16) or associated with 2419 antibodies.

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 17) or a 2419-linked antibody; HCDR2 containing the HCDR2 amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 18) or a 2419-linked antibody; or HCDR3 containing the HCDR3 amino acid sequence of a 2419 monoclonal antibody (e.g., SEQ ID NO: 13) or a 2419-linked antibody, and (ii) a VL containing: LCDR1 containing the LCDR1 amino acid sequence of a 2419 monoclonal antibody (e.g., SEQ ID NO: 14 ) or associated with 2419 antibodies; an LCDR2 containing the LCDR2 amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 15) or a 2419-linked antibody; and an LCDR3 containing the LCDR3 amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 16) or a 2419-linked antibody.

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the VH amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 19) or a 2419-linked antibody. In one embodiment, the antibody molecule contains a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the VL amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 20) or a 2419-linked antibody.

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 19) or a 2419-linked antibody; and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 20) or a 2419-linked antibody.

In one embodiment, the antibody molecule comprises: (i) a VH containing the VH amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 19) or a 2419-linked antibody; and (ii) a VL containing the VL amino acid sequence of a 2419 monoclonal antibody (eg, SEQ ID NO: 20) or a 2419-linked antibody.

In an embodiment, the antibody molecule is a 2419 monoclonal antibody. In one embodiment, the 2419 monoclonal antibody is a humanized 2419 monoclonal antibody. In one embodiment, the antibody molecule is an antibody molecule linked to 2419, e.g. -0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306, or 2419-1310 , for example, as described in Table 1 or 5. In one embodiment, the antibody molecule contains a VH containing the amino acid sequence of any of SEQ ID NOs: 209-214, 283, 288, 289, 291, 292, 294, 296, or 317, VL containing the amino acid sequence of any of SEQ ID NO: 215-219, 284, 286, 295 or 316 or both.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 21); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 32); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 33).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 2922 monoclonal antibody (e.g., SEQ ID NO: 34); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 35); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of the 2922 monoclonal antibody (e.g., SEQ ID NO: 36).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 2922 (for example, SEQ ID NO: 21); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 32 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 33) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 34); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 35 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 36).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 21); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 2922 (for example, SEQ ID NO: 32); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 2922 (eg, SEQ ID NO: 33) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 2922 (eg, SEQ ID NO: 34); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 35); and LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 36).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 37); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 38); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 33).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 2922 monoclonal antibody (e.g., SEQ ID NO: 34); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 35); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of the 2922 monoclonal antibody (e.g., SEQ ID NO: 36).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 2922 (for example, SEQ ID NO: 37); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 38 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 33) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 34); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 35 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 36).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 37); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 2922 (for example, SEQ ID NO: 38); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 2922 (eg, SEQ ID NO: 33) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 2922 (eg, SEQ ID NO: 34); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 35); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 36).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VH amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 39). In one embodiment, the antibody molecule contains a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the VL amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 40).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 39); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 40). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 2922 (eg, SEQ ID NO: 39); and (ii) a VL containing the VL amino acid sequence of the monoclonal antibody 2922 (eg, SEQ ID NO: 40).

In one embodiment, the antibody molecule is a 2922 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 2922 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 51); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 52); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 53).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3327 monoclonal antibody (e.g., SEQ ID NO: 54); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 55); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3327 monoclonal antibody (e.g., SEQ ID NO: 56).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3327 (for example, SEQ ID NO: 51); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 52 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 53) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 54); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 55 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 56).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 51); HCDR2 containing the amino acid sequence of the HCDR2 monoclonal antibody 3327 (for example, SEQ ID NO: 52); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3327 (for example, SEQ ID NO: 53) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3327 (for example, SEQ ID NO: 54); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 55); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 56).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 57); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 58); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 53).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3327 monoclonal antibody (e.g., SEQ ID NO: 54); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 55); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3327 monoclonal antibody (e.g., SEQ ID NO: 56).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3327 (for example, SEQ ID NO: 57); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 58 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 53) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 54); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 55 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 56).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 57); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3327 (for example, SEQ ID NO: 58); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3327 (for example, SEQ ID NO: 53) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3327 (for example, SEQ ID NO: 54); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 55); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 56).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 3327 monoclonal antibody (e.g., SEQ ID NO: 59). In one embodiment, the antibody molecule comprises a VL containing the amino acid a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology to the VL amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 60),

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 59); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 60). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 3327 (eg, SEQ ID NO: 59); and (ii) a VL containing the VL amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 60).

In one embodiment, the antibody molecule is a 3327 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3327 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of a 3530 monoclonal antibody (e.g., SEQ ID NO: 61); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 62); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR3 monoclonal antibody 3530 (e.g., SEQ ID NO: 63).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 67); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 45); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3530 (for example, SEQ ID NO: 61); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 62 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 63) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the LCDR1 monoclonal antibody 3530 (eg, SEQ ID NO: 67); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains: (i) VH containing: HCDR1 containing the amino acid sequence of HCDR1 monoclonal antibody 3530 (for example, SEQ ID NO: 61); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3530 (for example, SEQ ID NO: 62); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3530 (eg, SEQ ID NO: 63) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3530 (eg, SEQ ID NO: 67); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3530 (eg, SEQ ID NO: 45); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3530 (eg, SEQ ID NO: 46).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of a 3530 monoclonal antibody (e.g., SEQ ID NO: 64); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 65); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR3 monoclonal antibody 3530 (e.g., SEQ ID NO: 63).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 67); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 45); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3530 (for example, SEQ ID NO: 64); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 65 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 3530 (e.g., SEQ ID NO: 63) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the LCDR1 monoclonal antibody 3530 (eg, SEQ ID NO: 67); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains: (i) VH containing: HCDR1 containing the amino acid sequence of HCDR1 monoclonal antibody 3530 (for example, SEQ ID NO: 64); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3530 (for example, SEQ ID NO: 65); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3530 (eg, SEQ ID NO: 63) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3530 (eg, SEQ ID NO: 67); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3530 (eg, SEQ ID NO: 45); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3530 (eg, SEQ ID NO: 46).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 3530 monoclonal antibody (e.g., SEQ ID NO: 66). In one embodiment, the antibody molecule comprises a VL containing the amino acid a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology to the VL amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 70),

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 3530 monoclonal antibody (eg, SEQ ID NO: 66); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology to the VL amino acid sequence of a 3530 monoclonal antibody (eg, SEQ ID NO: 70). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 3530 (eg, SEQ ID NO: 66); and (ii) a VL containing the VL amino acid sequence of the monoclonal antibody 3530 (eg, SEQ ID NO: 70).

In one embodiment, the antibody molecule is a 3530 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3530 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 61); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 62); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR3 monoclonal antibody 3525 (e.g., SEQ ID NO: 63).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 44); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains:

(i) a VH containing: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino group, the HCDR1 acid sequence of monoclonal antibody 3525 (for example, SEQ ID NO: 61); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 62 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 63) and

(ii) a VL containing: an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino group, the LCDR1 acid sequence of the 3525 monoclonal antibody (for example, SEQ ID NO: 44); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 61); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3525 (for example, SEQ ID NO: 62); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3525 (eg, SEQ ID NO: 63) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3525 (eg, SEQ ID NO: 44); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 45); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 46).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 64); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 65); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR3 monoclonal antibody 3525 (e.g., SEQ ID NO: 63).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 44); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 45); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3525 (for example, SEQ ID NO: 64); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 65 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 63) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 44); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains: (i) VH containing: HCDR1 containing the amino acid sequence of HCDR1 monoclonal antibody 3525 (for example, SEQ ID NO: 64); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3525 (for example, SEQ ID NO: 65); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3525 (eg, SEQ ID NO: 63) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3525 (eg, SEQ ID NO: 44); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 45); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 46).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 3525 monoclonal antibody (e.g., SEQ ID NO: 66). In one embodiment, the antibody molecule comprises a VL containing the amino acid a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology to the VL amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 50),

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 66); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 50). In one embodiment, the antibody molecule contains: (i) a VH containing the amino acid sequence of the VH of the monoclonal antibody 3525 (eg, SEQ ID NO: 66); and (ii) a VL containing the VL amino acid sequence of the monoclonal antibody 3525 (eg, SEQ ID NO: 50).

In one embodiment, the antibody molecule is a 3525 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3525 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 21); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 22); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR3 monoclonal antibody 2621 (e.g., SEQ ID NO: 23).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 2621 monoclonal antibody (e.g., SEQ ID NO: 24); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 25); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 2621 monoclonal antibody (e.g., SEQ ID NO: 26).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 2621 (for example, SEQ ID NO: 21); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO: 22 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 23) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 24); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 25 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 26).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 21); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 2621 (for example, SEQ ID NO: 22); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 2621 (eg, SEQ ID NO: 23) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 2621 (eg, SEQ ID NO: 24); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 25); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 26).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 27); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 28); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR3 monoclonal antibody 2621 (e.g., SEQ ID NO: 23).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 2621 monoclonal antibody (e.g., SEQ ID NO: 24); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 25); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 2621 monoclonal antibody (e.g., SEQ ID NO: 26).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 2621 (for example, SEQ ID NO: 27); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 28 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 2621 (e.g., SEQ ID NO: 23) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 24); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 25 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 26).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 27); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 2621 (for example, SEQ ID NO: 28); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 2621 (eg, SEQ ID NO: 23) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 2621 (eg, SEQ ID NO: 24); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 25); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 26).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 2621 monoclonal antibody (e.g., SEQ ID NO: 29). In one embodiment, the antibody molecule comprises a VL containing the amino acid a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology to the VL amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 30).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 29); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 30). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 2621 (eg, SEQ ID NO: 29); and (ii) a VL containing the VL amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 30).

In an embodiment, the antibody molecule is a 2621 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 2621 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3125 monoclonal antibody (e.g., SEQ ID NO: 11); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3125 (e.g., SEQ ID NO: 42); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of a 3125 monoclonal antibody (e.g., SEQ ID NO: 43).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3125 monoclonal antibody (e.g., SEQ ID NO: 44); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3125 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3125 monoclonal antibody (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3125 (for example, SEQ ID NO: 11); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3125 (e.g., SEQ ID NO: 42 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 3125 (e.g., SEQ ID NO: 43) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the LCDR1 monoclonal antibody 3125 (eg, SEQ ID NO: 44); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3125 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3125 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 11); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3125 (for example, SEQ ID NO: 42); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3125 (eg, SEQ ID NO: 43) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3125 (eg, SEQ ID NO: 44); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 45); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 46).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3125 monoclonal antibody (e.g., SEQ ID NO: 47); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3125 (e.g., SEQ ID NO: 48); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of a 3125 monoclonal antibody (e.g., SEQ ID NO: 43).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3125 monoclonal antibody (e.g., SEQ ID NO: 44); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of a 3125 monoclonal antibody (e.g., SEQ ID NO: 45); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3125 monoclonal antibody (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3125 (for example, SEQ ID NO: 47); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3125 (e.g., SEQ ID NO: 48 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 3125 (e.g., SEQ ID NO: 43) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the LCDR1 monoclonal antibody 3125 (eg, SEQ ID NO: 44); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3125 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3125 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 47); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3125 (for example, SEQ ID NO: 48); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3125 (eg, SEQ ID NO: 43) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3125 (eg, SEQ ID NO: 44); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 45); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 46).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the VH amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 49). In one embodiment, the antibody molecule contains a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the VL amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 50).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 49); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 50). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 3125 (eg, SEQ ID NO: 49); and (ii) a VL containing the VL amino acid sequence of the monoclonal antibody 3125 (eg, SEQ ID NO: 50).

In an embodiment, the antibody molecule is a 3125 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3125 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 93); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4035 or 4035-062 ( for example, SEQ ID NO: 94); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 95).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 96); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4035 or 4035-062 ( for example, SEQ ID NO: 97); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 98).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 93); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 94); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 95) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the LCDR1 monoclonal antibody 4035 or 4035-062 (eg, SEQ ID NO: 96); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 97); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 98).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the amino acid sequence of HCDR1 monoclonal antibody 4035 or 4035-062 (eg, SEQ ID NO: 93); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 94); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 95) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 95 : 96); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 4035 or 4035-062 (eg, SEQ ID NO: 97); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 4035 or 4035-062 (eg, SEQ ID NO: 98).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 99); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4035 (e.g., SEQ ID NO: 100) or 4035-062 (eg SEQ ID NO: 273); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 95).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 96); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4035 or 4035-062 ( for example, SEQ ID NO: 97); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 98).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 99); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4035 (e.g., SEQ ID NO: 100 ) or 4035-062 (for example, SEQ ID NO: 273); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 95) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the LCDR1 monoclonal antibody 4035 or 4035-062 (eg, SEQ ID NO: 96); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 97); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 98).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the amino acid sequence of HCDR1 monoclonal antibody 4035 or 4035-062 (eg, SEQ ID NO: 99); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 4035 (eg, SEQ ID NO: 100) or 4035-062 (eg, SEQ ID NO: 273); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 95) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 4035 or 4035-062 (for example, SEQ ID NO: 95 : 96); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 4035 or 4035-062 (eg, SEQ ID NO: 97); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 4035 or 4035-062 (eg, SEQ ID NO: 98).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a monoclonal antibody 4035 (e.g., SEQ ID NO: 101) or 4035-062 (e.g., SEQ ID NO: 225 ). In one embodiment, the antibody molecule contains a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VL amino acid sequence of a monoclonal antibody 4035 (e.g., SEQ ID NO: 102) or 4035-062 (e.g., SEQ ID NO: 229 ).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4035 (e.g., SEQ ID NO: 101) or 4035-062 (e.g., SEQ ID NO: 225); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of a monoclonal antibody 4035 (eg, SEQ ID NO: 102) or 4035-062 (eg, SEQ ID NO: 229). In one embodiment, the antibody molecule contains: (i) a VH containing the amino acid sequence of the VH monoclonal antibody 4035 (eg, SEQ ID NO: 101) or 4035-062 (eg, SEQ ID NO: 225); and (ii) a VL containing the VL amino acid sequence of a monoclonal antibody 4035 (eg, SEQ ID NO: 102) or 4035-062 (eg, SEQ ID NO: 229).

In one embodiment, the antibody molecule is a 4035 monoclonal antibody. In one embodiment, the 4035 monoclonal antibody is a humanized 4035 monoclonal antibody (eg, antibody 4035-062). In another embodiment, the antibody molecule is antibody 4035-062. In one embodiment, the antibody molecule contains a VH containing the amino acid sequence of any of SEQ ID NOs: 220-227 or 262-265, a VL containing the amino acid sequence of any of SEQ ID NOs: 228-234, or both.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3934 monoclonal antibody (e.g., SEQ ID NO: 103); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 104); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of a 3934 monoclonal antibody (e.g., SEQ ID NO: 105).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3934 monoclonal antibody (e.g., SEQ ID NO: 106); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of a 3934 monoclonal antibody (e.g., SEQ ID NO: 107); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3934 monoclonal antibody (e.g., SEQ ID NO: 108).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3934 (for example, SEQ ID NO: 103); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 104 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 105) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 106); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 107 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 108).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 103); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3934 (for example, SEQ ID NO: 104); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3934 (eg, SEQ ID NO: 105) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3934 (eg, SEQ ID NO: 106); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 107); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 108).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3934 monoclonal antibody (e.g., SEQ ID NO: 109); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of the 3934 monoclonal antibody (e.g., SEQ ID NO: 110); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of a 3934 monoclonal antibody (e.g., SEQ ID NO: 105).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3934 monoclonal antibody (e.g., SEQ ID NO: 106); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of a 3934 monoclonal antibody (e.g., SEQ ID NO: 107); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3934 monoclonal antibody (e.g., SEQ ID NO: 108).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3934 (for example, SEQ ID NO: 109); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 110 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 105) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 106); LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 107 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 108).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 109); HCDR2 containing the amino acid sequence of the HCDR2 monoclonal antibody 3934 (for example, SEQ ID NO: 110); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3934 (eg, SEQ ID NO: 105) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3934 (eg, SEQ ID NO: 106); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 107); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 108).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 3934 monoclonal antibody (e.g., SEQ ID NO: 111). In one embodiment, the antibody molecule comprises a VL containing the amino acid a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology to the VL amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 112),

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 111); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 112). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 3934 (eg, SEQ ID NO: 111); and (ii) a VL containing the VL amino acid sequence of the monoclonal antibody 3934 (eg, SEQ ID NO: 112).

In one embodiment, the antibody molecule is a 3934 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3934 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 112); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 113); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 114).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3833 monoclonal antibody (e.g., SEQ ID NO: 115); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 116); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3833 monoclonal antibody (e.g., SEQ ID NO: 117).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3833 (for example, SEQ ID NO: 113); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 114 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 115) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 116); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 117 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 113); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3833 (for example, SEQ ID NO: 114); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3833 (eg, SEQ ID NO: 115) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3833 (eg, SEQ ID NO: 116); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 117); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 118).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 119); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 120); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 115).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3833 monoclonal antibody (e.g., SEQ ID NO: 116); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 117); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3833 monoclonal antibody (e.g., SEQ ID NO: 118).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3833 (for example, SEQ ID NO: 119); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 120 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 115) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 116); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 117 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In one embodiment, the antibody molecule contains: (i) VH containing: HCDR1 containing the amino acid sequence of HCDR1 monoclonal antibody 3833 (for example, SEQ ID NO: 119); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3833 (for example, SEQ ID NO: 120); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3833 (eg, SEQ ID NO: 115) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3833 (eg, SEQ ID NO: 116); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 117); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 118).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 3833 monoclonal antibody (e.g., SEQ ID NO: 121). In one embodiment, the antibody molecule comprises a VL containing the amino acid a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology to the VL amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 122),

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 121); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 122). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 3833 (eg, SEQ ID NO: 121); and (ii) a VL containing the VL amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 122).

In one embodiment, the antibody molecule is a 3833 monoclonal antibody. In one embodiment, the 3833 monoclonal antibody is a humanized 3833 monoclonal antibody. In one embodiment, the antibody molecule comprises a VH containing the amino acid sequence of any of SEQ ID NOs: 246-250, VL, containing the amino acid sequence of any of SEQ ID NO: 251-253, or both.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 123); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 124); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 125).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3631 monoclonal antibody (e.g., SEQ ID NO: 126); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3631 monoclonal antibody (e.g., SEQ ID NO: 128).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3631 (for example, SEQ ID NO: 123); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 124 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 125) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 126); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 127 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 123); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3631 (for example, SEQ ID NO: 124); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3631 (eg, SEQ ID NO: 125) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3631 (eg, SEQ ID NO: 126); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 127); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 128).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 129); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 130); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 125).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3631 monoclonal antibody (e.g., SEQ ID NO: 126); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3631 monoclonal antibody (e.g., SEQ ID NO: 128).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3631 (for example, SEQ ID NO: 129); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 130 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 125) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 126); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 129); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3631 (for example, SEQ ID NO: 130); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3631 (eg, SEQ ID NO: 125) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3631 (eg, SEQ ID NO: 126); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 127); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 128).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 3631 monoclonal antibody (e.g., SEQ ID NO: 131). In one embodiment, the antibody molecule comprises a VL containing the amino acid a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology to the VL amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 132),

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 131); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 132). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 3631 (eg, SEQ ID NO: 131); and (ii) a VL containing the VL amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 132).

In one embodiment, the antibody molecule is a 3631 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3631 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3732 monoclonal antibody (e.g., SEQ ID NO: 133); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 134); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 135).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3732 monoclonal antibody (e.g., SEQ ID NO: 136); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3732 monoclonal antibody (e.g., SEQ ID NO: 137).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3732 (for example, SEQ ID NO: 133); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 134 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 135) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 136); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 127 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 133); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3732 (for example, SEQ ID NO: 134); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3732 (eg, SEQ ID NO: 135) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3732 (eg, SEQ ID NO: 136); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 127); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 137).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of a 3732 monoclonal antibody (e.g., SEQ ID NO: 138); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 139); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 135).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 3732 monoclonal antibody (e.g., SEQ ID NO: 136); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of a 3732 monoclonal antibody (e.g., SEQ ID NO: 137).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 3732 (for example, SEQ ID NO: 138); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 139 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 135) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 136); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 127 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 138); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 3732 (for example, SEQ ID NO: 139); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 3732 (eg, SEQ ID NO: 135) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 3732 (eg, SEQ ID NO: 136); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 127); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 137).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 3732 monoclonal antibody (e.g., SEQ ID NO: 140). In one embodiment, the antibody molecule comprises a VL containing the amino acid a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology to the VL amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 141).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 140); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 141). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 3732 (eg, SEQ ID NO: 140); and (ii) a VL containing the VL amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 141).

In one embodiment, the antibody molecule is a 3732 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3732 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 11); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 142); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 143).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 4338 monoclonal antibody (e.g., SEQ ID NO: 144 or 146); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 107 or 147); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 145 or 148).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 4338 (for example, SEQ ID NO: 11); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 142 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO: 143) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4338 (eg, SEQ ID NO: 144 or 146); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 107 or 147); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 145 or 148).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the amino acid sequence of HCDR1 of monoclonal antibody 4338 (eg, SEQ ID NO: 11); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 4338 (for example, SEQ ID NO: 142); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 4338 (eg, SEQ ID NO: 143) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 4338 (eg, SEQ ID NO: 144 or 146); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 4338 (eg, SEQ ID NO: 107 or 147); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 4338 (eg, SEQ ID NO: 145 or 148).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 149); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 150); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 143).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of the 4338 monoclonal antibody (e.g., SEQ ID NO: 144 or 146); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 107 or 147); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 145 or 148).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 4338 (for example, SEQ ID NO: 149); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 150 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO: 143) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4338 (eg, SEQ ID NO: 144 or 146); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 107 or 147); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 145 or 148).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the amino acid sequence of HCDR1 of monoclonal antibody 4338 (eg, SEQ ID NO: 149); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 4338 (for example, SEQ ID NO: 150); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 4338 (eg, SEQ ID NO: 143) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 4338 (eg, SEQ ID NO: 144 or 146); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 4338 (eg, SEQ ID NO: 107 or 147); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 4338 (eg, SEQ ID NO: 145 or 148).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 4338 monoclonal antibody (e.g., SEQ ID NO: 151). In one embodiment, the antibody molecule comprises a VL containing the amino acid a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology to the VL amino acid sequence of monoclonal antibody 4338 (eg, SEQ ID NO: 152 or 153).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4338 (eg, SEQ ID NO: 151); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 4338 (eg, SEQ ID NO: 152 or 153). In one embodiment, the antibody molecule contains: (i) a VH containing the VH amino acid sequence of the monoclonal antibody 4338 (eg, SEQ ID NO: 150); and (ii) a VL containing the VL amino acid sequence of monoclonal antibody 4338 (eg, SEQ ID NO: 152 or 153).

In one embodiment, the antibody molecule is a 4338 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 4338 monoclonal antibody.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4540, 4540-063 or 4540-033 (for example, SEQ ID NO: 154); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibodies 4540, 4540-063, or 4540-033 (for example, SEQ ID NO: 155); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR3 monoclonal antibodies 4540, 4540-063 or 4540-033 (for example, SEQ ID NO: 156).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 4540 monoclonal antibody (e.g., SEQ ID NO: 116), 4540-063 (eg SEQ ID NO: 274) or 4540-033 (eg SEQ ID NO: 274); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 157), 4540-063 (eg SEQ ID NO: 275) or 4540-033 (eg SEQ ID NO: 275); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4540, 4540-063 or 4540-033 (for example, SEQ ID NO: 158).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 4540, 4540-063 or 4540-033 (eg, SEQ ID NO: 154); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4540, 4540-063, or 4540-033 (for example, SEQ ID NO: 155); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4540, 4540-063, or 4540- 033 (for example, SEQ ID NO: 156) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with monoclonal antibody LCDR1 amino acid sequence 4540 (eg, SEQ ID NO: 116), 4540-063 (eg, SEQ ID NO: 274) or 4540-033 (eg, SEQ ID NO: 274); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 157 ), 4540-063 (eg SEQ ID NO: 275) or 4540-033 (eg SEQ ID NO: 275); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4540, 4540-063, or 4540- 033 (for example, SEQ ID NO: 158).

In one embodiment, the antibody molecule contains: (i) a VH containing three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), where the heavy chain variable region contains: -033 (for example, SEQ ID NO: 154); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 4540, 4540-063 or 4540-033 (for example, SEQ ID NO: 155); and HCDR3 comprising the HCDR3 amino acid sequence of monoclonal antibody 4540, 4540-063, or 4540-033 (e.g. SEQ ID NO: 156) and (ii) a light chain variable region (VL) in which light (LCDR1, LCDR2 and LCDR3), where the variable region of the light chain contains: LCDR1 containing the amino acid sequence LCDR1 of a monoclonal antibody 4540 (for example, SEQ ID NO: 116), 4540-063 (for example, SEQ ID NO: 274) or 4540-033 (for example, SEQ ID NO: 274 ); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 4540 (eg, SEQ ID NO: 157), 4540-063 (eg, SEQ ID NO: 275) or 4540-033 (eg, SEQ ID NO: 275); and an LCDR3 containing the LCDR3 amino acid sequence of the monoclonal antibody 4540, 4540-063, or 4540-033 (eg, SEQ ID NO: 158).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR1 monoclonal antibody 4540 (e.g., SEQ ID NO: 159), 4540-063 (eg SEQ ID NO: 276) or 4540-033 (eg SEQ ID NO: 159); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 160), 4540-063 (eg SEQ ID NO: 277) or 4540-033 (eg SEQ ID NO: 278); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of the HCDR3 monoclonal antibodies 4540, 4540-063 or 4540-033 (for example, SEQ ID NO: 156).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of a 4540 monoclonal antibody (e.g., SEQ ID NO: 116), 4540-063 (eg SEQ ID NO: 274) or 4540-033 (eg SEQ ID NO: 274); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 157), 4540-063 (eg SEQ ID NO: 275) or 4540-033 (eg SEQ ID NO: 275); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4540, 4540-063 or 4540-033 (for example, SEQ ID NO: 158).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 4540 (eg, SEQ ID NO: 159), 4540-063 (eg, SEQ ID NO: 276) or 4540-033 (eg, SEQ ID NO: 159); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 160 ), 4540-063 (eg SEQ ID NO: 277) or 4540-033 (eg SEQ ID NO: 278); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4540, 4540-063, or 4540- 033 (for example, SEQ ID NO: 156) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with monoclonal antibody LCDR1 amino acid sequence 4540 (eg, SEQ ID NO: 116), 4540-063 (eg, SEQ ID NO: 274) or 4540-033 (eg, SEQ ID NO: 274); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 157 ), 4540-063 (eg SEQ ID NO: 275) or 4540-033 (eg SEQ ID NO: 275); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4540, 4540-063, or 4540- 033 (for example, SEQ ID NO: 158).

In one embodiment, the antibody molecule contains: (i) a VH containing one, two or all of the following: HCDR1 containing the amino acid sequence of HCDR1 of a monoclonal antibody 4540 (e.g. SEQ ID NO: 159), 4540 -063 (e.g. SEQ ID NO : 276) or 4540-033 (eg SEQ ID NO: 159); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 4540 (eg, SEQ ID NO: 160), 4540-063 (eg, SEQ ID NO: 277) or 4540-033 (eg, SEQ ID NO: 278); or HCDR3 containing the amino acid sequence of the HCDR3 monoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 156) and (ii) a VL containing one, two, or all of the following: LCDR1 containing the amino acid sequence of the LCDR1 monoclonal antibody 4540 (eg, SEQ ID NO: 116), 4540-063 (eg, SEQ ID NO: 274) or 4540-033 (eg, SEQ ID NO: 274); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 4540 (eg, SEQ ID NO: 157), 4540-063 (eg, SEQ ID NO: 275) or 4540-033 (eg, SEQ ID NO: 275); or an LCDR3 containing the LCDR3 amino acid sequence of the monoclonal antibody 4540, 4540-063, or 4540-033 (eg, SEQ ID NO: 158).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 161), 4540-063 (e.g., SEQ ID NO: 258 ) or 4540-033 (for example, SEQ ID NO: 256). In one embodiment, the antibody molecule contains a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VL amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 162), 4540-063 (e.g., SEQ ID NO: 261 ) or 4540-033 (for example, SEQ ID NO: 261).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 161), 4540-063 (e.g., SEQ ID NO: 258) or 4540-033 (eg SEQ ID NO: 256); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VL amino acid sequence of a monoclonal antibody 4540 (e.g., SEQ ID NO: 162), 4540-063 (e.g., SEQ ID NO: 261), or 4540 -033 (for example, SEQ ID NO: 261). In one embodiment, the antibody molecule comprises: (i) a VH comprising the amino acid sequence of the VH monoclonal antibody 4540 (e.g., SEQ ID NO: 161), 4540-063 (e.g., SEQ ID NO: 258), or 4540-033 (e.g., SEQ ID NO: 256); and (ii) a VL containing the VL amino acid sequence of the monoclonal antibody 4540 (eg, SEQ ID NO: 162), 4540-063 (eg, SEQ ID NO: 261) or 4540-033 (eg, SEQ ID NO: 261).

In one embodiment, the antibody molecule is a monoclonal antibody 4540, 4540-063, or 4540-033. In one embodiment, monoclonal antibody 4540 is a humanized monoclonal antibody 4540 (eg, antibodies 4540-063 or 4540-033). In one embodiment, the antibody molecule contains a VH containing the amino acid sequence of any of SEQ ID NOs: 254-258, a VL containing the amino acid sequence of any of SEQ ID NOs: 259-261, or both.

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 163); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 164); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 165).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 166); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 167); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 168).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 4237 (for example, SEQ ID NO: 163); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 164 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 165) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 166); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 167 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 168).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 163); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 4237 (for example, SEQ ID NO: 164); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 4237 (eg, SEQ ID NO: 165) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 4237 (eg, SEQ ID NO: 166); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 167); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 168).

In one embodiment, the antibody molecule comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following : (i) an HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 169); (ii) an HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 170); or (iii) an HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 165).

In one embodiment, the antibody molecule comprises a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following : (i) an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 166); (ii) an LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 167); or (iii) an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 168).

In one embodiment, the antibody molecule contains:

(i) a VH containing one, two, or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 monoclonal antibody 4237 (for example, SEQ ID NO: 169); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 170 ); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 165) and

(ii) a VL containing one, two, or all of the following: An LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 166); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 167 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 168).

In one embodiment, the antibody molecule contains: (i) a VH containing: HCDR1 containing the HCDR1 amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 169); HCDR2 containing the amino acid sequence of HCDR2 monoclonal antibody 4237 (for example, SEQ ID NO: 170); and HCDR3 containing the amino acid sequence of HCDR3 of monoclonal antibody 4237 (eg, SEQ ID NO: 165) and (ii) VL containing: LCDR1 containing the amino acid sequence of LCDR1 of monoclonal antibody 4237 (eg, SEQ ID NO: 166); LCDR2 containing the LCDR2 amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 167); and an LCDR3 containing the LCDR3 amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 168).

In one embodiment, the antibody molecule contains a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of the 4237 monoclonal antibody (e.g., SEQ ID NO: 171). In one embodiment, the antibody molecule comprises a VL containing the amino acid a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology to the VL amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 172).

In one embodiment, the antibody molecule contains: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 171); and (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 172). In one embodiment, the antibody molecule comprises: (i) a VH comprising the VH amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 171); and (ii) a VL containing the VL amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 172).

In an embodiment, the antibody molecule is a 4237 monoclonal antibody. In one embodiment, the 4237 monoclonal antibody is a humanized 4237 monoclonal antibody. the amino acid sequence of any one of SEQ ID NOs: 241-245, or both.

In another aspect, the disclosure is an anti-APRIL antibody molecule that:

(i) binds or substantially binds to human APRIL;

(ii) inhibits or substantially inhibits the binding of APRIL (eg, human APRIL, mouse APRIL, or both) to TACI (eg, human TACI, mouse TACI, or both);

(iii) inhibits or substantially inhibits the binding of APRIL (eg, human APRIL, murine APRIL, or both) to BCMA (eg, human BCMA, murine BCMA, or both); And

(iv) binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, 24, 25 or more residues within the range of human APRIL as defined in any of Tables 3-4 or 7-8.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way.

In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., at an EC ₅₀ of 1000 nM or greater, e.g., 2000 nM or greater, e.g., as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both), with an IC ₅₀ of 50 nM or less, for example, 40 nM or less 30 nM or less 20 nM or less 10 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less 5 nM or less 4 nM or less 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, such as 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM , 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), e.g., at an IC ₅₀ of 200 nM or less, 150 nM or less 100 nM or less 50 nM or less 40 nM or less 30 nM or less 20 nM or less 10 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less , 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, for example, from 0.01 nM to 50 nM, from 0, 1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0, 5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains APRIL residues from two monomers, such as one or more residues from monomer A and monomer B, as shown in Table 3. In one embodiment, the antibody molecule binds or substantially binds to one or more APRIL residues from the C-D loop (eg, the loop connecting β-sheets C and D), the G-H loop (eg, the loop connecting β-sheets G and H), or both. In one embodiment, the antibody molecule binds or substantially binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues of human APRIL positions 105-114 and/or one or more than (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues of mouse APRIL positions 96-105. In one embodiment, the antibody molecule does not bind or binds with low affinity to one, two, or all of Asp129, Arg233, or His203 of human APRIL.

In one embodiment, the antibody molecule contains one or both of the following:

(i) a heavy chain variable region (VH) containing one, two or all of the following: HCDR1 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues from or at least 85, 90, 95%, 99% or 100% amino acid sequence of HCDR1 monoclonal antibody selected from antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419- 1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 3327 3125 2621 4035 4035-062 3934 4338 4338 HCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the HCDR2 amino acid sequence of the (same) monoclonal antibody; or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of the (same) monoclonal antibody, or

(ii) a light chain variable region (VL) containing one, two, or all of the following: an LCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology with the LCDR1 amino acid sequence of the (same) monoclonal antibody; An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of the (same) monoclonal antibody; or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90%, 95, 99, or 100% homology with the LCDR3 amino acid sequence of the (same) monoclonal antibody.

In one embodiment, the antibody molecule contains one or both of the following:

(i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a monoclonal antibody selected from antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 4035-062, 3934, 4338, 4439 or 4237; or

(ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of the (same) monoclonal antibody.

In one embodiment, the antibody molecule is a synthetic antibody molecule. In one embodiment, the antibody molecule is an isolated antibody molecule. In one embodiment, the antibody molecule is a humanized antibody molecule, for example, containing one or more framework regions derived from human germline framework sequences.

In one embodiment, the antibody molecule is an IgG antibody molecule, e.g., containing an IgG heavy chain constant region, e.g., selected from IgG1, IgG2 (e.g., IgG2a), IgG3, or IgG4, e.g., IgG2 or IgG4. In one embodiment, the antibody molecule is an IgG1 antibody molecule. In one embodiment, the antibody molecule is an IgG2 antibody molecule. In one embodiment, the antibody molecule comprises a kappa or lambda light chain constant region.

In one embodiment, the antibody molecule contains an Fc region. In one embodiment, the Fc region contains one or more mutations located at the interface between the CH2 and CH3 domains (eg, to increase the binding affinity for the neonatal FcRn receptor and/or the half-life of the antibody molecule). In one embodiment, the Fc region contains one or more mutations, e.g., one or more (e.g., 2, 3, 4, 6, or all) mutations selected from T250Q, M252Y, S254T, T256E, M428L, H433K, N434F, or any of them. combinations, IgG1. In one embodiment, the Fc region contains one or more mutations at positions 233-236 or 322 of human IgG1 or IgG2, or one or more substitutions at positions 327, 330, or 331 of human IgG4 (e.g., to reduce complement-dependent cytotoxicity (CDC)) . In one embodiment, the Fc region contains one or more (e.g., 2, 3, 4, 6 7 or all) mutations selected from E233P, L234V, L235A, G236, K322A, A327G, A330S, P331S, or any combination thereof.

In one embodiment, the antibody molecule contains two heavy chain variable regions and two light chain variable regions. In one embodiment, the antibody molecule is a Fab, F(ab')2, Fv, Fd, or a single chain Fv fragment (scFv).

In one aspect, the disclosure is an anti-APRIL antibody that:

a) competes for binding to APRIL with an antibody molecule containing heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) of any of the monoclonal antibodies 2218, 2419, 2419- 0105 2419-0205 2419-0206 2419-0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, for example, as described 423 in Table 1 or 5; or

b) binds or substantially binds to an epitope that fully or partially overlaps with an epitope of an antibody molecule containing heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) of any of the monoclonal antibodies 2218 (for example, SEQ ID NO: 1-6 according to Chothia numbering or SEQ ID NO: 3-8 according to Kabat numbering), 2419 (for example, SEQ ID NO: 11-16 according to Chothia numbering or SEQ ID NO: 13-18 according to Kabat numbering), 2419-0105 (for example, SEQ ID NO: 11-13, 16, 280 and 281 according to Chothia numbering or SEQ ID NO: 13, 16, 17 and 280 - 282 according to Kabat numbering), 2419-0205 (for example, SEQ ID NOs: 11-13, 16, 280 and 281 according to Chotia numbering or SEQ ID NOs: 13, 16, 17 and 280-282 according to Kabat numbering), 2419-0206 (for example, SEQ ID NOs: 11-13, 16, 280 and 285 according to Chothia numbering or SEQ ID NOs: 13, 16, 17, 280, 282 and 285 according to Kabat numbering) , 24 19-0406 (e.g. SEQ ID NOs: 11-13, 16, 280 and 285 according to Chothia or SEQ ID NOs: 13, 16, 17, 280, 285 and 290 according to Kabat), 2419 -0605 (for example, SEQ ID NOs: 11-13, 16, 280 and 281 according to Chothia numbering or SEQ ID NOs: 13, 16, 17 and 280-282 according to Kabat numbering), 2419-0805 (for example , SEQ ID NOs: 11-13, 16, 280 and 281 according to Chotia numbering or SEQ ID NOs: 13, 16, 17, 280, 281 and 287 according to Kabat numbering), 2419-0806 (for example, SEQ ID NOs: 11-13, 16, 280 and 285 according to Chothia numbering or SEQ ID NOs: 13, 16, 17, 280, 285 and 287 according to Kabat numbering), 2419-1204 (e.g. SEQ ID NO: 11 -13, 16, 280 and 293 according to Chothia numbering or SEQ ID NOS: 13, 16, 17, 280, 282 and 293 according to Kabat numbering), 2419-1205 (for example, SEQ ID NOS: 11-13, 16, 280 and 281 according to Chothia numbering or SEQ ID NOS: 13, 16, 17 and 280-282 according to Kabat numbering), 2419-1210 (for example, SEQ ID NOS: 11-13, 16, 314 and 315 according to Chothia numbering or SEQ ID NOS: 13, 16, 17, 282, 314 and 315 according to Kabat numbering), 2419-1305 (for example, SEQ ID NOS: 11-13, 16, 280 and 281 according to Chothia numbering or SEQ ID NOs: 13, 16, 17 and 280-282 according to Kabat numbering), 2419-1306 (e.g. SEQ ID NOs: 11-13, 16, 280 and 285 according to Chothia or SEQ ID numbering NOs: 13, 16, 17, 280, 282 and 285 according to Kabat numbering), 2419-1310 (e.g. SEQ ID NOs: 11-13, 16, 314 and 315 according to Chothia numbering or SEQ ID NO: 13 , 16, 17, 282, 314 and 315 according to Kabat numbering), 2419-1406 (e.g. SEQ ID NOs: 11-13, 16, 280 and 285 according to Chotia or SEQ ID NOs: 13, 16, 17, 280, 282 and 285 according to Kabat numbering), 2922 (for example, SEQ ID NO: 21 and 32-36 according to Chothia numbering or SEQ ID NO: 33-38 according to Kabat numbering), 3327 (for example , SEQ ID NO: 51-56 according to Chothia numbering or SEQ ID NO: 53-58 according to Kabat numbering), 3530 (for example, SEQ ID NO: 61-63, 67, 45 and 46 according to Chothia numbering or SEQ ID NOs: 63-65, 67, 45 and 46 according to Kabat numbering), 3525 (e.g. SEQ ID NOs: 44-46 and 61-63 according to Chothia numbering or SEQ ID NOs: 44-46 and 63-65 according to Kabat numbering), 3125 (for example, SEQ ID NO: 11 and 42-46 according to Chotia numbering or SEQ ID NO: 43-48 according to Kabat numbering), 2621 (for example, SEQ ID NO : 21-26 according to Chotia numbering or SEQ ID NO: 23-28 according to Kabat numbering), 4035 (for example, SEQ ID NO: 93-98 according to Chotia numbering or SEQ ID NO: 95-100 according to with Kabat numbering), 4035-062 (for example, SEQ ID NO: 93-98 according to Chothia numbering or SEQ ID NO: 95-99 and 273 according to Kabat numbering), 3934 (for example, SEQ ID NO: 103- 108 according to Chothia numbering or SEQ ID NO: 105-110 according to Kabat numbering), 3833 (e.g. SEQ ID NO: 113-118 according to Chotia numbering or SEQ ID NO: 115-120 according to Kabat numbering ), 3631 (for example, SEQ ID NO: 123-128 according to Chothia numbering or SEQ ID NO: 125-130 according to Kabat numbering), 3732 (for example, SEQ ID NO: 127 and 133-137 according to Chothia or SEQ ID NOs: 127 and 135-139 according to Kabat numbering), 4338 (e.g. SEQ ID NOs: 11, 107 and 142-145, or SEQ ID NOs: 11, 142, 143 and 146-148 according to with Chothia numbering; or SEQ ID NOs: 107, 143-145 and 149-150 or SEQ ID NOs: 143 and 146-150 according to Kabat numbering), 4540 (e.g. SEQ ID NOs: 116 and 154-158 according to Chotia numbering or SEQ ID NOs: ID NOS: 116 and 156-160 according to Kabat numbering), 4540-063 (for example, SEQ ID NOs: 154-156, 158, 274 and 275 according to Chotia numbering or SEQ ID NO: 156, 158 and 274-277 according to Kabat numbering), 4540-033 (for example, SEQ ID NOS: 154-156, 158, 274 and 275 according to Chotia numbering or SEQ ID NOS: 156, 158, 159, 274, 275 and 278 according to Kabat numbering), 4439 (for example, SEQ ID NOs: 146-148 and 266-268 according to Chotia numbering or SEQ ID NOs: 146-148 and 269-270 according to Kabat numbering) or 4237 ( for example, SEQ ID NO: 163-168 according to Chothia numbering or SEQ ID NO: 165-170 according to Kabat numbering), for example, as described in Table 1 or 5.

In one embodiment, the antibody molecule is a synthetic antibody molecule. In one embodiment, the antibody molecule is an isolated antibody molecule.

In one embodiment, an antibody molecule competes for binding with two, three, four, five, six, seven, eight, nine, ten or more antibody molecules that contain HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of any of the 2218 monoclonal antibodies. 2419 2419-0105 2419-0205 2419-0206 2419-0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 , 2419-1310 2419-1406 2922 3327 3530 3525 3125 2621 4035 .

In one embodiment, an antibody molecule binds, or substantially binds, to an epitope that is completely or partially overlapped by epitopes of two, three, four, five, six, seven, eight, nine, ten or more antibody molecules that contain HCDR1, HCDR2, HCDR3 , LCDR1, LCDR2 and LCDR3 of any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-12 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 3327 3530 3525 3125 2621 4035 4035-062 3934 3833 363.4 4540-063, 4540-033, 4439 or 4237.

In one embodiment, an antibody molecule that contains HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of any of the monoclonal antibodies 0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 3327 3530 3833, 3631, 3732, 4338, 4540, 4439 or 4237, contains the variable heavy chain and variable light chain of any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419- 0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 4035, 3934, 3833, 3631, 3732, 4338, 4540, 4439 or 4237.

In one embodiment, an antibody molecule that contains HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of any of the monoclonal antibodies 0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 3327 3530 3525 3833, 3631, 3732, 4338, 4540, 4439 or 4237, is a monoclonal antibody 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0819, 0819-0805 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 3327 3530 3525 3125 2621 4035 4338, 4540, 4439 or 4237.

In one embodiment, the antibody molecule is a humanized monoclonal antibody , 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 3327 3530 3525 3125 2621 4035 4035-062 3934 , 4540-063, 4540-033, 4439, or 4237. In one embodiment, the antibody molecule comprises a heavy chain variable region (VH) having the amino acid sequence described in Table 1 or 5. In one embodiment, the antibody molecule comprises a light chain variable region (VL) having the amino acid sequence described in Table 1 or 5. In one embodiment, the antibody molecule comprises a heavy chain variable region (VH) having the amino acid sequence described in Table 1 or 5 and a light chain variable region (VL), having the amino acid sequence described in Table 1 or 5.

In one embodiment, the antibody molecule competes for binding to human APRIL, mouse APRIL, or both. In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, for example, from 0.001 nM to 100 nM, e.g., 0.001 nM to 50 nM, 0.01 nM to 20 nM, 0.1 nM to 20 nM, e.g., 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM up to 0.1 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule binds or substantially binds to murine APRIL at an EC ₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or 0, 6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less than, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 100 nM, such as 0.001 nM to 50 nM, 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule does not bind or binds to mouse APRIL with low affinity, eg at an EC ₅₀ of 1000 nM or more, eg 2000 nM or more, eg as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both), inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) with BCMA (eg, human BCMA, mouse BCMA, or both), or both.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both), with an IC ₅₀ of 50 nM or less, for example, 40 nM or less 30 nM or less 20 nM or less 10 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less 5 nM or less 4 nM or less 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, such as 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM , 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein.

In one embodiment, binding of the antibody molecule to APRIL (eg, human APRIL) inhibits or substantially inhibits binding of the CRD2 domain of TACI (eg, human TACI) to APRIL (eg, human APRIL).

In one embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits the binding of human TACI to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all of the human APRIL residues from Table 3. In one embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits the binding of human TACI with one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the human APRIL residues from Table 4. In one embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits binding human TACI with one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all of the human APRIL residues from Table 7. In one embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits binding of human TACI to one or more of, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or with all human APRIL residues from Table 8.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL, mouse APRIL, or both) to BCMA (eg, human BCMA, mouse BCMA, or both).

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), e.g., with an IC _{50 of} 200 nM or less, 150 nM or less 100 nM or less 50 nM or less 40 nM or less 30 nM or less 20 nM or less 10 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less , 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, for example, from 0.01 nM to 50 nM, from 0, 1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0, 5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule does not or does not substantially inhibit the binding of APRIL (eg, human APRIL, mouse APRIL, or both) to BCMA (eg, human BCMA, mouse BCMA, or both).

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more residues within the range of human APRIL as defined in any of Tables 3-4 or 7-8. In one embodiment, the antibody molecule binds or substantially binds to a conformational epitope.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more residues within the human APRIL region as defined in Table 3. In one embodiment, the antibody molecule binds to an epitope that contains or consists of one or more, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or of all human APRIL residues from Table 3. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains APRIL residues from two monomers, e.g., one or more residues from monomer A and monomer B, as shown in Table 3.

In one embodiment, the antibody molecule binds or substantially binds to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more residues within the human APRIL region as defined in Table 4. In one embodiment, the antibody molecule binds or substantially binds to an epitope that consists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the APRIL residues from Table 4. In one in an embodiment, the antibody molecule binds or substantially binds to an epitope that contains one or more APRIL residues from the C-D loop (e.g., the loop connecting C and D β-sheets), the G-H loop (e.g., the G-H ) or both.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or with all residues within the human APRIL region as defined in Table 7. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all human APRIL residues from Table 7. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 7.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all residues within the human APRIL region as defined in Table 8. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more, e.g. 24, 25, or all human APRIL residues from Table 8. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 8.

In one embodiment, the antibody molecule binds or substantially binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues of human APRIL positions 105-114 and/or one or more than (eg, 2, 3, 4, 5, 6, 7, 8, 9 or all) residues of murine APRIL positions 96-105. In one embodiment, the antibody molecule does not or substantially does not bind to one, two or all of the Asp129, Arg233 or His203 of human APRIL.

In one embodiment, the antibody molecule is an IgG antibody molecule, e.g., containing an IgG heavy chain constant region, e.g., selected from IgG1, IgG2 (e.g., IgG2a), IgG3, or IgG4, e.g., IgG2 or IgG4. In one embodiment, the antibody molecule is an IgG1 antibody molecule. In another embodiment, the antibody molecule is an IgG2 antibody molecule. In one embodiment, the antibody molecule comprises a kappa or lambda light chain constant region.

In one embodiment, the antibody molecule contains an Fc region. In one embodiment, the Fc region contains one or more mutations located at the interface between the CH2 and CH3 domains (eg, to increase the binding affinity for the neonatal FcRn receptor and/or the half-life of the antibody molecule). In one embodiment, the Fc region contains one or more mutations, e.g., one or more (e.g., 2, 3, 4, 6, or all) IgG1 mutations selected from T250Q, M252Y, S254T, T256E, M428L, H433K, N434F, or any combination of them. In one embodiment, the Fc region contains one or more mutations at positions 233-236 or 322 of human IgG1 or IgG2, or one or more substitutions at positions 327, 330, or 331 of human IgG4 (e.g., to reduce complement-dependent cytotoxicity (CDC)) . In one embodiment, the Fc region contains one or more (e.g., 2, 3, 4, 6 7 or all) mutations selected from E233P, L234V, L235A, G236, K322A, A327G, A330S, P331S, or any combination thereof.

In one embodiment, the antibody molecule is a humanized antibody molecule, for example, containing one or more framework regions derived from a human germline framework sequence. In one embodiment, the antibody molecule contains two heavy chain variable regions and two light chain variable regions. In one embodiment, the antibody molecule is a Fab, F(ab')2, Fv, Fd, or a single chain Fv fragment (scFv).

In one aspect, the disclosure is an anti-APRIL antibody molecule as described herein, eg, a synthetic or isolated anti-APRIL antibody molecule as described herein.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 2218 (eg, SEQ ID NO: 1 or 7); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 2 or 8); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 3) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 2218 (eg, SEQ ID NO: 4); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 5 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 6).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 2218 (e.g., SEQ ID NO: 9); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 2218 (eg, SEQ ID NO: 10).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 71 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 72 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 2218 monoclonal antibody. In one embodiment, the 2218 monoclonal antibody is a humanized 2218 monoclonal antibody. In one embodiment, the antibody molecule comprises a VH containing the amino acid sequence of any of SEQ ID NOs: 190-101, VL, containing the amino acid sequence of any of SEQ ID NO: 202-208, or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 1 nM or less, such as about 0.6 nM. In one embodiment, the antibody molecule does not bind to mouse APRIL or binds to mouse APRIL with low affinity, e.g., at an EC ₅₀ of 1000 nM or greater, e.g., 2000 nM or greater, e.g., as determined by the method described herein,

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human TACI with an IC _{50 of} 50 nM or less, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less , 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0, 6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, for example, from 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 1 nM or less, eg, about 0.74 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 200 nM or less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as defined in this document in a way. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 0.5 nM or less, eg, about 0.22 nM.

In one embodiment, the antibody molecule contains one or both of the following:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid sequence G-Y-T-F-T-D-Y (SEQ ID NO: 11); HCDR2 containing the amino acid sequence Y-P-L-R-G-S (SEQ ID NO: 12); or HCDR3 containing the amino acid sequence H-G-A-Y-Y-S-N-A-F-D-Y (SEQ ID NO: 13) or

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid the sequence X1-X2-S-X4-S-V-D-N-D-G-I-R-F-X14-H (SEQ ID NO: 327), where X1 is R or K; X2 is A or S; X4 is E or Q; and X14 is M or L; LCDR2 containing the amino acid sequence R-A-S-X4-X5-X6-X7 (SEQ ID NO: 328), where X4 is N or T; X5 is L or R; X6 is E or A; and X7 is S or T; or an LCDR3 containing the amino acid sequence QQSNKDPYT (SEQ ID NO: 16).

In another embodiment, the antibody molecule contains one or both of the following:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid sequence D-Y-T-I-H (SEQ ID NO: 17); HCDR2 containing the amino acid sequence W-I-Y-P-L-R-G-S-I-N-Y-X12-X13-X14-F-X16-X17 (SEQ ID NO: 329), where X12 is N, S or A, X13 is E, P or Q; X14 is K or S; X16 is K or Q; and X17 is D or G; or HCCDR3 containing the amino acid sequence H-G-A-Y-Y-S-N-A-F-D-Y (SEQ ID NO: 13) or

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid the sequence X1-X2-S-X4-S-V-D-N-D-G-I-R-F-X14-H (SEQ ID NO: 327), where X1 is R or K; X2 is A or S; X4 is E or Q; and X14 is M or L; LCDR2 containing the amino acid sequence R-A-S-X4-X5-X6-X7 (SEQ ID NO: 328), where X4 is N or T; X5 is L or R; X6 - E or A; and X7 is S or T; or an LCDR3 containing the amino acid sequence QQSNKDPYT (SEQ ID NO: 16).

In one embodiment, the antibody molecule is any of antibodies 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419 -1210, 2419-1305, 2419-1306, 2419-1310 or 2419-1406.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 0.01 nM or less, such as about 0.001-0.005 nM or 0.002-0.004 nM, such as about 0.001, 0.002, 0.003, 0.004, or 0.005 nM. In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., at an EC ₅₀ of 1000 nM or greater, e.g., 2000 nM or greater, e.g., as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human TACI with an IC _{50 of} 50 nM or less, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less , 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0, 6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, for example, from 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 0.5 nM or less, such as about 0.1-0.5 nM or 0.2-0.4 nM, such as about 0.1 , 0.2, 0.3, 0.4, or 0.5 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 200 nM or less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as defined in this document in a way. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 0.5 nM or less, such as about 0.1-0.5 nM or 0.2-0.4 nM, such as about 0.1 , 0.2, 0.3, 0.4, or 0.5 nM.

In another embodiment, the antibody molecule comprises (i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region contains one, two, or all of the following: An HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 11 or 17); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 12 or 18); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 13) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 2419 (eg, SEQ ID NO: 14); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 15 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 16).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 2419 (eg, SEQ ID NO: 19); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of monoclonal antibody 2419 (eg, SEQ ID NO: 20).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 73 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 74 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 2419 monoclonal antibody. In one embodiment, the 2419 monoclonal antibody is a humanized 2419 monoclonal antibody. In one embodiment, the antibody molecule comprises a VH containing the amino acid sequence of any of SEQ ID NOs: 209-214, VL, containing the amino acid sequence of any of SEQ ID NO: 215-219 or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 1 nM or less, eg, about 0.8 nM, about 0.003 nM, or about 0.002 nM. In one embodiment, the antibody molecule does not bind, or binds to mouse APRIL with low affinity, such as an EC ₅₀ of 500 nM or more.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human TACI with an IC _{50 of} 50 nM or less, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, for example, from 0, 01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM , 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 1 nM or less, eg, about 0.74 nM, about 0.4 nM, 0.3 nM, or 0.2 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 200 nM or less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as defined in this document in a way. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 5 nM or less, e.g., about 4 nM, about 2 nM, or about 1 nM, or 0.5 nM or less, for example, about 0.22 nM, about 1 nM, about 0.7 nM, about 0.3 nM, about 0.2 nM, or about 0.1 nM.

In another embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the amino acid sequence of the 2419-linked antibody HCDR1 (e.g., SEQ ID NO: 11 or 17) ; An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of an HCDR2 associated with a 2419 antibody (e.g., SEQ ID NO: 12, 282, 287 or 290); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of an HCDR3 associated with a 2419 antibody (e.g., SEQ ID NO : 13) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the amino acid sequence of LCDR1 associated with a 2419 antibody (e.g., SEQ ID NO: 280 or 314) ; An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of an LCDR2 associated with a 2419 antibody (e.g., SEQ ID NO: 281, 285, 293 or 315); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of an LCDR3 associated with a 2419 antibody (e.g., SEQ ID NO : 16).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 2419-linked antibody (e.g., SEQ ID NOs: 283, 288, 289, 291, 292, 294, 296 or 317); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of the 2419-bound antibody (eg, SEQ ID NO: 284, 286, 295, or 316).

In one embodiment, the antibody molecule contains a VH encoded by the 2419-bound antibody VH nucleotide sequence (e.g., SEQ ID NO: 304, 307, 308, 309, 310, 311, 313, or 319) (or a nucleotide sequence substantially identical thereto) or VL encoded by the 2419 antibody-bound VL nucleotide sequence (eg, SEQ ID NO: 305, 306, 312, or 318) (or a nucleotide sequence substantially identical thereto), or both.

In one embodiment, the 2419-bound antibody molecule is selected from antibodies 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419- 1210, 2419-1305, 2419-1306, 2419-1310 or 2419-1406. In one embodiment, the 2419-linked antibody is a humanized antibody molecule. In one embodiment, the antibody molecule contains a VH containing the amino acid sequence of any of SEQ ID NO: 209-214, 283, 288, 289, 291, 292, 294, 296 or 317, VL containing the amino acid sequence of any of SEQ ID NO: 215 -219, 284, 286, 295 or 316 or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, for example, from 0.001 nM to 20 nM, e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, e.g., 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, e.g. , as determined by the method described herein. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 1 nM or less, eg, about 0.8 nM, about 0.003 nM, or about 0.002 nM.

In one embodiment, the antibody molecule does not bind, or binds to mouse APRIL with low affinity, such as an EC ₅₀ of 500 nM or more.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human TACI with an IC _{50 of} 50 nM or less, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, for example, from 0, 01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM , 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 1 nM or less, eg, about 0.74 nM, about 0.4 nM, 0.3 nM, or 0.2 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 200 nM or less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as defined in this document in a way. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 5 nM or less, e.g., about 4 nM, about 2 nM, or about 1 nM, or 0.5 nM or less, for example, about 0.22 nM, about 1 nM, about 0.7 nM, about 0.3 nM, about 0.2 nM, or about 0.1 nM.

In another embodiment, the antibody molecule comprises (i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region contains one, two, or all of the following: An HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of the 2922 monoclonal antibody (e.g., SEQ ID NO: 21 or 37); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 32 or 38); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 33) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 34); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 35 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2922 (e.g., SEQ ID NO: 36).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 39); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 2922 (eg, SEQ ID NO: 40).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 77 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 78 (or a nucleotide sequence essentially identical to them) or both.

In one embodiment, the antibody molecule is a 2922 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 2922 monoclonal antibody.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, for example, 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 5 nM or less, eg, about 3.3 nM. In one embodiment, the antibody molecule does not bind or binds to mouse APRIL with low affinity, eg at an EC ₅₀ of 1000 nM or more, eg 2000 nM or more, eg as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human TACI with an IC _{50 of} 50 nM or less, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, for example, from 0, 01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM , 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 50 nM or less, eg, about 31.64 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 200 nM or less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as defined in this document in a way. In one embodiment, the IC ₅₀ is 50 nM or less. In one embodiment, the antibody molecule inhibits the binding of human TACI to human BCMA with an IC ₅₀ of 25 nM or less, eg, about 21.96 nM.

In another embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 51 or 57); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 52 or 58); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 53) and

(ii) a light chain variable region (VH), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 54); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 55 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3327 (e.g., SEQ ID NO: 56).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 59); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or at least least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VL amino acid sequence of monoclonal antibody 3327 (eg, SEQ ID NO: 60).

In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 81 (or a nucleotide sequence substantially identical thereto) or a VL encoded by a nucleotide sequence of SEQ ID NO: 82 (or a nucleotide sequence substantially identical thereto) or both , and other.

In one embodiment, the antibody molecule is a 3327 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3327 antibody.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 100 nM, such as 0.001 nM to 50 nM, 0.01 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM or 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM or 0.01 nM to 0.1 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule does not bind or binds to mouse APRIL with low affinity, eg at an EC ₅₀ of 1000 nM or more, eg 2000 nM or more, eg, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human TACI with an IC _{50 of} 50 nM or less, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, for example, from 0, 01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM , 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 5 nM or less, eg, about 3.16 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 200 nM or less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as defined in this document in a way. In one embodiment, the IC ₅₀ is 50 nM or less. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 5 nM or less, eg, about 2.35 nM.

In another embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of the HCDR1 monoclonal antibody 4035 (eg, SEQ ID NO: 93 or 99); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4035 (e.g., SEQ ID NO: 94 or 100); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4035 (e.g., SEQ ID NO: 95) and

(ii) a light chain variable region (VH), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4035 (eg, SEQ ID NO: 96); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4035 (e.g., SEQ ID NO: 97 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4035 (e.g., SEQ ID NO: 98).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4035 (eg, SEQ ID NO: 101); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology to the VL amino acid sequence of monoclonal antibody 4035 (eg, SEQ ID NO: 102).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 173 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 174 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 4035 monoclonal antibody. In one embodiment, the 4035 monoclonal antibody is a humanized 4035 monoclonal antibody. 265, VL containing the amino acid sequence of any of SEQ ID NOs: 228-234, or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 0.01 nM or less, such as about 0.001-0.002 nM. In one embodiment, the antibody molecule does not bind or binds to mouse APRIL with low affinity, eg at an EC ₅₀ of 1000 nM or more, eg 2000 nM or more, eg, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human TACI with an IC _{50 of} 50 nM or less, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, for example, from 0, 01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM , 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 5 nM or less, such as about 3.16 nM or about 0.1-0.5 nM or 0.2-0.4 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 200 nM or less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as defined in this document in a way. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 5 nM or less, such as about 2.35 nM or about 0.1-0.5 nM or 0.1-0.2 nM.

In another embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of monoclonal antibody 4035-062 (e.g., SEQ ID NO: 93 or 99 ); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4035-062 (e.g., SEQ ID NO : 94 or 273); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4035-062 (e.g., SEQ ID NO: 95) and

(ii) a light chain variable region (VH), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4035-062 (eg, SEQ ID NO: 96); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4035-062 (e.g., SEQ ID NO : 97); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4035-062 (e.g., SEQ ID NO: 98).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4035-062 (eg, SEQ ID NO: 225); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of monoclonal antibody 4035-062 (eg, SEQ ID NO: 229).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 299 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 300 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a monoclonal antibody 4035-062.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 0.01 nM or less, such as about 0.001-0.002 nM. In one embodiment, the antibody molecule does not bind or binds to mouse APRIL with low affinity, eg at an EC ₅₀ of 1000 nM or more, eg 2000 nM or more, eg, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human TACI with an IC _{50 of} 50 nM or less, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, for example, from 0, 01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM , 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 1 nM or less, eg, about 0.1-0.5 nM or 0.2-0.4 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 200 nM or less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as defined in this document in a way. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 1 nM or less, eg, about 0.1-0.5 nM or 0.1-0.2 nM.

In another embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid sequence I-Y-D-V-H (SEQ ID NO: 99); HCDR2 containing the amino acid sequence V-I-W-S-D-G-S-T-D-Y-N-X12-X13-X14-X15-S (SEQ ID NO: 342), X12 is A or P, X13 is A or S, X14 is F or L, and X15 is I or K; or HCDR3 containing the amino acid sequence N-W-V-D-Q-A-W-F-A-Y (SEQ ID NO: 95) and

(ii) a light chain variable region (VH), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid the sequence R-A-S-K-N-I-Y-S-Y-L-A (SEQ ID NO: 96); LCDR2 containing the amino acid sequence N-A-K-T-L-P-E (SEQ ID NO: 97); or an LCDR3 containing the amino acid sequence Q-H-H-Y-G-T-P-L-T (SEQ ID NO: 98).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99 or 100% homology with the amino acid sequence of SEQ ID NO: 101 or 225; or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 102 or 229.

In one embodiment, the antibody molecule is monoclonal antibody 4035. In one embodiment, the antibody molecule is monoclonal antibody 4035-062.

In another embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 103 or 109); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 104 or 110); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 105) and

(ii) a light chain variable region (VH), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 106); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 107 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3934 (e.g., SEQ ID NO: 108).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 111); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 3934 (eg, SEQ ID NO: 112).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 175 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 176 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 3934 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3934 monoclonal antibody.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule does not bind or binds to mouse APRIL with low affinity, eg at an EC ₅₀ of 1000 nM or more, eg 2000 nM or more, eg, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human TACI with an IC _{50 of} 50 nM or less, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, for example, from 0, 01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM , 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 5 nM or less, eg, about 3.16 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 200 nM or less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as defined in this document in a way. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 5 nM or less, eg, about 2.35 nM.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4338 (eg, SEQ ID NO: 11 or 149); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 142 or 150); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO: 143) and

(ii) a light chain variable region (VH), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 144 or 146); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 107 or 147); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4338 (e.g., SEQ ID NO: 145 or 148).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4338 (eg, SEQ ID NO: 151); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology to the VL amino acid sequence of monoclonal antibody 4338 (eg, SEQ ID NO: 152 or 153).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 183 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 184 or 185 (or a nucleotide sequence essentially identical to it ), or both.

In one embodiment, the antibody molecule is a 4338 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 4338 monoclonal antibody.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule does not bind or binds to mouse APRIL with low affinity, eg at an EC ₅₀ of 1000 nM or more, eg 2000 nM or more, eg, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human TACI with an IC _{50 of} 50 nM or less, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, for example, from 0, 01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM , 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 5 nM or less, eg, about 3.16 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 200 nM or less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as defined in this document in a way. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 5 nM or less, eg, about 2.35 nM.

In another embodiment, the antibody molecule comprises (i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region contains one, two, or all of the following: An HCDR1 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 163 or 169); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 164 or 170); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 165) and

(ii) a light chain variable region (VH), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 166); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 167 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4237 (e.g., SEQ ID NO: 168).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 171); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of monoclonal antibody 4237 (eg, SEQ ID NO: 172).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 188 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 189 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 4237 monoclonal antibody. In one embodiment, the 4237 monoclonal antibody is a humanized 4237 monoclonal antibody. In one embodiment, the antibody molecule comprises a VH containing the amino acid sequence of any of SEQ ID NOs: 235-240, VL, containing the amino acid sequence of any of SEQ ID NOs: 241-245, or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule does not bind or binds to mouse APRIL with low affinity, eg at an EC ₅₀ of 1000 nM or more, eg 2000 nM or more, eg, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human TACI with an IC _{50 of} 50 nM or less, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, for example, from 0, 01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM , 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 5 nM or less, eg, about 3.16 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 200 nM or less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as defined in this document in a way. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 5 nM or less, eg, about 2.35 nM.

In another embodiment, the antibody molecule contains one or both of the following:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid the sequence G-Y-X3-X4-T-X6-X7-Y (SEQ ID NO: 330), where X3 is S or T; X4 is I or F; X6 is S or absent; and X7 is G, D or S; HCDR2 containing the amino acid sequence X3-X4-X5-X6-X7-X8 (SEQ ID NO: 331), where X3 is absent, N or Y; X4 is S or P, X5 is Y, L or R; X6 is D, N or R; X7 is G or S; and X8 is Y, D or S; or HCCDR3 containing the amino acid sequence X1-X2-X3-X4-Y-X6-X7-X8-X9-F-X11-X12 (SEQ ID NO: 332), where X1 is Y, E or H; X2 missing or G; X3 is Y, D or A; X4 is D, G or Y; X6 is E, absent or D; X7 is D, Y, S or K; X8 is W, N or R; X9 is Y, A or G; X11 is G or D; and X12 is V or Y, or

(ii) a light chain variable region (VL), where the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid the sequence X1-AS-X4-SV-X7-X8-X9-G-X11-X12-X13-X14-X15 (SEQ ID NO: 333), where X1 is R or K; X4 is E or Q; X7 is D or S; X8 is N, F, I or N; X9 is Y, A, I or D; X11 - I or T; X12 is S, N or R; X13 is F, L or S; X14 is M or I; and X15 is N or H; LCDR2 containing the amino acid sequence X1-A-S-N-X5-X6-X7 (SEQ ID NO: 334), where X1 is A, R or H; X5 - Q or L; X6 is G or E; and X7 is S, P or T; or an LCDR3 containing the amino acid sequence X1-QS-X4-X5-X6-P-X8-T (SEQ ID NO: 335), where X1 is Q or L; X4 is K, R or N; X5 - E or K; X6 is V, Y, I or D; and X8 is R, W, or Y.

In one embodiment, the antibody molecule is any of the monoclonal antibodies 2218, 2419, 2922, or 3327.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule does not bind or binds to mouse APRIL with low affinity, eg at an EC ₅₀ of 1000 nM or more, eg 2000 nM or more, eg, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human TACI with an IC _{50 of} 50 nM or less, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, or 0.1 nM or less, e.g., 0.1 to 50 nM, e.g., 0.1 nM to 25 nM, 0.1 nM up to 10 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 200 nM or less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as defined in this document in a way.

In another embodiment, the antibody molecule contains one or both of the following:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid the sequence X6-X7-Y-X9-X10-X11 (SEQ ID NO: 336), where X6 is S or absent; X7 is G, D or S; X9 is Y, F, T or D; X10 is W, M, I or V; and X11 is N, H or F; HCDR2 containing the amino acid sequence X1-I-X3-X4-X5-X6-X7-X8-X9-X10-YN-X13-X14-X15-K-X17 (SEQ ID NO: 337), where X1 is Y, R or W; X3 absent, N or Y; X4 is S or P, X5 is Y, L or R; X6 is D, N or R; X7 is G or S; X8 is Y, D or S; X9 is N, T or I; X10 is N, F or K; X13 is P, Q or E; X14 is S or K; X15 is L or F; and X17 is N, G or D; or HCCDR3 containing the amino acid sequence X1-X2-X3-X4-Y-X6-X7-X8-X9-F-X11-X12 (SEQ ID NO: 332), where X1 is Y, E or H; X2 missing or G; X3 is Y, D or A; X4 is D, G or Y; X6 - E, missing or D; X7 is D, Y, S or K; X8 is W, N or R; X9 is Y, A or G; X11 is G or D; and X12 is V or Y, or

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid the sequence X1-AS-X4-SV-X7-X8-X9-G-X11-X12-X13-X14-X15 (SEQ ID NO: 333), where X1 is R or K; X4 is E or Q; X7 is D or S; X8 is N, F, I or N; X9 is Y, A, I or D; X11 is I or T; X12 is S, N or R; X13 is F, L or S; X14 is M or I; and X15 is N or H; LCDR2 containing the amino acid sequence X1-A-S-N-X5-X6-X7 (SEQ ID NO: 334), where X1 is A, R or H; X5 is Q or L; X6 is G or E; and X7 is S, P or T; or an LCDR3 containing the amino acid sequence X1-QS-X4-X5-X6-P-X8-T (SEQ ID NO: 335), where X1 is Q or L; X4 is K, R or N; X5 - E or K; X6 is V, Y, I or D; and X8 is R, W, or Y.

In one embodiment, the antibody molecule is any of the monoclonal antibodies 2218, 2419, 2922, or 3327. In one embodiment, the antibody molecule is a humanized monoclonal antibody 2218, 2419, 2922, or 3327.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule does not bind or binds to mouse APRIL with low affinity, eg at an EC ₅₀ of 1000 nM or more, eg 2000 nM or more, eg, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human TACI with an IC _{50 of} 50 nM or less, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, for example, from 0, 01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM , 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of human APRIL to human BCMA with an IC _{50 of} 200 nM or less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as defined in this document in a way.

In another embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 3530 (eg, SEQ ID NO: 61 or 64); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 62 or 65); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 63) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3530 (eg, SEQ ID NO: 67); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 3530 monoclonal antibody (eg, SEQ ID NO: 66); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology to the VL amino acid sequence of a 3530 monoclonal antibody (eg, SEQ ID NO: 70).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 83 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 84 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 3530 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3530 monoclonal antibody.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL, mouse APRIL, or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 5 nM or less, eg, about 2.7 nM.

In one embodiment, the antibody molecule binds or substantially binds to murine APRIL at an EC ₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 100 nM, such as 0.001 nM to 50 nM, 0.01 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM or 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM or 0.01 nM to 0.1 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both), with an IC ₅₀ of 50 nM or less, for example, 40 nM or less 30 nM or less 20 nM or less 10 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less 5 nM or less 4 nM or less 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, such as 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM , 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 5 nM or less, eg, about 4.95 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), with an IC ₅₀ of 200 nM or less than 150 nM, or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less 6 nM or less , 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM , 0.1 nM to 25 nM, 0.1 nM and 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0 .5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 1 nM or less, eg, about 0.68 nM.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 61 or 64); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 62 or 65); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 63) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 44); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3525 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of a 3525 monoclonal antibody (eg, SEQ ID NO: 66); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 3525 (eg, SEQ ID NO: 50).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 83 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 80 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 3525 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3525 monoclonal antibody.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL, mouse APRIL, or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, for example, 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 5 nM or less, eg, about 2.5 nM.

In one embodiment, the antibody molecule binds or substantially binds to murine APRIL at an EC ₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 100 nM, such as 0.001 nM to 50 nM, 0.01 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM or 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM or 0.01 nM to 0.1 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both), with an IC ₅₀ of 50 nM or less, for example, 40 nM or less 30 nM or less 20 nM or less 10 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less 5 nM or less 4 nM or less 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, such as 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM , 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 5 nM or less, eg, about 4.05 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), with an IC ₅₀ of 200 nM or less than 150 nM, or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less 6 nM or less , 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM , 0.1 nM to 25 nM, 0.1 nM and 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0 .5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 1 nM or less, eg, about 0.85 nM.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 113 or 119); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 114 or 120); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 115) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 116); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 117 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99 or 100% homology with the VH amino acid sequence of monoclonal antibody 3833 (eg SEQ ID NO: 121); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 3833 (eg, SEQ ID NO: 122).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 177 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 178 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 3833 monoclonal antibody. In one embodiment, the 3833 monoclonal antibody is a humanized 3833 monoclonal antibody. In one embodiment, the antibody molecule comprises a VH containing the amino acid sequence of any of SEQ ID NOs: 246-250, VL, containing the amino acid sequence of any of SEQ ID NO: 251-253, or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL, mouse APRIL, or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 5 nM or less, eg, about 2.5 nM.

In one embodiment, the antibody molecule binds or substantially binds to murine APRIL at an EC ₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 100 nM, such as 0.001 nM to 50 nM, 0.01 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM or 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM or 0.01 nM to 0.1 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both), with an IC ₅₀ of 50 nM or less, for example, 40 nM or less 30 nM or less 20 nM or less 10 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less 5 nM or less 4 nM or less 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, such as 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM , 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 5 nM or less, eg, about 4.05 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), with an IC ₅₀ of 200 nM or less than 150 nM, or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less 6 nM or less , 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM , 0.1 nM to 25 nM, 0.1 nM and 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0 .5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 1 nM or less, such as about 0.85 nM.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 123 or 129); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 124 or 130); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 125) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 126); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 127 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99 or 100% homology with the VH amino acid sequence of monoclonal antibody 3631 (eg SEQ ID NO: 131); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of monoclonal antibody 3631 (eg, SEQ ID NO: 132).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 179 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 180 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 3631 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3631 monoclonal antibody.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL, mouse APRIL, or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 5 nM or less, eg, about 2.5 nM.

In one embodiment, the antibody molecule binds or substantially binds to murine APRIL at an EC ₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 100 nM, such as 0.001 nM to 50 nM, 0.01 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM or 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM or 0.01 nM to 0.1 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both), with an IC ₅₀ of 50 nM or less, for example, 40 nM or less 30 nM or less 20 nM or less 10 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less 5 nM or less 4 nM or less 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, such as 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM , 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 5 nM or less, eg, about 4.05 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), with an IC ₅₀ of 200 nM or less than 150 nM, or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less 6 nM or less , 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM , 0.1 nM to 25 nM, 0.1 nM and 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0 .5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 1 nM or less, such as about 0.85 nM.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 133 or 138); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 134 or 139); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 135) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 136); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 127 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 140); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 3732 (eg, SEQ ID NO: 141).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 181 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 182 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 3732 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3732 monoclonal antibody.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL, mouse APRIL, or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 5 nM or less, eg, about 2.5 nM.

In one embodiment, the antibody molecule binds or substantially binds to murine APRIL at an EC ₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 100 nM, such as 0.001 nM to 50 nM, 0.01 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM or 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM or 0.01 nM to 0.1 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both), with an IC ₅₀ of 50 nM or less, for example, 40 nM or less 30 nM or less 20 nM or less 10 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less 5 nM or less 4 nM or less 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, such as 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM , 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 5 nM or less, eg, about 4.05 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), with an IC ₅₀ of 200 nM or less than 150 nM, or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less 6 nM or less , 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM , 0.1 nM to 25 nM, 0.1 nM and 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0 .5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 1 nM or less, such as about 0.85 nM.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4540 (eg, SEQ ID NO: 154 or 159); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO: 155 or 160); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR3 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 156) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4540 (eg, SEQ ID NO: 116); LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 157 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4540 (e.g., SEQ ID NO: 158).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99 or 100% homology with the VH amino acid sequence of monoclonal antibody 4540 (eg SEQ ID NO: 161); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 4540 (eg, SEQ ID NO: 162).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 186 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 187 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 4540 monoclonal antibody. In one embodiment, the 4540 monoclonal antibody is a humanized 4540 monoclonal antibody. In one embodiment, the antibody molecule comprises a VH containing the amino acid sequence of any of SEQ ID NOs: 254-258, VL, containing the amino acid sequence of any of SEQ ID NO: 259-261, or both.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4540-063 (e.g., SEQ ID NO: 154 or 276 ); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of monoclonal antibody 4540-063 (e.g., SEQ ID NO : 155 or 277); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4540-063 (e.g., SEQ ID NO: 156) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4540-063 (e.g., SEQ ID NO: 274); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4540-063 (e.g., SEQ ID NO : 275); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4540-063 (e.g., SEQ ID NO: 158).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4540-063 (eg, SEQ ID NO: 258); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology to the VL amino acid sequence of monoclonal antibody 4540-063 (eg, SEQ ID NO: 261).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 301 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 302 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a monoclonal antibody 4540-063.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4540-033 (e.g., SEQ ID NO: 154 or 159 ); HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of monoclonal antibody 4540-033 (e.g., SEQ ID NO : 155 or 278); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4540-033 (e.g., SEQ ID NO: 156) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4540-033 (eg, SEQ ID NO: 274); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4540-033 (e.g., SEQ ID NO : 275); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4540-033 (e.g., SEQ ID NO: 158).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4540-033 (eg, SEQ ID NO: 256); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology to the VL amino acid sequence of monoclonal antibody 4540-033 (eg, SEQ ID NO: 261).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 303 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 302 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a monoclonal antibody 4540-033.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region contains three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), where the VH contains one, two, or all of the following: HCDR1 containing the amino acid sequence D-Y-Y- X4-N (SEQ ID NO: 343), where X4 is I or M; HCDR2 containing the amino acid sequence W-I-F-P-G-S-G-S-T-Y-Y-X12-X13-K-X15-X16-G, where X12 is N or A, X13 is E or Q, X15 is F or L, and X16 is K or Q (SEQ ID NO: 344); or HCDR3 containing the amino acid sequence G-D-S-G-R-A-M-D-Y (SEQ ID NO: 156) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the VL contains one, two, or all of the following: An LCDR1 containing the amino acid sequence X1- A-S-Q-D-I-N-K-Y-I-A, where X1 is K or Q (SEQ ID NO: 345); LCDR2 containing the amino acid sequence Y-T-S-T-L-X6-X7, where X6 is Q or E and X7 is S or T (SEQ ID NO: 346); or an LCDR3 containing the amino acid sequence L-Q-Y-D-N-L-L-T (SEQ ID NO: 158).

In another embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region contains three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), where the VH contains one, two, or all of the following: HCDR1 containing the amino acid sequence G-Y-T-F-A-D-Y ( SEQ ID NO: 154); HCDR2 containing the amino acid sequence F-P-G-S-G-S (SEQ ID NO: 155); or HCDR3 containing the amino acid sequence G-D-S-G-R-A-M-D-Y (SEQ ID NO: 156) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the VL contains one, two, or all of the following: An LCDR1 containing the amino acid sequence X1-A-S-Q-D-I-N-K-Y-I-A where X1 is K or Q (SEQ ID NO: 345); LCDR2 containing the amino acid sequence Y-T-S-T-L-X6-X7 (SEQ ID NO: 346), where X6 is Q or E and X7 is S or T; or an LCDR3 containing the amino acid sequence L-Q-Y-D-N-L-L-T (SEQ ID NO: 158).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99 or 100% homology with the amino acid sequence of SEQ ID NO: 161, 256 or 258; or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology to the amino acid sequence of SEQ ID NO: 162 or 261.

In one embodiment, the antibody molecule is monoclonal antibody 4540. In another embodiment, the antibody molecule is monoclonal antibody 4540-063. In another embodiment, the antibody molecule is a monoclonal antibody 4540-033.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL, mouse APRIL, or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less or 0.1 nM or less, e.g., 0.1 nM to 20 nM, e.g., 0.1 nM to 10 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, e.g. as determined by the method described herein. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 5 nM or less, eg, about 2.5 nM.

In one embodiment, the antibody molecule binds or substantially binds to murine APRIL at an EC ₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, or 0.1 nM or less, such as 0.1 nM to 20 nM, such as 0.1 nM to 10 nM, from 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI), BCMA (eg, human BCMA), or both.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both), with an IC ₅₀ of 50 nM or less, for example, 40 nM or less 30 nM or less 20 nM or less 10 nM or less 9 nM or less 8 nM or less 7 nM or less 6 nM or less 5 nM or less 4 nM or less 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, such as 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM , 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 5 nM or less, eg, about 4.05 nM.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), with an IC ₅₀ of 200 nM or less than 150 nM, or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less 6 nM or less , 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g., 0.01 nM to 50 nM, 0.1 nM to 50 nM , 0.1 nM to 25 nM, 0.1 nM and 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0 .5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA with an IC ₅₀ of 1 nM or less, such as about 0.85 nM.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 2621 (for example, SEQ ID NO: 21 or 27); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 22 or 28); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 2621 (e.g., SEQ ID NO: 23) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 24); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 25 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 2621 (e.g., SEQ ID NO: 26).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 96, 97, 98, 99 or 100% homology with the VH amino acid sequence of monoclonal antibody 2621 (eg SEQ ID NO: 29); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to the VL amino acid sequence of monoclonal antibody 2621 (eg, SEQ ID NO: 30).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 75 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 76 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 2621 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 2621 monoclonal antibody.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, for example, 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 1 nM or less, such as about 0.7 nM. In one embodiment, the antibody molecule does not bind or binds to mouse APRIL with low affinity, eg at an EC ₅₀ of 1000 nM or more, eg 2000 nM or more, eg as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI). In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL) to TACI (e.g., human TACI) at an IC ₅₀ of 50 nM or less, such as 40 nM or less, 30 nM or less than 20 nM, or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less 1 nM or less , 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of about 1 nM or less.

In one embodiment, the antibody molecule does not or does not substantially inhibit the binding of APRIL (eg, human APRIL) to BCMA (eg, human BCMA).

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 11 or 47); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 3125 (e.g., SEQ ID NO: 42 or 48); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 3125 (e.g., SEQ ID NO: 43) and

(ii) a light chain variable region (VH), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 44); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 3125 (e.g., SEQ ID NO: 45 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 3125 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 49); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of monoclonal antibody 3125 (eg, SEQ ID NO: 50).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 79 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 80 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 3125 monoclonal antibody. In one embodiment, the antibody molecule is a humanized 3125 monoclonal antibody.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule binds or substantially binds to human APRIL at an EC ₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM, or less than, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, such as 0.001 nM to 20 nM e.g., 0.01 nM to 20 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.5 nM to 5 nM, 1 nM to 5 nM, 0.001 nM to 0.1 nM, 0.001 nM to 0.01 nM, 0.001 nM to 0.005 nM, 0.01 nM to 0.05 nM, or 0.01 nM to 0.1 nM, for example, as defined herein document way. In one embodiment, the antibody molecule binds to human APRIL at an EC ₅₀ of 20 nM or less, such as about 13 nM. In one embodiment, the antibody molecule does not bind or binds to mouse APRIL with low affinity, eg at an EC ₅₀ of 1000 nM or more, eg 2000 nM or more, eg, as determined by the method described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (eg, human APRIL) to TACI (eg, human TACI). In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL (e.g., human APRIL) to TACI (e.g., human TACI) at an IC ₅₀ of 50 nM or less, such as 40 nM or less, 30 nM or less than 20 nM, or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less 1 nM or less , 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nM or less, 0.01 nM to 50 nM, 0.1 nM to 50 nM, 0.1 nM to 25 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.5 nM to 5 nM, or 1 nM to 5 nM, for example, as determined by the method described herein. In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI with an IC ₅₀ of 150 nM or less, eg, about 112.97 nM. In one embodiment, the antibody molecule does not or does not substantially inhibit the binding of APRIL (eg, human APRIL) to BCMA (eg, human BCMA).

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99%, or 100% homology with the HCDR1 amino acid sequence of monoclonal antibody 4439 (eg, SEQ ID NO: 266 or 269); An HCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the HCDR2 amino acid sequence of monoclonal antibody 4439 (e.g., SEQ ID NO: 267 or 270); or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of monoclonal antibody 4439 (e.g., SEQ ID NO: 268) and

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology with the LCDR1 amino acid sequence of monoclonal antibody 4439 (eg, SEQ ID NO: 146); An LCDR2 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the LCDR2 amino acid sequence of monoclonal antibody 4439 (e.g., SEQ ID NO: 147 ); or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or has at least 85%, 90, 95, 99, or 100% homology with the LCDR3 amino acid sequence of monoclonal antibody 4439 (e.g., SEQ ID NO: 148).

In one embodiment, the antibody molecule contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with the VH amino acid sequence of monoclonal antibody 4439 (eg, SEQ ID NO: 271); or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with the VL amino acid sequence of monoclonal antibody 4439 (eg, SEQ ID NO: 272).

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 297 (or a nucleotide sequence substantially identical to it), or a VL encoded by the nucleotide sequence of SEQ ID NO: 298 (or a nucleotide sequence essentially identical to it) or both.

In one embodiment, the antibody molecule is a 4439 monoclonal antibody. In one embodiment, the 4439 monoclonal antibody is a humanized 4439 monoclonal antibody.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more residues within the range of human APRIL as defined in any of Tables 3-4 or 7-8.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more residues within the human APRIL region as defined in Table 3. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more, e.g. 24, 25, or all human APRIL residues from Table 3. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 3. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains APRIL residues from two monomers, such as one or more residues from monomer A and monomer B, as shown in Table 3.

In one embodiment, the antibody molecule binds or substantially binds to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more residues within the human APRIL region as defined in Table 4 In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all of the human APRIL residues from Table 4. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 4. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains one or more APRIL residues from a C-D loop (eg, a loop connecting β-sheets C and D), a G-H loop (eg, a loop connecting β-sheets G and H), or both.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or with all residues within the human APRIL region as defined in Table 7. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all human APRIL residues from Table 7. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 7.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more residues within the human APRIL region as defined in Table 8. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more e.g. 24, 25, or all human APRIL residues from Table 8. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 8. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains APRIL residues from two monomers, such as one or more residues from monomer A and monomer B, as shown in Table 8.

In one embodiment, the antibody molecule is an IgG antibody molecule, e.g., containing an IgG heavy chain constant region, e.g., selected from IgG1, IgG2 (e.g., IgG2a), IgG3, or IgG4, e.g., IgG2 or IgG4. In one embodiment, the antibody molecule is an IgG1 antibody molecule. In another embodiment, the antibody molecule is an IgG2 antibody molecule. In one embodiment, the antibody molecule comprises a kappa or lambda light chain constant region.

In one embodiment, the antibody molecule contains an Fc region. In one embodiment, the Fc region contains one or more mutations located at the interface between the CH2 and CH3 domains (eg, to increase the binding affinity for the neonatal FcRn receptor and/or the half-life of the antibody molecule). In one embodiment, the Fc region contains one or more mutations, e.g., one or more (e.g., 2, 3, 4, 6, or all) IgG1 mutations selected from T250Q, M252Y, S254T, T256E, M428L, H433K, N434F, or any combination of them. In one embodiment, the Fc region contains one or more mutations at positions 233-236 or 322 of human IgG1 or IgG2, or one or more substitutions at positions 327, 330, or 331 of human IgG4 (e.g., to reduce complement-dependent cytotoxicity (CDC)) . In one embodiment, the Fc region contains one or more (e.g., 2, 3, 4, 6, 7 or all) mutations selected from E233P, L234V, L235A, G236, K322A, A327G, A330S, P331S, or any combination thereof .

In one embodiment, the antibody molecule is a humanized antibody molecule, eg, as described in Table 5, eg, containing one or more framework regions derived from a human germline framework sequence.

In one embodiment, the antibody molecule contains two heavy chain variable regions and two light chain variable regions. In one embodiment, the antibody molecule is a Fab, F(ab')2, Fv, Fd, or a single chain Fv fragment (scFv).

In one aspect, the disclosure relates to a composition, such as a pharmaceutical composition, containing the antibody molecule described herein. In one embodiment, the composition further comprises a pharmaceutically acceptable carrier.

In one aspect, the disclosure relates to a nucleic acid molecule encoding a heavy chain variable region (VH), a light chain variable region (VL), or both, of the antibody molecule described herein.

In one aspect, the disclosure relates to a vector containing the nucleic acid molecule described herein.

In one aspect, the disclosure relates to a cell, such as an isolated cell, containing the nucleic acid molecule described herein, or the vector described herein.

In one aspect, the disclosure relates to a kit containing the antibody molecule described herein and instructions for using the antibody molecule.

In one aspect, the disclosure relates to a container containing an antibody molecule described herein.

In one aspect, the disclosure relates to a method for producing an anti-APRIL antibody molecule, the method comprising culturing the cell described herein under conditions that allow the production of the antibody molecule, thereby producing the antibody molecule.

In one embodiment, the method further comprises isolating the antibody molecule.

In one aspect, the disclosure relates to a method for treating IgA nephropathy, the method comprising administering to a patient in need thereof an effective amount of an antibody molecule described herein or a composition described herein, thereby treating IgA nephropathy.

In one embodiment, the antibody molecule is administered intravenously to a patient.

In one vardoant, an antibody molecule is administered to a patient at a dose of 0.1 to 50 mg/kg, for example, from 0.2 to 25 mg/kg, from 0.5 mg/kg to 10 mg/kg, from 0.5 mg /kg to 5 mg/kg, from 0.5 mg/kg to 3 mg/kg, from 0.5 mg/kg to 2.5 mg/kg, from 0.5 mg/kg to 2 mg/kg, from 0.5 mg/kg to 1.5 mg/kg, 0.5 mg/kg to 1 mg/kg, 1 mg/kg to 1.5 mg/kg, 1 mg/kg to 2 mg/kg , from 1 mg/kg to 2.5 mg/kg, from 1 mg/kg to 3 mg/kg, from 1 mg/kg to 2.5 mg/kg doldo from 1 mg/kg to 5 mg/kg.

In one embodiment, the antibody molecule is administered to the patient at a fixed dose of 10 and 1000 mg, e.g., 10 to 500 mg, 10 to 250 mg, 10 to 150 mg, 10 mg to 100 mg, 10 to 50 mg, 250 to 500 mg 150 to 500 mg 100 to 500 mg 50 to 500 mg 25 to 250 mg 50 to 150 mg 50 to 100 mg 100 to 150 mg 100 mg to 200 mg or 150 mg to 250 mg.

In one embodiment, the antibody molecule is administered once a week, twice a week, every two weeks, every three weeks, every four weeks, once every eight weeks, once a month, once every two months, or once at three months.

In one embodiment, the introduction of the antibody molecule reduces the level of IgA in peripheral tissue, such as serum, mucosa, bone marrow, or any combination thereof.

In one embodiment, the introduction of the antibody molecule reduces the level of IgA1. In one embodiment, the introduction of the antibody molecule reduces the level of IgA1 in polymeric form (pIgA1). In one embodiment, administration of the antibody molecule reduces the level of IgA1 with O-linked glycosylation variants (eg, aberrant or reduced galactose composition in the CH1 hinge region).

In one embodiment, the method further comprises determining an IgA level in a peripheral tissue sample from the patient, such as from serum, mucosal tissue, or bone marrow.

In one embodiment, the method further comprises administering a second IgA Nephropathy therapy to the patient. In one embodiment, the second therapy is selected from an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), omega-3 fatty acids, an immunosuppressant (e.g., a corticosteroid, e.g., prednisone), a statin, mycophenolate mofetil, or any combination thereof.

In one aspect, the disclosure relates to a method for treating diabetic nephropathy, the method comprising administering to a patient in need thereof an effective amount of an antibody molecule described herein or a composition described herein, thereby treating diabetic nephropathy.

In one aspect, the disclosure relates to a method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of an antibody molecule described herein or a composition described herein, thereby treating the cancer.

In one embodiment, the cancer is a hematological cancer. In one embodiment, the hematologic cancer is selected from B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, multiple myeloma, Waldenström's macroglobulinemia, or lymphoplasmic lymphoma. In one embodiment, the cancer is multiple myeloma.

In one aspect, the disclosure relates to a method of treating an immunoproliferative disorder, the method comprising administering to a patient in need thereof an effective amount of an antibody molecule described herein or a composition described herein, thereby treating the immunoproliferative disorder.

In one embodiment, the immunoproliferative disorder is monoclonal IgA hypergammaglobulinemia.

In one aspect, the disclosure relates to a method for treating vasculitis, the method comprising administering to a patient in need thereof an effective amount of an antibody molecule described herein or a composition described herein, thereby treating the vasculitis.

In one embodiment, the vasculitis is renal vasculitis. In one embodiment, the vasculitis is IgA associated vasculitis (eg, Henoch-Schonlein purpura) or post-streptococcal glomerulonephritis.

In one aspect, the disclosure relates to a method for treating an autoimmune disease, the method comprising administering to a patient in need thereof an effective amount of an antibody molecule described herein or a composition described herein, thereby treating the autoimmune disorder.

In one embodiment, the autoimmune disorder is selected from rheumatoid arthritis, systemic lupus erythematosus, linear IgA-dependent bullous disease (eg, linear immunoglobulin A (IgA)-dependent dermatosis), or IgA-mediated epidermolysis bullosa acquired (EBA).

In one aspect, the disclosure relates to a method of treating IgA pemphigus, the method comprising administering to a patient in need thereof an effective amount of an antibody molecule described herein or a composition described herein, thereby subjecting IgA pemphigus to treatment.

In one aspect, the disclosure relates to a method for treating celiac disease, the method comprising administering to a patient in need thereof an effective amount of an antibody molecule described herein or a composition described herein, thereby treating celiac disease.

In one aspect, the disclosure relates to a method of treating alcoholic cirrhosis, the method comprising administering to a patient in need thereof an effective amount of an antibody molecule described herein or a composition described herein, thereby treating alcoholic cirrhosis.

In one aspect, the disclosure relates to a method for reducing IgA levels in a cell or patient, the method comprising contacting the cell or patient, or administering to a patient in need thereof, an effective amount of an antibody molecule described herein or a composition described herein, thereby thereby lowering IgA levels.

In one embodiment, the antibody molecule is administered intravenously to a patient.

In one embodiment, the antibody molecule is administered to a patient at a dose of 0.1 to 50 mg/kg, e.g., 0.2 to 25 mg/kg, 0.5 mg/kg to 10 mg/kg, 0.5 mg /kg to 5 mg/kg, from 0.5 mg/kg to 3 mg/kg, from 0.5 mg/kg to 2.5 mg/kg, from 0.5 mg/kg to 2 mg/kg, from 0.5 mg/kg to 1.5 mg/kg, 0.5 mg/kg to 1 mg/kg, 1 mg/kg to 1.5 mg/kg, 1 mg/kg to 2 mg/kg , 1 mg/kg to 2.5 mg/kg, 1 mg/kg to 3 mg/kg, 1 mg/kg to 2.5 mg/kg, or 1 mg/kg to 5 mg/kg.

In one embodiment, the antibody molecule is administered to a patient at a fixed dose of 10 to 1000 mg, e.g., 10 and 500 mg, 10 to 250 mg, 10 to 150 mg, 10 mg to 100 mg, 10 to 50 mg, 250 to 500 mg 150 to 500 mg 100 to 500 mg 50 to 500 mg 25 to 250 mg 50 to 150 mg mg 50 to 100 mg 100 mg to 150 mg 100 mg to 200 mg or 150 mg to 250 mg.

In one embodiment, the antibody molecule is administered once a week, twice a week, once every two weeks, once every three weeks, once every four weeks, once every eight weeks, once a month, once every two months, once at three months.

In one embodiment, the introduction of the antibody molecule reduces the level of IgA in peripheral tissue, such as serum, mucosa, bone marrow, or any combination thereof.

In one embodiment, the introduction of the antibody molecule reduces the level of IgA1. In one embodiment, the introduction of the antibody molecule reduces the level of IgA1 in polymeric form (pIgA1). In one embodiment, administration of the antibody molecule reduces the level of IgA1 with O-linked glycosylation variants (eg, aberrant or reduced galactose composition in the CH1 hinge region).

In one aspect, the disclosure relates to the use of an antibody molecule described herein or a composition described herein in the treatment of or in the manufacture of a medicament for the treatment of a disorder described herein.

In another aspect, the disclosure relates to an antibody molecule or composition described herein for use in the treatment of a disorder described herein.

In one aspect, the disclosure relates to a method for detecting an APRIL molecule, the method comprising contacting a cell or patient sample with an antibody molecule described herein, thereby detecting an APRIL molecule.

In one embodiment, the antibody molecule is linked to a detectable label. In one embodiment, the APRIL molecule is detected in vitro or ex vivo . In another embodiment, the APRIL molecule is detected in vivo .

The disclosure contemplates all combinations of any one or more of the above aspects and/or embodiments, as well as combinations with any one or more of the embodiments set forth in the Detailed Description and Examples.

Other features, objects and advantages of the compositions and methods of the present description will be apparent from the description and drawings and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B show profiling of anti-APRIL antibodies from mouse-derived hybridomas. CD-1 mice were immunized with recombinant multimeric APRIL (human or mouse) as described. Splenocytes from anti-APRIL seropositive mice were immortalized by myeloma fusion to produce hybridomas. ELISA-based screening methods were used to evaluate anti-APRIL antibodies present in the conditioned media of immunoglobulin-producing hybridomas. Cell culture supernatants were first screened for both target binding (APRIL) by indirect ELISA and functional activity for the ability to block the interaction of APRIL with the recombinant soluble human TNF receptor TACI-Fc (blocking ELISA). Screening against human and mouse APRIL was performed to identify potentially cross-reactive antibodies. Relative potency is based on spot measurements after normalization of immunoglobulin concentration to 10 µg/mL when possible. The APRIL immunogen for final tail vein booster is shown in bold. Hybridoma-derived antibodies lacking blocking activity for both human and murine APRIL (as originally determined to block receptors less than 10% in this first run screening assay) are not included in this summary table. Ig isotopes for individual hybridomas are noted.

FIG. 2A-2B depict APRIL receptor blocking activity with exemplary anti-APRIL antibodies. The functional activities of selected anti-APRIL antibodies purified from mouse-derived hybridoma clones were assessed by ELISA using recombinant TACI-Fc as the soluble receptor. The assay includes two steps: 1) preincubation of APRIL with various concentrations of purified mouse antibody; 2) subsequent measurement of APRIL binding to immobilized TACI-Fc, as quantified by ELISA, using an appropriate epitope labeled APRIL detection secondary antibody. APRIL receptor binding interference was measured as loss of A450. Hybridoma antibodies are represented by solid symbols. Control and comparative antibodies are shown as open symbols. Apry-1-1 is a mouse-specific blocking antibody used as a control. Human neutralizing antibodies 0201 and 1313 were also used as controls and for comparative purposes with antibodies reported in the scientific literature. The data presented are representative of the assay and method for assessing antibody inhibition (receptor blocking). FIG. 2A (human APRIL); FIG. 2B (mouse APRIL). The IC ₅₀ values are shown in FIG. 3.

FIG. 3 shows the activity profiles of selected, purified mouse-derived anti-APRIL antibodies. Binding and blocking activities were extrapolated from the data presented in FIG. 2A-2B and are based on non-linear regression of antibody titration with a three-parameter curve fitted using Graphpad Prism. Dotted lines indicate lack of activity.

FIG. 4 depicts inhibition of APRIL-mediated TACI signaling in HEK 293 cells. Functional inhibition of human APRIL mediated receptor activation was assessed using a cell line derived from 293 cells with stably transfected NF-κB reporter and transiently transfected human APRIL TACI receptor. HA-labeled GCN4 human APRIL (R&D Systems) was used as the source of APRIL. As a positive control, already existing mAb 1313 (human-specific with already established blocking activity) was used; mouse specific antibody against APRIL Apry-1-1 was used as a negative control. The data is illustrative of an orthogonal biologically relevant assay for evaluating the activity of anti-APRIL murine antibodies.

FIG. 5 shows the binding of anti-APRIL antibodies to human APRIL. The relative binding of selected anti-APRIL antibodies was measured by indirect ELISA. Selected antibodies based on preliminary screening of hybridomas were recombinantly produced (based on VH and VL sequencing of the immunoglobin gene) as described. HA-labeled GCN4 human APRIL (R&D Systems) was used as the source of APRIL. Binding data was analyzed by non-linear regression using a three-parameter curve. MAb 1313, 0201 and Aprily-5 were included for comparative purposes; Apry-1-1 was used as a negative control. The extrapolated EC ₅₀ values are summarized in FIG. 6.

FIG. 6 shows the relative binding affinities of selected anti-APRIL antibodies. Data were obtained from indirect ELISA (summarized in FIG. 5). The dotted line indicates the absence of binding activity.

FIG. 7 depicts antibody inhibition of APRIL binding to TACI. The assay is based on a blocking ELISA using recombinant human APRIL (R&D Systems) and human TACI-Fc. Inhibition was analyzed by non-linear regression using a four-parameter fitted curve. MAb 1313 and 0201 were used as controls and for comparative purposes. A non-neutralizing anti-APRIL mAb, Aprily-5, was used as a negative control.

FIG. 8 shows antibody inhibition of APRIL binding to BCMA. The assay is based on blocking ELISA using recombinant human APRIL and human BCMA-Fc. For details, see the description of FIG. 7.

FIG. 9 depicts antibody inhibition of APRIL binding to both human TACI-Fc and human BCMA-Fc. Relative inhibitory activities are summarized. Data obtained from non-linear regression analyzes of antibody inhibition curves as depicted in FIG. 7-8, using a four-parameter fit, % inhibition was normalized without antibody control (100% inhibition) after background subtraction (0% inhibition). The dotted line means no calculated IC ₅₀ values due to poor or no blocking activity.

FIGS. 10A-10B show cross-reactivity between anti-APRIL antibodies. Anti-APRIL antibodies with blocking activity (summarized in FIG. 9) were evaluated for the ability to block the binding of human and mouse APRIL to human TACI-Fc and BCMA-Fc. Recombinant murine and human APRIL with other identical HA-tagged GCN4 N-terminal fusions were used as receptor ligands (R&D Systems). Selection data is included for illustrative purposes. Antibodies 3530 and 3525 showed any cross-species activity for blocking the TACI-Fc receptor (FIG. 10A). A similar cross-neutralization with respect to the binding of APRIL to BCMA-Fc was only partially achieved (FIG. 10B). Neutralizing antibody 1313 (human specific) and Apry-1-1 antibody (mouse specific) were used as controls. Filled characters, human APRIL; unfilled symbols, mouse APRIL.

FIG. 11A-11B depict antibody inhibition of APRIL-mediated receptor signaling. Inhibition of APRIL receptor-mediated intracellular NF-κB signaling was assessed using the HEK 293 NF-κB reporter cell line after transient transfection with either a vector expressing the cDNA of the full-length human TACI receptor of the TNF receptor family or a vector expressing the cDNA of the full-length BCMA. Data were normalized to activity against no antibody treatment. The y-axis scale ranges from 0 to 1. Inhibition of APRIL-mediated receptor signaling was measured at three different antibody concentrations (0.08 μg/ml, 0.4 μg/ml and 10 μg/ml). FIG. 11A shows inhibition of TACI-mediated NFB signaling; FIG. 11B shows inhibition of BCMA-mediated NF-κB signaling.

FIGS. 12A-12B depict the in vivo efficacy of an anti-APRIL antibody in reducing serum IgA levels. The suitability of using an anti-APRIL antibody to modulate IgA production in vivo was assessed based directly on the reduction in serum IgA levels following administration of a neutralizing anti-APRIL antibody in a laboratory rodent model. For this purpose, the specific, blocking anti-APRIL antibody Apry-1-1 (Adipogen), which has hitherto been used as a control for evaluating the activity of an anti-APRIL antibody in vitro , was also used as a test antibody for demonstration of concept. Male B6C3F1 mice aged (6-10 weeks) were injected with 20 mg/kg antibody twice a week by ip injection for a total of 8 weeks. Salt solution for injection was used as a negative control (vehicle) (VC). Serum isotype-specific immunoglobulin levels (IgG, IgM and IgA) were monitored individually by ELISA approximately every 12 days. FIG. 12A shows the effect of treatment on serum IgA levels; FIG. 12B shows the effect of treatment versus control on serum total immunoglobulin levels. Data are summation of IgG+IgA+IgM levels measured separately.

FIG. 13 shows the sequence alignment of human and mouse APRIL (SEQ ID NOs: 85 and 91, respectively). Soluble APRIL sequence alignment was determined using CLUSTALW. Amino acid sequences correspond to SwissProt accession numbers O75888 (human) and Q9D777 (mouse).

FIG. 14 depicts a structural definition of an exemplary APRIL epitope for antibody targeting. The space filling model of the trimeric APRIL is depicted. An exemplary (spatially defined) region that should be targeted by an antibody molecule is depicted in dark gray and indicated by an arrow. This epitope includes positions in APRIL that link the monomers. Differences between murine and human APRIL sequences are highlighted by corresponding amino acid differences at these indicated positions. The putative N-glycosylation site (N124) is marked in black and indicated by an arrow.

FIG. 15 depicts a structural definition of an exemplary APRIL epitope for antibody targeting. A ribbon model of trimeric APRIL is depicted, with the main epitope for targeting an anti-APRIL antibody highlighted in dark grey.

FIG. 16 shows the binding of exemplary anti-APRIL antibodies to human APRIL. The relative binding of exemplary anti-APRIL antibodies was measured by indirect ELISA. The extrapolated EC ₅₀ values are summarized in FIG. 17.

FIG. 17 depicts the relative binding affinities of exemplary anti-APRIL antibodies. Data were obtained from indirect ELISA (summarized in FIG. 16).

FIG. 18A-18B depict the inhibition of antibodies by APRIL mediated receptor signaling. Inhibition of APRIL receptor-mediated intracellular signaling NFκB was assessed using the HEK 293 NFκB reporter cell line after transient transfection with either a vector expressing the cDNA of the full-length human TACI receptor of the TNFa receptor family (FIG. 18A) or a vector expressing the cDNA of the full-length BCMA (FIG. 18B) . Exemplary antibodies are shown for illustrative purposes.

FIG. 19A-19B depict antibody inhibition of APRIL binding to the TACI TNFSF (FIG. 19A) and BCMA (FIG. 19B) receptors. The assay is based on blocking ELISA using recombinant human APRIL (R&D Systems) and human TACI-Fc. Inhibition was analyzed by non-linear regression using a four-parameter fit. The IC ₅₀ values are summarized in FIG. 20.

FIG. 20 depicts antibody inhibition of APRIL binding to both human TACI-Fc and human BCMA-Fc (summation of relative inhibitory activities). Data obtained from non-linear regression analyzes of antibody inhibition curves are depicted in FIG. 19 using a four parameter fit. % inhibition was normalized without antibody control (100% inhibition) after background subtraction (0% inhibition). The dotted line indicates no calculated IC ₅₀ values due to poor or partial measured blocking activity.

FIGS. 21A-21B depict anti-APRIL antibody activities, cross-species APRIL cross-blocking. The ability of anti-APRIL antibodies to block the binding of both human (FIG. 21A) and murine (FIG. 21B) APRIL to BCMA was assessed by ELISA. The respective blocking activities of exemplary antibodies (3833, 4540, 3530, 3631 and 3732) with previously determined cross-species binding of APRIL (mouse and human) are shown.

FIG. 22 depicts site-directed variants of human APRIL used for epitope mapping. APRIL is shown as a trimer. A typical epitope containing a high affinity receptor binding site for CRD2 is depicted in dark grey. The positions of amino acid substitutions are marked using the number of the previous wild-type amino acid and subsequent mutation (eg, R233G represents a mutation of arginine at position 233 to glycine).

FIG. 23A-23B depicts epitope mapping of antibody 4035 (FIG. 23A) (comparison is made with reference antibody 1313, see FIG. 23B). The binding of the antibody to human and mouse variants was assessed by ELISA. FLAG-labeled APRIL was captured from the cell culture medium using an anti-FLAG antibody. Human APRIL variants are depicted as open bars; mouse APRIL variants are depicted as filled bars.

On FIG.24A-24B shows the mapping of the epitopes of the antibody 2419 (FIG.24A) (comparison is carried out with the reference antibody 1313, see FIG.24B). The binding of the antibody to human and mouse variants was assessed by ELISA. Human APRIL variants are depicted as open bars; mouse APRIL variants are depicted as filled bars.

FIG. 25A-25B depict the epitope mapping of antibody 3833 (FIG. 25A) (comparison is with reference antibody 1313, see FIG. 25B). The binding of the antibody to human and mouse variants was assessed by ELISA. FLAG-labeled APRIL was captured from the cell culture medium using an anti-FLAG antibody. Human APRIL variants are depicted as open bars; mouse APRIL variants are depicted as filled bars.

FIG. 26 shows differentiated epitope mapping of anti-APRIL antibodies by site-directed mutagenesis. Primary characterization of the human APRIL binding site was performed by site-directed mutagenesis of selected amino acid positions in APRIL followed by evaluation of antibody binding to these variants by ELISA. For illustrative purposes, illustrative data for three antibodies against APRIL 4035 (solid circles), 2419 (solid squares) and 1313 (open triangles) are shown.

FIG. 27A-27B depict exemplary anti-APRIL antibodies binding to human APRIL. Antibodies include humanized variants of mouse antibodies 4035 (FIG. 27A) and 2419 (FIG. 27B). The relative binding of exemplary anti-APRIL antibodies was measured by indirect ELISA. Comparison of humanized anti-APRIL antibodies with parental (non-humanized) mouse antibodies is performed for comparative purposes. The extrapolated EC ₅₀ values are summarized in FIG. 29A.

FIGS. 28A-28B show binding of the humanized variant of the human-mouse cross-reactive antibody 4540-063 to both human APRIL (FIG. 28A) and murine APRIL (FIG. 28B). The relative binding of an exemplary anti-APRIL antibody was measured by indirect ELISA. Parental (non-humanized) antibody comparisons are made for comparative purposes. The extrapolated EC ₅₀ values are summarized in FIG. 29b.

FIG. 29A-29B depict relative binding affinities of exemplary anti-APRIL antibodies. Data (EC ₅₀ values) were obtained from indirect ELISA (summarized in FIGS. 27A-27B and FIGS. 28A-28B). FIG. 29A shows the relative binding affinities of exemplary humanized anti-APRIL antibodies based on 2419 and 4035. FIG. 29B shows the relative binding affinities of cross-reactive antibody 4540 and its humanized variant 4540-063. Binding data for both human and murine APRIL are included.

FIG. 29C-29D depict the binding affinity of antibodies 2419-1406 and 4035-062 to trimeric human APRIL measured by ELISA. The trimer was stabilized by N-terminal fusion of APRIL with the isoleucine zipper domain (GCN4). The binding of APRIL to human TACI-Fc is shown for comparative purposes.

EC ₅₀ values obtained from the binding curves depicted in FIG. 29C are summarized in FIG. 29D.

FIG. 30A-30B depict antibody inhibition of APRIL binding to the TNFSF TACI and BCMA receptors by humanized IgG2κ variants of the murine parent antibody 2419. The assay is based on receptor blocking ELISA using recombinant human APRIL (R&D Systems) and human TACI-Fc (FIG. .30A) or BCMA-Fc (FIG. 30B). The parent, chimeric 2419 (mouse VH-VL transplanted onto human IgG1κ constant regions), was included for comparative purposes as a chimeric anti-human APRIL antibody 4035. Inhibition was analyzed by non-linear regression using a four-parameter fitted curve after normalization to 100% activity (no antibody control). The IC ₅₀ values are summarized in FIG. 33.

FIG. 31A-31B depict inhibition of APRIL binding to TNFSF receptors TACI (FIG. 31A) and BCMA (FIG. 33B) by additional humanized 2419 (IgG2κ) variants 2419-0205 and 2419-1406 and a humanized variant (4035-062) of the parent antibody. 4035. Humanized 4035-062 is of the IgG1κ subtype. Chimeric, non-humanized variants of mouse antibodies 4035 and 2419 and 1313 are included for comparison purposes. mAb1313 is a control antibody against APRIL. TACI-Fc and BCMA-Fc were used. The IC ₅₀ values are summarized in FIG. 33.

FIG. 32A-32B depict antibody inhibition of APRIL binding to TNFSF receptors TACI (FIG. 32A) and BCMA (FIG. 32B) with humanized variants of the murine/human APRIL cross-neutralizing antibody 4540. The humanized antibody 4540 belongs to the IgG1κ subtype. Parental 4540 (non-humanized chimeric) and humanized 4035-062 (FIGS. 30A-30B) are included for comparative purposes. Inhibition was analyzed by non-linear regression using a four-parameter fitted curve as described for FIG. 29A-29B and FIG. 30A-30B. IC ₅₀ values are also summarized in FIG. 33.

FIG. 33 depicts IC ₅₀ values for antibody inhibition of APRIL receptor binding. The IC ₅₀ values are based on a non-linear regression analysis of the data presented in FIG. 30A-32B. The data are also normalized (relative activity) to parental mouse antibody 2419.

In FIG. 34A-34B depict antibody inhibition of APRIL mediated receptor signaling. Inhibition of APRIL receptor-mediated intracellular NFκB signaling was assessed using the HEK 293 NFκB reporter cell line after transient transfection with either a vector expressing full length human TNF receptor TACI cDNA or a vector expressing BCMA cDNA. Data are normalized without antibody control (100%). FIG. 34A shows inhibition of TACI-mediated NFκB signaling. FIG. 34B shows inhibition of BCMA-mediated NFκB signaling.

FIG. 35 depicts approximate IC ₅₀ values for antibody inhibition of APRIL-mediated receptor signaling. The data is extrapolated from FIG. 34A-34B based on non-linear regression analysis using variable slope, three-parameter fitting of anti-response antibody concentrations. A negative antibody control (no APRIL binding) showed no activity in this assay (data not shown).

FIG. 36 depicts an analysis of the binding reactivity of the APRIL antibody to other members of the TNFSF13 cytokine family. A select group of recombinant TNFSF-related cytokines (Adipogen) was used to test for antibody cross-reactivity as measured by ELISA. The panel included human APRIL (specific target) and structurally related BAFF. Illustrative antibodies are included for illustrative purposes. As predicted, strong binding of anti-APRIL antibodies to human APRIL was found. However, cross-reactivity with BAFF and other non-target members (human APRIL) was generally not substantially detectable above assay background level (measured here using BSA and assay diluent alone, 1xPBS controls). Antibody 4338, a previously identified BAFF cross-reactive antibody, was used as a positive (BAFF reactive) control. A control antibody, mAb1313, was also included.

FIG. 37A-37C depict minimal protein cross-reactivity between mAb 2419-1406 and mAb 4035-062 on a large-scale array of over 4500 heterologously expressed human membrane proteins in the HEK293-based assay and confirmation/secondary screen. An example of a protein expression chip design is shown in FIG. 37A. FIG. 37B-37C depict confirmation/secondary screening of 12 proteins. Expression levels of the secondary screen chip of 12 membrane proteins in GFP-based 293 cells are shown in the left panels of FIG. 37B-37C. The binding of the antibody to the same chip is shown in the right panel of FIG. 37B-37C.

FIG. 38A depicts the molecular interaction of anti-APRIL mAb 2419 with APRIL based on combined low-resolution crystallography data for human APRIL (amino acids 115-250) and mouse Fab region 2419. Structure was resolved by molecular replacement using the mouse APRIL described in the database. protein structure data. Epitope 2419 in APRIL was indicated by an arrow. Also indicated are the heavy and light chains of the mAb 2419 variable region. The structure of APRIL is depicted as a trimer.

FIG. 38B depicts residues in APRIL that contain a subset of epitope 2419. This structural depiction of epitope 2419 also highlights the fact that 2419 binds to a non-linear quaternary epitope spanning two different APRIL monomers within a larger trimeric complex, depicted here as monomer A and monomer B. Epitopes on monomer A and epitope on monomer B are indicated. Epitope 2419 essentially overlaps with a high affinity receptor binding site (CRD2) and a low affinity receptor binding site (CRD1) critical for APRIL mediated receptor signaling. The CRD2 receptor binding site and the CRD1 receptor binding site are labeled and indicated.

FIG. 39A-39B depict the thermal stability of mAbs 2419-1406 and 4035-062 measured using the Sypro-Orange® fluorescence scan assay. Thermal melt temperatures (Tm values) for 2419-1406 and 4035-062 are shown in FIG. 3.

FIG. 40A-40B depict the PK profiles of mAb 2419-1406 and 4035-062 in the tg32 transgenic mouse line carrying the humanized FcRn. Tg32 mice were given a single dose of 5 mg/kg mAb 2419-1406 or mAb 4035-062 by intravenous injection. Serum antibody levels were determined by ELISA following time points obtained up to 20 days. The PK values are shown in FIG. 40V.

FIG. 41 shows the decrease in basal serum IgA levels in mice treated with mAb 4540 and mAb 3833. 11-week-old C57/BL6 mice were subchronically dosed (once a week by ip injection) with 20 mg/kg of mAb 4540 or an isotype control antibody in within seven weeks. The basal serum level of total IgA was determined by ELISA. Median IgA levels are plotted; N=5 mice per group.

DETAILED DESCRIPTION

Disclosed herein are antibody molecules that bind to APRIL, eg, human APRIL, mouse APRIL, or both, with high affinity and specificity. Advantageously, certain antibody molecules described herein have an improved ability to reduce (eg, inhibit, block, or neutralize) one or more of the biological activities of APRIL. Also provided are nucleic acid molecules encoding antibody molecules, expression vectors, host cells, compositions (eg, pharmaceutical compositions), kits, and methods for producing antibody molecules. The antibody molecules and pharmaceutical compositions disclosed herein may be used (alone or in combination with other agents or therapeutic modalities) for the treatment, prevention and/or diagnosis of disorders and conditions, e.g. disorders and conditions associated with APRIL, e.g. IgA nephropathy.

Definitions

As used herein, the term one refers to one or more than one (eg, at least one) item grammatical object.

The term "or" is used herein to refer to and is used interchangeably with the term "and/or" unless the context clearly indicates otherwise.

"About" and "approximately" usually means an acceptable degree of error for the quantity measured, given the nature or accuracy of the measurements. Exemplary degrees of error are within 20% (%), typically within 10%, and more typically within 5% of a given value or range of values.

Compositions and methods disclosed herein include polypeptides and nucleic acids having said sequences, or sequences substantially identical or similar thereto, such as sequences at least 85%, 90%, 95% or greater identical to said sequence.

In the context of amino acid sequence, the term "substantially identical" is used herein to refer to the first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical or ii) conservative substitutions of aligned amino acid residues in the second amino acid sequence such that the first and the second amino acid sequence may have a common structural domain and/or a common functional activity. For example, amino acid sequences that contain a common structural region having at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with reference sequence, for example with the sequence presented in the present description.

In the context of a nucleotide sequence, the term "substantially identical" is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having general functional activity, or encode a general structural polypeptide domain or general functional polypeptide activity. For example, nucleotide sequences that have at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a reference sequence, such as the sequence presented in the present description.

The term "functional variant" refers to polypeptides that have a substantially identical amino acid sequence to a naturally occurring sequence, or are encoded by a substantially identical nucleotide sequence, and are capable of having one or more activities of the naturally occurring sequence.

The calculation of homology or sequence identity between sequences (the terms are used interchangeably herein) is performed as follows.

To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison (e.g., gaps can be introduced in one or both of the first and second amino acid or nucleotide sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes). In a typical embodiment, the length of the reference sequence aligned for comparison purposes is at least 30%, such as at least 40%, 50%, 60%, such as at least 70%, 80%, 90%, 100% the length of the reference sequence. Amino acid residues or nucleotides are then compared at the corresponding amino acid positions or nucleotide positions. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules at that position are identical.

The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that must be entered to optimally align the two sequences.

Sequence comparison and determination of percent identity between two sequences can be performed using a mathematical algorithm. In some embodiments, percent identity between two amino acid sequences is determined using the algorithm of Needleman and Wunsch ((1970) J. Mol. Biol. 48: 444-453), which was included in the GAP program in the GCG software package (see www.gcg .com) using either a Blossum 62 die or a PAM250 die and a gap size of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In some embodiments, the percent identities between two nucleotide sequences are determined using the GAP program in the GCG software package (see www.gcg.com) using NWSgapdna.CMP and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4 , 5, or 6. One suitable set of parameters (and the one that should be used unless otherwise noted) is a Blossum scoring matrix of 62 with a gap penalty of 12, a gap lengthening penalty of 4, and a frameshift penalty of 5.

The percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4: 11-17), which was included in the ALIGN program (version 2.0), using the PAM120 residue weight table , a gap length penalty of 12, and a gap penalty of 4.

The nucleic acid and protein sequences described herein can be used as a "query sequence" to perform open database searches, for example, to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST (version 2.0) programs of Altschul et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed using the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to nucleic acid as described herein. A BLAST protein search can be performed using the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the protein molecules described herein. To obtain discontinuous alignments for comparison purposes, Gapped BLAST can be used as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When using BLAST and gapped BLAST programs, the default settings for the respective programs (eg XBLAST and NBLAST) can be used. See www.ncbi.nlm.nih.gov.

Used in the present description, the term "hybridizes under conditions of low stringency, medium stringency, high stringency or very high stringency" describes the conditions for hybridization and washing. Guidelines for conducting hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, NY (1989), 6.3.1-6.3.6, which is incorporated by reference. Aqueous and non-aqueous methods are described in this reference and may be used. Specific hybridization conditions referred to herein are as follows: 1) low stringency hybridization conditions in 6x sodium chloride/sodium citrate (SSC) at about 45°C, followed by two washes in 0.2xSSC, 0.1% SDS, at least 50°C (washing temperature can be increased up to 55°C for low severity conditions); 2) medium stringency hybridization conditions in 6xSSC at about 45°C followed by one or more washes in 0.2xSSC, 0.1% SDS at 60°C; 3) high stringency hybridization conditions in 6xSSC at about 45°C followed by one or more washes in 0.2xSSC, 0.1% SDS at 65°C; and preferably 4) Very stringent hybridization conditions are 0.5M sodium phosphate, 7% SDS at 65°C followed by one or more washes in 0.2xSSC, 1% SDS at 65°C. Very high stringency conditions 4) are the appropriate conditions and are the ones to be used unless otherwise noted.

It is understood that the molecules described herein may have additional conservative or non-essential amino acid substitutions that do not significantly affect their function.

The term "amino acid" is intended to encompass all molecules, whether natural or synthetic, that include both amino functionality and acid functionality and can be incorporated into a polymer of natural amino acids. Examples of amino acids include natural amino acids; analogues, derivatives and their congeners; amino acid analogs with variant side chains; and all stereoisomers of any of the above. Used in the present description, the term "amino acid" includes both D - and L-optical isomers and peptidomimetics.

A "conservative amino acid substitution" is a "conservative amino acid substitution" in which an amino acid residue is replaced by an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are defined in the art. These families include amino acids with basic side chains (e.g. lysine, arginine, histidine), acidic side chains (e.g. aspartic acid, glutamic acid), uncharged polar side chains (e.g. glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (eg, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (eg, threonine, valine, isoleucine), and aromatic side chains (eg, tyrosine, phenylalanine , tryptophan, histidine).

The terms "polypeptide", "peptide" and "protein" (if one chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may contain modified amino acids, and it may be interrupted by non-amino acids. The terms also cover an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation such as conjugation with a labeled moiety. The polypeptide may be isolated from natural sources, may be obtained by recombinant methods from a eukaryotic or prokaryotic host, or may be the product of synthetic procedures.

The terms "nucleic acid", "nucleic acid sequence", "nucleotide sequence" or "polynucleotide sequence" and "polynucleotide" are used interchangeably. They refer to the polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or their analogues. The polynucleotide can be either single stranded or double stranded, and if single stranded, it can be a coding strand or a non-coding (antisense) strand. The polynucleotide may contain modified nucleotides such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides can be interrupted by non-nucleotide components. The polynucleotide can be further modified after polymerization, for example by conjugation with a labeled moiety. The nucleic acid may be a recombinant polynucleotide or a polynucleotide of genomic, cDNA, semi-synthetic or synthetic origin that either does not occur in nature or is linked to another polynucleotide in a non-natural environment.

Used in the present description, the term "isolated" refers to material that is removed from its original or native environment (for example, the natural environment, if it occurs in nature). For example, a natural polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide separated by human intervention from some or all of the coexisting materials in the natural system is isolated. Such polynucleotides may be part of a vector, and/or such polynucleotides or polypeptides may be part of a composition and yet be isolated in the sense that such vector or composition is not part of the environment in which it occurs naturally.

As used herein, the term "treatment", eg, IgA nephropathy, means that a patient (eg, human) who has a disorder, eg, IgA nephropathy and/or is experiencing a symptom of the disorder, eg, IgA nephropathy, will, in one embodiment, be less severe symptom and/or recover faster when the antibody molecule is administered than if the antibody molecule were never administered. In one embodiment, in the treatment of IgA nephropathy, a kidney biopsy will demonstrate less or no deposition of IgA, eg, as immune complexes in the mesangium of the kidney, following effective treatment of IgA nephropathy. For example, a diagnostic assay using immunofluorescence or electron microscopy will detect less absence of IgA deposition in a patient biological sample following administration of the antibody molecule described herein for effective treatment of IgA nephropathy. Other tests, urinalysis, blood tests, iothalamate removal tests, or kidney imaging (eg, ultrasound, X-ray, or cystoscopy) may also be used to monitor a patient's treatment or to detect the presence, such as a decrease in the presence (or absence), of an IgA-symptom. nephropathy after treatment of IgA nephropathy in a patient. The treatment may, for example, partially or completely, alleviate, ameliorate, attenuate, inhibit or lessen the severity and/or reduce the incidence and possibly delay the onset of one or more manifestations of the effects or symptoms, signs and/or causes of the disorder, e.g., IgA nephropathy. . In one embodiment, the treatment refers to a patient who does not show certain signs of a disorder, such as IgA nephropathy, and/or a patient who shows only early signs of a disorder, such as nephropathy. In one embodiment, the treatment refers to a patient who exhibits one or more established features of the disorder, such as IgA nephropathy. In one embodiment, the treatment refers to a patient who has been diagnosed as suffering from a disorder, such as IgA nephropathy.

As used herein, the term "prevent" a disorder, eg, IgA nephropathy, means that a patient (eg, a human) is less likely to have a disorder, eg, IgA nephropathy, if the patient receives an antibody molecule.

Various aspects of the compositions and methods are described herein in more detail below. Additional definitions are presented in the description of the invention.

APRIL

APRIL (proliferation-inducing ligand), also known as CD256, TNF- and APOL-associated leukocyte-expressed ligand 2 (TALL-2) or TNF-associated death ligand 1 (TRDL-1), is a TNF family cytokine encoded by the member gene 13 tumor necrosis factor (TNFF13) ligand superfamily (also known as APRIL, TALL2, or ZTNF2). APRIL plays a role in a number of biological processes such as signal transduction, regulation of cell proliferation, and IgA class switching (Hahne et al. (1998) J. Exp. Med. 188: 1185-1190 (1998); Castigli et al. Proc. Natl Acad. Sci. U.S.A. 101:3903-3908 (2004)).

APRIL is functionally and structurally related to BAFF (B-cell activating factor F13B), also known as BLyS (B-lymphocyte stimulator). Both cytokines are involved in the regulation of key aspects of innate and adaptive immune functions. Both APRIL and BAFF bind to lymphocyte receptors TACI (transmembrane activator and CAML interacting agent) and BCMA (B-cell maturation antigen). APRIL and BAFF appear to interact heterologously with each other through protein-protein interactions. While both APRIL and BAFF have biochemical (receptor binding), immunological, and even some structural overlap (eg, as it relates to the three-dimensional topology of their respective receptor binding domains), the two cytokines are nonetheless structurally and functionally distinct. APRIL binds to the biologically significant heparan sulfate (present in the extracellular matrix of cells as heparan sulfate proteoglycans); BAFF - no. This interaction plays a critical biological function in relation to promoting APRIL's oligomerization state in conjunction with its localized interaction with TACI, which also requires HSPGS for full activity. Unlike BAFF, which acts as a potent B cell activator, including both proliferation and differentiation, APRIL appears to function more specifically to modulate B cell phenotype, for example, as it is associated with IgA production and differentiation. /survival of IgA-positive plasma cells. In fact, targeted disruption of APRIL receptor signaling is expected to have less perturbative effect on B-cell homeostasis and overall immune function compared to other immunological therapies that target BAFF (eg, belimumab) or anti-CD20 antibody therapy. (eg, rituximab), which mainly target pre-B cells and early B cells. APRIL has also been shown to be highly expressed in other bone marrow and lymphoid tissues, as well as in hematological cancer cells (eg, myeloma, chronic lymphocytic leukemia (CLL)) and in solid tumor cells ( such as the colon, thyroid, and breasts).

Exemplary amino acid and nucleotide sequences of human APRIL are described, for example, in Hahne et al. J. Exp. Med. 188: 1185-1190 (1998); Shu et al. J. Leukoc. Biol. 65:680-683 (1999); Kelly et al. Cancer Res. 60: 1021-1027 (2000); and Pradet-Balade et al. EMBO J. 21:5711-5720 (2002).

The amino acid sequence of human APRIL (alpha isoform, also referred to as the "canonical" sequence (SEQ ID NO: 85)) is shown below.

> huAPRIL

MPASSPFLLAPKGPPGNMGGPVREPALSVALWLSWGAALGAVACAMALLTQQTELQSLRREVSRLQGTGGPSQNGEGYPWQSLPEQSSDALEAWENGERSRKRRAVLTQKQKKQHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFVKL

There are several isoforms of human APRIL obtained by alternative splicing.

The beta isoform has the following amino acid sequence (SEQ ID NO: 86):

>sp | O75888-2 | TNF13_HUMAN Isoform Beta member 13 of the tumor necrosis factor superfamily OS=Homo sapiens GN=TNFSF13

MPASSPFLLAPKGPPGNMGGPVREPALSVALWLSWGAALGAVACAMALLTQQTELQSLRREVSRLQGTGGPSQNGEGYPWQSLPEQSSDALEAWENGERSRKRRAVLTQKQKNDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLGFSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPSHPDRAYNSCYSGDIVLTK

The beta isoform sequence differs from the canonical sequence as follows: amino acids 113-129 SEQ ID NO: 85: KQHSVLHLVPINATSKD → N

The gamma isoform has the following amino acid sequence (SEQ ID NO: 87):

>sp | O75888-3 | TNF13_Human Isoform of tumor necrosis factor superfamily member gamma 13 OS=Homo sapiens GN=TNFSF13

MPASSPFLLAPKGPPGNMGGPVREPALSVALWLSWGAALGAVACAMALLTQQTELQSLRREVSRLQGTGGPSQNGEGYPWQSLPEQSSDALEAWENGERSRKRRAVLTQKQKKQHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGL

The gamma isoform sequence differs from the canonical sequence as follows: amino acids 247-249: absent.

Isoform 4 has the following amino acid sequence (SEQ ID NO: 88):

>sp | O75888-4 | TNF13_Human Isoform 4 tumor necrosis factor superfamily member 13 OS=Homo sapiens GN=TNFSF13

MPASSPFLLAPKGPPGNMGGPVREPALSVALWLSWGAALGAVACAMALLTQQTELQSLRREVSRLQGTGGPSQNGEGYPWQSLPEQHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQLPHGDILS

The sequence of isoform 4 differs from the canonical sequence as follows: amino acids 86-113: absent.

The TWE-PRIL isoform has the following amino acid sequence (SEQ ID NO: 89):

>sp | O43508-2 | TNF12_human TWE-PRIL isoform of tumor necrosis factor superfamily member 12 OS=Homo sapiens GN=TNFSF12

MAARRSQRRRGRRGEPGTALLVPLALGLGLALACLGLLLAVVSLGSRASLSAQEPAQEELVAEEDQDPSELNPQTEESQDPAPFLNRLVRPRRSAPKGRKTRARRAIAAHYEVHPRPGQDGAQAGVDGTVSGWEEARINSSSPLRYNRQIGEFIVTRAGLYYLYCQSSDALEAWENGERSRKRRAVLTQKQKKQHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFVKL

Isoform 5 has the following amino acid sequence (SEQ ID NO: 90):

>sp | O75888-5 | TNF13_human isoform 5 tumor necrosis factor superfamily member 13 OS=Homo sapiens GN=TNFSF13

MGGPVREPALSVALWLSWGAALGAVACAMALLTQQTELQSLRREVSRLQGTGGPSQNGEGYPWQSLPEQHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIPRARATFLNLSPHG

The sequence of isoform 5 differs from the canonical sequence as follows: amino acids 1-17: absent; amino acids 87-114: None.

Other variants and alternative sequences of human APRIL are described, for example, in The MGC Project Team, Genome Res. 14:2121-2127 (2004); Ota et al. Nat. Genet. 36:40-45 (2004); and Kelly et al. Cancer Res. 60:1021-1027 (2000).

As used herein, when an anti-APRIL antibody molecule binds or substantially binds to human APRIL, it binds or substantially binds to one or more human APRIL isoforms, such as one or more of the human APRIL isoforms described herein. In one embodiment, the antibody molecule binds or substantially binds to human APRIL having the amino acid sequence of SEQ ID NO: 85.

Exemplary amino acid and nucleotide sequences of murine APRIL are described, for example, in Yu et al. Nat. Immunol. 1: 252-256 (2000); Carninci et al. Science 309:1559-1563 (2005); The MGC Project Team, Genome Res. 14:2121-2127 (2004); and Bossen et al. J Biol Chem. 281: 13964-13971 (2006).

The amino acid sequence of mouse APRIL isoform 1 (SEQ ID NO: 91) is shown below.

> muAPRIL

MPASSPGHMGGSVREPALSVALWLSWGAVLGAVTCAVALLIQQTELQSLRREVSRLQRSGGPSQKQGERPWQSLWEQSPDVLEAWKDGAKSRRRRAVLTQKHKKKHSVLHLVPVNITSKADSDVTEVMWQPVLRRGRGLEAQGDIVRVWDTGIYLLYSQVLFHDVTFTMGQVVSREGQGRRETLFRCIRSMPSDPDRAYNSCYSAGVFHLHQGDIITVKIPRANAKLSLSPHGTFLGFVKL

The amino acid sequence of mouse APRIL isoform 2 (SEQ ID NO: 92) is shown below.

MPASSPGHMGGSVREPALSVALWLSWGAVLGAVTCAVALLIQQTELQSLRREVSRLQRSGGPSQKQGERPWQSLWEQSPDVLEAWKDGAKSRRRRAVLTQKHKKKHSVLHLVPVNITSKDSDVTEVMWQPVLRRGRGLEAQGDIVRVWDTGIYLLYSQVLFHDVTFTMGQVVSREGQGRRETLFRCIRSMPSDPDRAYNSCYSAGVFHLHQGDIITVKIPRANAKLSLSPHGTFLGFVKL

As used herein, when an anti-APRIL antibody molecule binds or substantially binds to mouse APRIL, it binds or substantially binds to one or more mouse APRIL isoforms, such as one or more of the mouse APRIL isoforms described herein. In one embodiment, the antibody molecule binds or substantially binds to a murine APRIL having the amino acid sequence of SEQ ID NO: 91, SEQ ID NO: 92, or both.

As used herein, when an anti-APRIL antibody molecule does not or substantially does not bind to murine APRIL, it does not or does not substantially bind to one or more isoforms of murine APRIL, such as one or more isoforms of murine APRIL described herein. document. In one embodiment, the antibody molecule does not or does not substantially bind to mouse APRIL having the amino acid sequence of SEQ ID NO: 91 or 92. In a typical embodiment, the antibody molecule does not or does not substantially bind to mouse APRIL having the amino acid sequence of SEQ ID NO: 91, and with mouse APRIL having the amino acid sequence of SEQ ID NO: 92.

The sequence alignment of exemplary human and mouse APRIL proteins (SEQ ID NOs: 85 and 91, respectively) is shown in FIG. 13.

epitope

An antibody molecule described herein can bind to an epitope on APRIL (eg, human APRIL, mouse APRIL, or both). For example, an epitope bound by an antibody molecule described herein may include one or more of the contact points of the epitopes described herein.

In one embodiment, the antibody molecule contacts (eg, binds or substantially binds) one or more residues, or one or more regions, as described in any of Tables 3-4 or 6-8, or in any of FIGS. 14, 22, 23A-23B, 24A-24B, 25A-25B or 38A-38B.

In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all) of the amino acid residues shown in Table 3. In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds) all amino acid residues shown in Table 3. For example, antibody molecules described herein can contact the amino acid residues shown in Table 3 such that they involve binding through two APRIL monomers (for example, as shown in Table 3 as A v. B). Regardless of theory, it is believed that in one embodiment, at least some of the amino acid residues shown in Table 3 contribute to a high affinity interaction between APRIL and the TACI CDR2 domain. In one embodiment, contacting one or more amino acid residues in Table 3 with an antibody molecule described herein inhibits or substantially inhibits the binding of APRIL to TACI.

Exemplary human APRIL amino acid residues that can bind to the anti-APRIL antibody molecules described herein are shown in Table 3. The structural representation of this epitope (eg, defined both spatially and conformationally) is depicted in FIG. 14.

Table 3 Exemplary human APRIL amino acid residues that bind to anti-APRIL antibodies (amino acid numbering based on SEQ ID NO: 85)

Monomer Amino acid position Amino acid A 130 asp A 131 Ser A 132 asp A 174 Val A 175 Thr A 176 Phe A 177 Thr A 178 Met A 179 gly A 180 Gln A 181 Val A 192 Thr A 195 Arg A 196 Cys A 197 ile A 200 Met A 201 Pro A 202 Ser A 208 Tyr A 230 Pro A 231 Arg A 232 Ala A 241 His B 170 Leu B 205 asp B 206 Arg

In another embodiment, the antibody molecule contacts (e.g., binds or substantially binds) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all) amino acid residues shown in Table 4. In another embodiment, the antibody molecule contacts (e.g., binds or substantially binds) all of the amino acid residues shown in Table 4. In one embodiment, the antibody molecule binds to, or substantially binds to, the C-D loop (e.g. β-sheets C and D), loop G-H (eg, β-sheet binding loop G and H), or both on APRIL.

The structural (spatial) presentation of this epitope (sometimes referred to herein as the "core region") is depicted in FIG. 15. As shown in FIG. 15, each APRIL protein molecule contains two packed anti-parallel eight-stranded β-sheets (A-G), one internal and one external, in a β roll topology. These B sheets are linked by loops that also define (based on secondary structure definitions) the target epitope. Regardless of theory, it is believed that since these positions/structures define a subset of key interactions with APRIL and the CRD2 domain of TACI, it would be possible to achieve optimal inhibition of APRIL binding to TACI with such an antibody.

Table 4 Exemplary human APRIL amino acid residues that bind to anti-APRIL antibodies (amino acid numbering based on SEQ ID NO: 85)

Amino acid position Amino acid 174 Val 175 Thr 176 Phe 177 Thr 178 Met 179 gly 180 Gln 181 Val 230 Pro 231 Arg 232 Ala

In another embodiment, the antibody molecule does not bind to one, two, or all of Asp129, Arg233, or HIS203 on human APRIL (eg, SEQ ID NO: 85). For example, one or more mutations at these positions, such as Asp129Ala, Arg233Asn, His203Asp, or any combination thereof, would not reduce or reduce the binding affinity of the antibody molecule to human APRIL or the inhibitory effect of the antibody molecule on human APRIL activity (e.g., neutralization of APRIL binding to TACI).

In yet another embodiment, the antibody molecule binds or substantially binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues of human APRIL (e.g., SEQ ID NO: 85) from positions 105-114 and/or with one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or all) mouse APRIL residues (e.g., SEQ ID NO: 91) from positions 96- 105.

In another embodiment, the antibody molecule contacts (e.g., binds or substantially binds to) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, or all) of the amino acid residues shown in Table 7. In another embodiment, the antibody molecule contacts (e.g., binds or substantially binds to all) the amino acid residues shown in Table 7.

Table 7 Exemplary human APRIL amino acid residues that bind to anti-APRIL antibodies (amino acid numbering based on SEQ ID NO: 85)

Amino acid position Amino acid 132 asp 170 Leu 175 Thr 176 Phe 177 Thr 178 Met 181 Val 192 Thr 195 Arg 197 ile 205 asp 206 Arg 208 Tyr 228 ISO 230 Pro 231 Arg 232 Ala 241 His

In one embodiment, an antibody molecule, e.g., an anti-APRIL antibody molecule having one, two, three, four, five, or six CDRs of any of the monoclonal antibodies 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 0605, 2419-0805, 2419-0806, 2419-1204, 2419-1210, 2419-1305, 2419-1306, 2419-1310, or 2419-1406 binds to one or more of the amino acids described in Table 7. In another embodiment, an antibody molecule, for example, a human-specific anti-APRIL antibody molecule, for example, having one, two, three, four, five, or six CDRs of any of the monoclonal antibodies 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, binds to mouse APRIL when one or more 3, 4 or all) the following positions in mouse APRIL (mouse APRIL numbering is used) are mutated, for example, as follows: A120D, N224R, H163Q, K219I or R181Q. In yet another embodiment, an antibody molecule, e.g., a human-specific anti-APRIL antibody molecule, e.g., having one, two, three, four, five, or six CDRs of any of the monoclonal antibodies , 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406 219 (mouse APRIL numbering is used) are mutated to, for example, isoleucine (ie K219I).

In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds to) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or all) human APRIL amino acid residues shown in Table 6. In one in an embodiment, the antibody molecule is an antibody molecule as described herein, e.g., monoclonal antibody 2218, 2419, 2621, 2622, 3125, 3327, 3525, 3530, 4035, 3934, 3833, 3631, 3732, 4338, 4540, or 4237,

In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds to) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) human APRIL amino acid residues selected from D132, V174, F176, V181, Q190, R195, R206, Y208, I228 or N237. In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds to) one or more (e.g., 2, 3, 4, 5, or all) human APRIL amino acid residues selected from V174, F176, Q190, R195, R206 or Y208. In one embodiment, the antibody molecule contacts (eg, binds or substantially binds to) one or more (eg, 2, 3, or all) amino acid residues of human APRIL selected from F176, V181, Q190, or I228. In one embodiment, the antibody molecule contacts (eg, binds or substantially binds to) one or more (eg, 2 or all) human APRIL amino acid residues selected from V174, R206, or Y208.

In one embodiment, the antibody molecule does not contact (e.g., does not bind or substantially does not bind) at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, or 20) of the human APRIL amino acid residues shown in Table 6. In one embodiment, the antibody molecule is an antibody molecule as described herein, e.g., monoclonal antibody 2218, 2419 , 2621, 2622, 3125, 3327, 3525, 3530, 4035, 3934, 3833, 3631, 3732, 4338, 4540 or 4237,

In one embodiment, the antibody molecule does not contact (e.g., does not bind or substantially does not bind) one or more (e.g., 2, 3, 4, 5, 6, or all) human APRIL amino acid residues selected from F176, V181, Q190, S226, I228, Y208 or N237. In one embodiment, the antibody molecule does not contact (e.g., does not bind or substantially does not bind) one or more (e.g., 2, 3, or all) human APRIL amino acid residues selected from V181, S226, I228, or N237. In one embodiment, the antibody molecule does not contact (eg, does not bind or substantially does not bind) one or both of the human APRIL amino acid residues selected from Y208 or N237. In one embodiment, the antibody molecule does not contact (e.g., does not bind or substantially does not bind) one or more (e.g., 2, 3, or all) human APRIL amino acid residues selected from F176, V181, Q190, or N237.

In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds to) one or more (e.g., 2, 3, 4, 5, or all) human APRIL amino acid residues selected from V174, F176, Q190, R195, R206 or Y208; and does not contact (eg, does not bind or substantially does not bind) one or more (eg, 2, 3, or all) of human APRIL amino acid residues selected from V181, S226, I228, or N237. In one embodiment, the antibody molecule contacts (eg, binds or substantially binds to) one or both of human APRIL amino acid residues selected from V174 or R206; and does not contact (eg, does not bind or substantially does not bind) one or both of the human APRIL amino acid residues selected from V181 or N237 (and optionally S226). In one embodiment, the antibody molecule contains one or more (e.g., two or three) heavy chain CDRs, one or more (e.g., two or three) light chain CDRs, or both of the 4035 monoclonal antibody. In one embodiment, the antibody molecule contains a heavy chain region, a light chain variable region, or both, of the 4035 monoclonal antibody. In one embodiment, the 4035 monoclonal antibody is a humanized antibody molecule.

In one embodiment, the antibody molecule contacts (eg, binds or substantially binds to) one or more (eg, 2, 3, or all) of human APRIL amino acid residues selected from F176, V181, Q190, or I228; and does not contact (eg, does not bind or substantially does not bind) one or both of the human APRIL amino acid residues selected from Y208 or N237. In one embodiment, the antibody molecule contacts (eg, binds or substantially binds) amino acid residue I228 of human APRIL; and does not contact (eg, does not bind or substantially does not bind) one or both of the human APRIL amino acid residues selected from Y208 or N237. In one embodiment, the antibody molecule contains one or more (e.g., two or three) heavy chain CDRs, one or more (e.g., two or three) light chain CDRs, or both of the 2419 monoclonal antibody. In one embodiment, the antibody molecule contains a heavy chain region, a light chain variable region, or both, of the 2419 monoclonal antibody. In one embodiment, the 2419 monoclonal antibody is a humanized antibody molecule.

In one embodiment, the antibody molecule contacts (eg, binds or substantially binds) one or more (eg, 2 or all) of human APRIL amino acid residues selected from V174, R206, or Y208; and does not contact (eg, does not bind or substantially does not bind) one or more (eg, 2, 3, or all) of human APRIL amino acid residues selected from F176, V181, Q190, or N237. In one embodiment, the antibody molecule contacts (eg, binds or substantially binds) one or both of human APRIL amino acid residues selected from V174 or R206; and does not contact (eg, does not bind or substantially does not bind) one or more (eg, 2, 3, or all) of human APRIL amino acid residues selected from F176, V181, Q190, or N237. In one embodiment, the antibody molecule contains one or more (e.g., two or three) heavy chain CDRs, one or more (e.g., two or three) light chain CDRs, or both of a 3833 monoclonal antibody. In one embodiment, the antibody molecule contains a heavy chain region, a light chain variable region, or both, of the 3833 monoclonal antibody. In one embodiment, the 3833 monoclonal antibody is a humanized antibody molecule.

In an embodiment, the epitope overlaps with the CRD2 receptor binding site. In one embodiment, the epitope is a non-linear epitope, eg, that extends along a monomer boundary. In one embodiment, the epitope is in a region associated with blocking both TACI and BCMA receptors.

In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , or all) from human APRIL amino acid residues selected from V133, V181, E185, Q187, G188, R189, Q190, E191, T192, R195, H218, L219, H220, S226, I228, P230 (located in monomer A) . In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) of human APRIL amino acid residues selected from V121 , I123, Q139, P140, A141, L142, N237, S239, P240, or H241 (located in monomer B). In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or all) of human APRIL amino acid residues selected from V133, V181, E185, Q187, G188, R189, Q190, E191, T192, R195, H218, L219, H220, S226, I228, P230 (found in monomer A); V121, I123, Q139, P140, A141, L142, N237, S239, P240, or H241 (located in monomer B).

In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds) one or more (e.g., 2, 3, or all) of human APRIL amino acid residues selected from V181, Q190, T192, and I228 (located in monomer A ). In one embodiment, the antibody molecule contacts (eg, binds or substantially binds) one or both of human APRIL amino acid residues selected from A141 or H241 (located in monomer B). In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds) one or more (e.g., 2, 3, 4, 5, or all) of human APRIL amino acid residues selected from V181, Q190, T192, and I228 (located in monomer A); A141 or H241 (located in monomer B).

In one embodiment, the antibody molecule contains one or more (e.g., two or three) heavy chain CDRs, one or more (e.g., two or three) light chain CDRs, or both of the 2419 monoclonal antibody. In one embodiment, the antibody molecule contains a heavy chain region, a light chain variable region, or both, of the 2419 monoclonal antibody. In one embodiment, the 2419 monoclonal antibody is a humanized antibody molecule.

In one embodiment, the epitope contains one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 21, 22, 23, 24, 25 or all) from human APRIL amino acid residues selected from V133, V181, E185, Q187, G188, R189, Q190, E191, T192, R195, H218, L219, H220, S226, I228, P230 (located in monomer A); V121, I123, Q139, P140, A141, L142, N237, S239, P240, or H241 (located in monomer B). In one embodiment, the epitope contains one or more (eg, 2, 3, 4, 5, or all) of human APRIL amino acid residues selected from V181, Q190, T192, and I228 (located in monomer A); A141 or H241 (located in monomer B).

In one embodiment, the structural representation of this epitope is shown in FIG. 3. In one embodiment, the epitope contains one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or all) of the amino acid residues shown in Table 8.

In one embodiment, the antibody molecule contacts (eg, binds or substantially binds) all of the amino acid residues shown in any of Tables 3-4 or 7-8. In one embodiment, the epitope contains or consists of all of the amino acid residues shown in any of Tables 3-4 or 7-8.

In one embodiment, an antibody molecule has one or more of the following properties described herein, eg one or more (eg two, three, or all): (i) binds or substantially binds to human APRIL; (ii) binds or substantially binds to murine APRIL; (iii) inhibits or substantially inhibits the binding of APRIL (eg, human APRIL, mouse APRIL, or both) to TACI (eg, human TACI, mouse TACI, or both); or (iv) inhibits or substantially inhibits the binding of APRIL (eg, human APRIL, murine APRIL, or both) to BCMA (eg, human BCMA, murine BCMA, or both). In one embodiment, the antibody molecule binds or substantially binds to murine APRIL. In another embodiment, the antibody molecule does not bind or binds with low affinity to mouse APRIL.

Antibody molecules

Disclosed herein are antibody molecules that bind to APRIL, such as the APRIL molecule described herein.

As used herein, the term "antibody molecule" refers to a protein, such as an immunoglobulin chain or fragment thereof, containing at least one immunoglobulin variable domain sequence. The term "antibody molecule" includes, for example, full-length, mature antibodies and antigen-binding antibody fragments. For example, an antibody molecule may include a heavy (H) chain variable domain sequence (abbreviated here as VH) and a light (L) chain variable domain sequence (abbreviated here as VL). In another example, an antibody molecule contains two heavy (H) chain variable domain sequences and two light chain (L) variable domain sequences, thus forming two antigen binding sites such as Fab, Fab', F(ab') 2, Fc, Fd, Fd', Fv, single chain antibodies (e.g. scFv), single variable region antibodies, diabodies (Dab) (bivalent and bispecific) and chimeric (e.g. humanized) antibodies, which can be obtained by modification of whole antibodies or synthesized de novo using recombinant DNA technology. These functional antibody fragments retain the ability to bind selectively to their respective antigen or receptor. Antibodies and antibody fragments can be from any class of antibodies, including but not limited to IgG, IgA, IgM, IgD, and IgE, and from any subclass (eg, IgG1, IgG2, IgG3, and IgG4) of antibodies. Antibody molecules can be monoclonal or polyclonal. The antibody molecule may also be a human, humanized, CDR-grafted or in vitro derived antibody. The antibody molecule may have a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3, or IgG4. The antibody molecule may also have a light chain selected from, for example, kappa or lambda. The term "immunoglobulin" (Ig) is used herein interchangeably with the term "antibody".

Examples of antigen-binding fragments include: (i) Fab fragment, a monovalent fragment consisting of VL, VH, CL and CH1 domains; (ii) an F(ab')2 fragment, a divalent fragment containing two Fab fragments connected by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of one antibody arm, (v) a diabody fragment (dAb) which consists of a VH domain; (vi) camel or camel variable domain; (vii) single chain Fv (scFv), see, for example, Bird et al. (1988) Science 242: 423-426; and Huston et al. (1988) Proc. Natl. Acad. sci. USA, 85: 5879-5883); (viii) single domain antibody. These antibody fragments can be obtained using any suitable method, including several conventional methods known to those skilled in the art, and the fragments can be screened for utility in the same manner as intact antibodies.

The term "antibody" includes intact molecules as well as their functional fragments. Antibody constant regions can be altered, such as mutated to modify a property of the antibody (eg, to increase or decrease one or more of Fc receptor binding, antibody glycosylation, cysteine residues, effector cell function, or complement function).

The antibody molecule may be a single chain antibody. The single chain antibody (scFv) may be engineered (see, for example, Colcher, D. et al. (1999) Ann NY Acad Sci 880: 263-80; and Reiter, Y. (1996) Clin Cancer Res 2:245-52 ). A single chain antibody can be dimerized or multimerized to produce polyvalent antibodies with specificity for different epitopes of the same target protein.

The antibody molecules disclosed herein may also be single domain antibodies. Single domain antibodies may include antibodies whose complementarity determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain containing antibodies, antibodies inherently devoid of light chains, single domain antibodies derived from conventional 4 chain antibodies, engineered antibodies, and single domain scaffolds other than those derived from antibodies. Single domain antibodies can be any known in the art or any future single domain antibodies. Single domain antibodies can be derived from any species including, but not limited to, mouse, human, camel, llama, fish, shark, goat, rabbit, and bull. In some aspects, the single domain antibody is a naturally occurring single domain antibody known as a heavy chain antibody lacking light chains. Such single domain antibodies are disclosed, for example, in WO 94/04678. For the sake of clarity, this variable domain derived from a heavy chain antibody inherently devoid of a light chain is known herein as the VHH or nanobody to distinguish it from the conventional VH domain of four chain immunoglobulins. Such a VHH molecule can be derived from antibodies derived from camelid species, such as camelids, llamas, dromadars, alpacas and guanacos. Species other than camelids can produce heavy chain antibodies that are inherently devoid of the light chain; such VHHs are also provided.

The VH and VL regions can be subdivided into regions of hypervariability called "complementarity determining regions" (CDRs) that alternate with more conserved regions called "framework regions" (FRs or FWs). The terms "complementarity determining region" and "CDR" as used herein refer to amino acid sequences in the variable regions of an antibody that confer antigen specificity and binding affinity. Used in the present description, the terms "frame", "FW" and "FR" are used interchangeably.

The extent of the framework region and CDR is accurately determined by a number of methods (see, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Chothia , C. et al (1987) J. Mol Biol 196: 901-917 and the AbM determination used by AbM antibody modeling software from Oxford Molecular See, in general, for example, Protein Sequence and Structure Analysis of Antibody Variable Domains In: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg) In one embodiment, the following definitions are used: AbM CDR1 definition of the heavy chain variable domain and Kabat definitions for other CDRs.In one embodiment, the Kabat definitions are used for all CDRs.In addition, the embodiments described with respect to Kabat or AbM CDRs can also be implemented using Chothia hypervariable loops.Each VH and VL typically includes three CDRs and four FRs, located from the N-terminus to the C-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

As used herein, the term "immunoglobulin variable domain sequence" refers to an amino acid sequence that can form an immunoglobulin variable domain structure. For example, the sequence may include all or part of the amino acid sequence of a naturally occurring variable domain. For example, the sequence may or may not include one, two or more N- or C-terminal amino acids, or may include other changes that are compatible with the formation of a protein structure.

The term "antigen binding region" refers to the portion of an antibody molecule that contains determinants that form a binding surface that binds to an antigen, such as APRIL, or an epitope thereof. With respect to proteins (or protein mimetics), the antigen-binding region typically includes one or more loops (at least, for example, four amino acids or amino acid mimetics) that form a binding surface that binds to an antigen, such as APRIL. Typically, the antigen-binding region of an antibody molecule comprises at least one or two CDRs and/or hypervariable loops, or more typically at least three, four, five, or six CDRs and/or hypervariable loops.

The terms "compete" or "cross-compete" are used interchangeably herein to refer to the ability of an antibody molecule to prevent an anti-APRIL antibody molecule, such as the anti-APRIL antibody molecule described herein, from binding to a target, such as APRIL. Interfering with binding can be direct or indirect (eg, through allosteric modulation of the antibody or target molecule). The extent to which an antibody molecule can prevent another antibody molecule from binding to a target, and therefore where it can be said to compete, can be determined using a competitive binding assay, such as a FACS, ELISA, or BIACORE assay. In one embodiment, the competitive binding assay is a quantitative competitive assay. In one embodiment, the first anti-APRIL antibody molecule is said to compete for target binding with the second anti-APRIL antibody molecule when the binding of the first antibody molecule to the target is reduced by 10% or more, e.g., 20% or more, 30% or more, 40% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more in a competitive binding assay (eg, in a competitive assay described herein).

The terms "monoclonal antibody" or "monoclonal antibody composition" as used herein refers to a preparation of antibody molecules of a single molecular composition. The composition of monoclonal antibodies exhibits binding specificity and affinity for a particular epitope. The monoclonal antibody can be produced by hybridoma technology or by methods that do not use hybridoma technology (eg, recombinant methods).

An "effectively human" protein is one that does not elicit a neutralizing antibody response, such as a human anti-mouse antibody (HAMA) response. HAMA can be problematic in some cases, for example if the antibody molecule is repeatedly administered, for example in the treatment of a chronic or relapsing disease. The HAMA response can make repeated administration of the antibody potentially ineffective due to increased serum antibody clearance (see e.g. Saleh et al., Cancer Immunol. Immunother., 32: 180-190 (1990)), as well as potential allergic reactions (see, for example, LoBuglio et al., Hybridoma, 5: 5117-5123 (1986)).

The antibody molecule may be a polyclonal or monoclonal antibody. In some embodiments, the implementation of the antibody can be obtained recombinantly, for example, using any suitable phage display or combinatorial methods.

Various types of phage display and combinatorial methods for producing antibodies are known in the art (as described, for example, in Ladner et al. US Patent No. 5223409; Kang et al. International Publication No. WO 92/18619; Dower et al. International Publication No. WO 91/17271 Winter et al International Publication WO 92/20791 Markland et al International Publication No WO 92/15679 Breitling et al International Publication WO 93/01288 McCafferty et al International Publication No WO 92/01047 Garrard et al International Publication No WO 92/09690 Ladner et al International Publication No WO 90/02809 Fuchs et al (1991) Bio/Technology 9: 1370-1372 Hay et al (1992) Hum Antibod Hybridomas 3: 81-85; Huse et al. (1989) Science 246: 1275-1281; Griffths et al. (1993) EMBO J 12: 725-734; Hawkins et al. (1992) J Mol Biol 226: 889-896 ; Clackson et al. (1991) Nature 352: 624-628; Gram et al. (1992) PNAS 89: 3576-3580; Garrad et al. (1991) Bio/Technology 9: 1373-1377; Hoogenboom et al. ( 1991) Nuc Acid Res 19: 4133-4137; and Barbas et al. (1991) PNAS 88: 7978-7982, the contents of which are incorporated herein by reference).

In one embodiment, the antibody molecule is a fully human antibody (e.g., an antibody derived from a mouse that has been genetically engineered to produce an antibody from a human immunoglobulin sequence), or a non-human antibody, such as a rodent (mouse or rat), goat, primate (for example, monkeys), camel. In one embodiment, the non-human antibody is a rodent (mouse or rat antibody). Methods for producing rodent antibodies are known in the art.

Human monoclonal antibodies can be generated using transgenic mice carrying human immunoglobulin genes rather than the mouse gene system. Splenocytes from these transgenic mice immunized with an antigen of interest are used to generate hybridomas that secrete human mAbs with specific affinity for human protein epitopes (see, for example, Wood et al. International application WO 91/00906, Kucherlapati et al. Publication PCT WO 91/10741 Lonberg et al WO 92/03918 Kay et al International 92/03917 Lonberg, N. et al 1994 Nature 368:856-859 Green, L. L. et al 1994 Genet Genet 7: 13-21 Morrison, SL et al 1994 Proc Natl Acad Sci USA 81: 6851-6855 Bruggeman et al 1993 Year Immunol 7:33-40 Tuaillon et al 1993 PNAS 90 : 3720-3724; Bruggeman et al. 1991 Eur J Immunol 21: 1323-1326).

The antibody may be an antibody in which the variable region or portion thereof, such as the CDR, is generated in a non-human organism, such as a rat or mouse. Chimeric, CDR-transplanted and humanized antibodies are within the scope of the invention. Antibodies produced in a non-human organism, eg rat or mouse, and then modified, eg in a variable framework or constant region, to reduce antigenicity in humans are within the scope of the invention.

Chimeric antibodies can be generated using any suitable recombinant DNA technique. Some of them are known in the art (see Robinson et al., International Patent Application Publication No. WO1987/002671, Akira et al., European Patent Application Publication No. 184187, Taniguchi, M., European Patent Application Publication No. 171496; Morrison et al. al., European Patent Application Publication No. 173494, Neuberger et al., International Patent Application Publication No. WO 86/01533, Cabilly et al. (1988 Science 240: 1041-1043); Liu et al. (1987) PNAS 84: 3439-3443; Liu et al., 1987, J. Immunol. 139: 3521-3526; Sun et al. (1987) PNAS 84: 214-218; Nishimura et al., 1987, Canc. Res. 47:999-1005; Wood et al. (1985) Nature 314: 446-449; and Shaw et al., 1988, J. Natl Cancer Inst. 80: 1553-1559).

A humanized or CDR-grafted antibody will have at least one or two, but typically all three, recipient CDRs (from immunoglobulin heavy and light chains) replaced by donor CDRs. The antibody may be replaced with at least a portion of the non-human CDRs, or only some of the CDRs may be replaced with non-human CDRs. It is only necessary to change the number of CDRs needed to bind the humanized antibody to lipopolysaccharide. In one embodiment, the donor will be a rodent antibody, such as a rat or mouse antibody, and the recipient will be a human framework or consensus human framework. Generally, an immunoglobulin providing a CDR is referred to as a "donor" and an immunoglobulin providing a structure is referred to as an "acceptor". In some embodiments, the donor immunoglobulin is of non-human origin (eg, from a rodent). An acceptor framework is typically a natural (eg, human) framework or a consensus framework or sequence that is about 85% or more, eg, 90%, 95%, 99% or more, identical to them.

As used herein, the term "consensus sequence" refers to a sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related sequences (see, e.g., Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987), In the family proteins, each position in the consensus sequence is occupied by the most frequently occurring amino acid at that position in the family.If two amino acids occur equally often, then they can be included in the consensus sequence."Consensus framework sequence"refers to the framework region in the consensus sequence of an immunoglobulin.

The antibody can be humanized by any suitable method, and several such methods are known in the art (see, for example, Morrison, SL, 1985, Science 229: 1202-1207, Oi et al., 1986, BioTechniques 4: 214 and Queen et al. US 5585089, US 5693761 and US 5693762, the contents of which are incorporated herein by reference in their entirety).

Humanized or CDR-grafted antibodies can be obtained by CDR-grafting or CDR substitution, where one, two or all of the CDRs of the immunoglobulin chains can be replaced. See, for example, US Pat. No. 5,225,539; Jones et al. 1986 Nature 321:552-525; Verhoeyan et al. 1988 Science 239: 1534; Beidler et al. 1988 J. Immunol. 141: 4053-4060; Winter US 5225539, the contents of which are incorporated herein by reference in their entirety. Winter describes a CDR transplantation method that can be used to produce humanized antibodies (UK patent application GB 2188638A, filed March 26, 1987, Winter US 5225539), the contents of which are expressly incorporated by reference.

Humanized antibodies are also provided in which certain amino acids have been replaced, removed or added. The criteria for selecting amino acids from a donor are described, for example, in US 5585089, for example, in columns 12-16 of US 5585089, the content of which is incorporated into the present description by reference. Other methods for humanizing antibodies are described in Padlan et al. EP 519596 A1 published December 23, 1992.

In one embodiment, the antibody molecule has a heavy chain constant region selected, for example, from IgG1, IgG2 (eg, IgG2a), IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE heavy chain constant regions; in particular selected from, for example, heavy chain constant regions of IgG1, IgG2, IgG3 and IgG4 (eg human). In another embodiment, the antibody molecule has a light chain constant region selected, for example, from kappa or lambda (eg, human) light chain constant regions. The constant region can be altered, such as mutated, to modify properties of the antibody molecule (eg, to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, cysteine residue count, effector cell function, and/or complement function). In one embodiment, the antibody molecule has an effector function and can fix complement. In another embodiment, the antibody molecule does not recruit effector cells or fix complement. In some embodiments, the antibody molecule has reduced or no ability to bind to the Fc receptor. For example, it may be an isotype or subtype, fragment or other mutant that does not support binding to the Fc receptor, eg it has a mutagenic or deleted Fc receptor binding region.

In one embodiment, the constant region of the antibody molecule is changed. Methods for changing the constant region of an antibody are known in the art. Antibody molecules with altered function, such as altered affinity for an effector ligand, such as an FcR on a cell, or for the C1 component of complement, can be generated by substituting at least one amino acid residue in the constant portion of an antibody for another residue (see, e.g., , EP 388151 A1, US Patent No. 5624821 and US Patent 5648260, the contents of each of which are incorporated herein by reference). human IgG4. Changes of a similar type can be described which, when applied to a murine or other type of immunoglobulin, would reduce or eliminate these functions.

In one embodiment, the only amino acids in the antibody molecule are the canonical amino acids. In one embodiment, the antibody molecule contains naturally occurring amino acids; analogues, derivatives and their congeners; amino acid analogs with variant side chains; and/or all stereoisomers of any of the above. An antibody molecule may include D- or L-optical isomers of amino acids and peptidomimetics.

The polypeptide of the antibody molecule described herein may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acid components. The antibody molecule can also be modified; for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation such as conjugation with a labeled moiety. The polypeptide may be isolated from natural sources, may be obtained by recombinant methods from a eukaryotic or prokaryotic host, or may be the product of synthetic procedures.

The antibody molecule described herein may be used alone in unconjugated form, or may be associated with a substance, such as a toxoid or fragment (e.g., a therapeutic drug; a radiation-emitting compound; molecules of plant, fungal, or bacterial origin; or a biological protein ( e.g. protein toxoid) or with a particle (e.g. a recombinant viral particle, e.g. via viral envelope protein). - and γ-emitting compound.

An antibody molecule may be modified or linked to another functional molecule (eg, another peptide or protein). As used herein, the term "modified" antibody molecule is modified. Methods of modification include, but are not limited to, the addition of a fluorescent moiety, a radiolabeled nucleotide, a toxin, an enzyme, or an affinity ligand such as biotin. Accordingly, antibody molecules are intended to include modified and other modified forms of the antibodies described herein, including immunoadhesion molecules. For example, an antibody molecule may be operably linked (by chemical bonding, genetic fusion, non-covalent association, or otherwise) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or diabody), a detectable agent, a toxin, a pharmaceutical agent, and /or a protein or peptide that can mediate the association of an antibody or antibody portion with another molecule (such as a streptavidin core or polyhistidine tag).

Some types of modified antibody molecule are obtained by cross-linking two or more antibodies (of the same type or different types, for example, to create bispecific antibodies). Suitable crosslinkers include those that are heterobifunctional, with two separate reactive groups separated by a suitable spacer (eg, m-maleimidobenzoyl-N-hydroxysuccinimide ester), or that are homobifunctional (eg, disuccinimidyl suberate). Such linkers are available from Pierce Chemical Company, Rockford, Ill.

Useful detectable agents by which an anti-dengue antibody molecule can be modified (or labeled) to include fluorescent compounds, various enzymes, prosthetic groups, luminescent substances, bioluminescent substances that fluorescently emit metal atoms, such as europium (Eu) and other antanides , and radioactive substances (described below). Examples of fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-naphthalenesulfonyl chloride, phycoerythrin and the like. The antibody can also be modified with detectable enzymes such as alkaline phosphatase, horseradish peroxidase, β-galactosidase, acetylcholinesterase, glucose oxidase, and the like. When an antibody is modified with a detectable enzyme, it is detected by adding additional reagents that the enzyme uses to produce a detectable reaction product. For example, when the detectable agent horseradish peroxidase is present, the addition of hydrogen peroxide and diaminobenzidine results in a colored reaction product that can be detected. The antibody molecule can also be modified with a prosthetic group (eg streptavidin/biotin and avidin/biotin). For example, an antibody can be modified with biotin and detected by indirect measurement of avidin or streptavidin binding. Examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; and examples of bioluminescent materials include luciferase, luciferin, and aecorin.

Labeled antibody molecules can be used, for example, for diagnostic and/or experimental purposes in a number of contexts, including (i) isolation of a predetermined antigen by standard techniques such as affinity chromatography or immunoprecipitation; (ii) detecting a predetermined antigen (eg, in a cell lysate or cell supernatant) to assess protein abundance and expression profile; (iii) monitoring tissue protein levels as part of a clinical trial procedure, for example, to determine the efficacy of a given treatment regimen.

An antibody molecule may be conjugated to another molecular entity, typically a label or therapeutic (eg, antimicrobial (eg, antibacterial or bactericidal), immunomodulatory, immunostimulatory, cytotoxic, or cytostatic) agent or component. Radioactive isotopes can be used in diagnostic or therapeutic applications. Radioactive isotopes that can be associated with antibody molecules include, but are not limited to, α-, β-, or γ-emitting compounds, or β- and γ-emitting compounds. Such radioactive isotopes include, but are not limited to, iodine ( ¹³¹ I or ¹²⁵ I), yttrium ( ⁹⁰ Y), lutetium ( ¹⁷⁷ Lu), actinium ( ²²⁵ Ac), praseodymium, astatine ( ²¹¹ At), rhenium ( ¹⁸⁶ Re) , bismuth ( ²¹² Bi or ²¹³ Bi), indium ( ¹¹¹ In), technetium ( ⁹⁹ mTc), phosphorus ( ³² P), rhodium ( ¹⁸⁸ Rh), sulfur ( ³⁵ S), carbon ( ¹⁴ C), tritium ( ³ H ), chromium ( ⁵¹ Cr), chlorine ( ³⁶ Cl), cobalt ( ⁵⁷ Co or ⁵⁸ Co), iron ( ⁵⁹ Fe), selenium ( ⁷⁵ Se) or gallium ( ⁶⁷ Ga). Radioisotopes used as therapeutic agents include yttrium ( ⁹⁰ Y), lutetium ( ¹⁷⁷ Lu), actinium ( ²²⁵ Ac), praseodymium, astatine ( ²¹¹ At), rhenium ( ¹⁸⁶ Re), bismuth ( ²¹² Bi or ²¹³ Bi), and rhodium ( ¹⁸⁸ Rh). Radioisotopes used as labels, for example for use in diagnostics, include iodine ( ¹³¹ I or ¹²⁵ I), indium ( ¹¹¹ In), technetium ( ⁹⁹ mTc), phosphorus ( ³² P), carbon ( ¹⁴ C) and tritium ( ³ H) or one or more of the therapeutic isotopes listed above.

The present disclosure provides radioactively labeled antibody molecules and methods for labeling them. In one embodiment, a method for labeling an antibody molecule is disclosed. The method includes contacting an antibody molecule with a chelating agent, thereby obtaining a conjugated antibody. The conjugated antibody is radiolabeled with a radioisotope such as ¹¹¹ indium, ⁹⁰ yttrium, and ¹⁷⁷ lutetium, thereby producing a labeled antibody molecule.

In some aspects, the present disclosure provides a method for producing the antibody molecule disclosed in the present description. The method includes: providing an antigen, such as APRIL or a fragment thereof; obtaining an antibody molecule that specifically binds to the antigen; evaluating the effectiveness of the antibody molecule in modulating the activity of the antigen and/or the organism expressing the antigen, such as APRIL. The method may further include administering an antibody molecule, including a derivative thereof (eg, a humanized antibody molecule) to a patient, eg a human.

The present disclosure provides an isolated nucleic acid molecule encoding the above antibody molecule, vectors and their host cells. A nucleic acid molecule includes, but is not limited to, RNA, genomic DNA, and cDNA.

The amino acid and nucleotide sequences of exemplary antibody molecules are described in Tables 1 and 2, respectively. The amino acid sequences of additional exemplary humanized antibody molecules are described in Table 5.

Table 1. The amino acid sequences of the heavy chain variable region (VH) and the light chain variable region (VL) of exemplary anti-APRIL antibodies are shown below. CDRs defined according to the Kabat system are underlined and in bold, and CDRs defined according to the Chothia system are in italics.

Table 2 Nucleotide sequences of heavy chain variable regions (VH) and light chain variable regions (VL) of exemplary antibody molecules

Antibody Chain Nucleotide sequence SEQID NO 2218 vh GATGTACAGCTTCAGGAGTCAGGACCTGGCCTCGTGAAACCTTCTCAGTCTCTGTCTCTCACCTGCTCTGTCACTGGCTACTCCATCACCAGTGGTTATTACTGGAACTGGATCCGGCAGTTTCCAGGAAACAAACTGGAATGGATGGGCTACATAAGCTACGATGGTTACAATAACTACAACCCATCTCTCAAAAATCGAATCTCCATCACTCGTGACACATCTAAGAACCAGTTTTTCCTGAAGTTGAATTCTGTGACTACTGAGGACACAGCCACATATTACTGTGCAAACTACTATGATTACGAAGACTGGTACTTCGGTGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA 71 VL GACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTATGTCTCTAGGGAAGAGGGCCACCATCTCCTGCAGAGCCAGCGAAAGTGTCAGTATTATTGGTACTAATTCAATACACTGGTACCAACAGAAACCAGGACAGCCACCCAAACTCCTCATCTATCATGCATCCAACCTAGAAACTGGAGTCCCTGCCAGGTTCAGTGGCAGTGGGTCTAGAACAGACTTCACCCTCACCATTGATCCTGTGGAGGAAGATGATGTTGCAATCTATTACTGTCTGCAAAGTAGGAAGATTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA 72 2419 vh CAGGTCCAGCTGCAGCAGTCTGGAGCTGAGCTGGTGAAACCCGGGGCATCAGTGAGGCTGTCCTGCGAGGCTTCTGGCTACACCTTCACGGACTATACTATACACTGGGTAAAGCAGAGGTCTGGACAGGGTCTTGAGTGGATTGGATGGATTTACCCTCTAAGAGGTAGTATAAACTACAATGAGAAATTCAAGGACAAGGCCACATTGACTGCGGACAAATCCTCCAGCACAGTCTATTTGGAGCTTGGTAGATTGACATCTAAGGACTCTGCGGTCTATTTCTGTGCAAGACACGGAGCCTACTATAGTAACGCCTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA 73 VL AACATTGTAATGACCCAATCTCCAGCTTCATTGGCTGTGTCTCTAGGTCAGAGGGCCACCATCTCCTGCAGAGCCAGCGAGAGTGTTGATAATGATGGCATTAGATTTATGCACTGGTACCAGCAGAAACCAGGACAGCCACCCAAACTCCTCATCTATCGTGCATCCAACCTAGAATCTGGGATCCCTGCCAGGTTCAGTGGCAGTGGGTCTAGGACAGACTTCACCCTCACTATTAATCCTGTGGAGACTGATGATGTTGCAACCTATTACTGTCAGCAAAGTAATAAGGATCCGTACACGTTCGGAGGGGGGACCAAGCTGGAGCTGAAA 74 2419-1305 vh CAAGTTCAGTTGGTGCAAAGCGGGGCAGAAGTGAAGAAACCTGGTGCTTCTGTGAAAGTTTCCTGCAAGGCCAGCGGCTACACCTTTACTGATTACACAATACACTGGGTACGGCAGGCAACTGGGCAAGGATTGGAATGGATGGGGTGGATATACCCATTGCGAGGGTCTATAAACTACGCACAGAAATTTCAAGGTCGAGTAACAATGACAGCCAACAAATCAATAAGCACCGTTTATATGGAACTCTCATCTCTCAGGAGTGAGGATACCGCCGTGTATTTCTGCGCACGACACGGTGCATATTACTCAAACGCTTTCGACTATTGGGGCCAGGGCACCCTTGTGACTGTTAGTAGC 304 VL GAGATAGTAATGACTCAGTCTCCCGCTACACTTAGTGTAAGCCCAGGGGAGCGAGCAACCCTCAGTTGCAGAGCATCTGAGAGTGTTGATAATGATGGAATACGTTTTCTCCATTGGTATCAACAAAAACCAGGGCAGGCCCCCAGATTGCTGATCTACCGTGCTTCCAATCGCGAGACTGGCATTCCTGCACGTTTCAGCGGCAGCGGCTCCGGAACCGAGTTTACACTTACTATTAGCTCACTCCAGTCTGAAGACTTCGCTGTGTATTACTGTCAGCAATCCAACAAGGACCCATACACTTTCGGAGGCGGCACTAAGGTTGAGATCAAA 305 2419-1306 vh CAAGTTCAGTTGGTGCAAAGCGGGGCAGAAGTGAAGAAACCTGGTGCTTCTGTGAAAGTTTCCTGCAAGGCCAGCGGCTACACCTTTACTGATTACACAATACACTGGGTACGGCAGGCAACTGGGCAAGGATTGGAATGGATGGGGTGGATATACCCATTGCGAGGGTCTATAAACTACGCACAGAAATTTCAAGGTCGAGTAACAATGACAGCCAACAAATCAATAAGCACCGTTTATATGGAACTCTCATCTCTCAGGAGTGAGGATACCGCCGTGTATTTCTGCGCACGACACGGTGCATATTACTCAAACGCTTTCGACTATTGGGGCCAGGGCACCCTTGTGACTGTTAGTAGC 304 VL GAGATAGTTATGACTCAGTCTCCCGCCACACTTTCAGTAAGTCCCGGTGAACGCGCCACCCTGTCCTGCCGTGCTTCCGAATCAGTGGATAATGACGGCATTAGGTTTTTGCACTGGTACCAACAAAAGCCCGGACAGGCCCCCCGCCTGCTGATATATCGTGCATCAACACGAGCAACAGGGATCCCCGCTCGATTTAGTGGATCCGGAAGCAGGACCGAATTTACACTTACCATTTCCTCACTTCAGTCAGAAGATTTCGCCGTTTACTACTGTCAGCAGTCAAATAAGGATCCTTACACATTTGGGGGCGGTACAAAAGTCGAGATCAAA 306 2419-1310 vh CAAGTTCAGTTGGTGCAAAGCGGGGCAGAAGTGAAGAAACCTGGTGCTTCTGTGAAAGTTTCCTGCAAGGCCAGCGGCTACACCTTTACTGATTACACAATACACTGGGTACGGCAGGCAACTGGGCAAGGATTGGAATGGATGGGGTGGATATACCCATTGCGAGGGTCTATAAACTACGCACAGAAATTTCAAGGTCGAGTAACAATGACAGCCAACAAATCAATAAGCACCGTTTATATGGAACTCTCATCTCTCAGGAGTGAGGATACCGCCGTGTATTTCTGCGCACGACACGGTGCATATTACTCAAACGCTTTCGACTATTGGGGCCAGGGCACCCTTGTGACTGTTAGTAGC 304 VL GACATTGTAATGACCCAGTCTCCCGATAGCCTCGCTGTCTCACTCGGAGAACGCGCAACCATCAACTGCAAGTCCTCCCAAAGCGTTGACAATGACGGCATTAGGTTTTTGCACTGGTACCAGCAGAAACCCGGTCAACCTCCTAAGTTGCTCATTTACCGAGCATCTACCCGCGAGTCAGGAGTACCTGATCGCTTTTCCGGTAGCGGTAGTGGAACAGATTTTACTCTGACCATTAGTTCACTCCAGGCAGAAGATGTGGCTGTCTACTACTGCCAACAGTCAAATAAAGACCCTTATACCTTCGGTGGGGGTACCAAAGTAGAGATCAAA 318 2419-0806 vh GAGGTCCAGTTGGTCCAGTCAGGAGCCGAAGTCAAGAAGCCTGGGGAAAGCCTGAAAATAAGTTGCAAAGCTAGTGGATATACATTTACAGATTATACCATTCATTGGGTCCGGCAAATGCCAGGAAAAGGCTTGGAGTGGATGGGGTGGATTTATCCCCTCCGAGGCTCAATAAATTATAGTCCTAGTTTTCAGGGGCAGGTAACTATTAGCGCTGATAAAAGTATTTCTACAGTTTATTTGCAGTGGAGTTCATTGAAGGCTAGTGACACCGCTATGTATTTCTGCGCTAGACATGGTGCATATTATTCAAATGCCTTCGACTATTGGGGCCAGGGCACCCTCGTCACTGTGAGTTCC 307 VL GAGATAGTTATGACTCAGTCTCCCGCCACACTTTCAGTAAGTCCCGGTGAACGCGCCACCCTGTCCTGCCGTGCTTCCGAATCAGTGGATAATGACGGCATTAGGTTTTTGCACTGGTACCAACAAAAGCCCGGACAGGCCCCCCGCCTGCTGATATATCGTGCATCAACACGAGCAACAGGGATCCCCGCTCGATTTAGTGGATCCGGAAGCAGGACCGAATTTACACTTACCATTTCCTCACTTCAGTCAGAAGATTTCGCCGTTTACTACTGTCAGCAGTCAAATAAGGATCCTTACACATTTGGGGGCGGTACAAAAGTCGAGATCAAA 306 2419-0205 vh CAGGTGCAACTTGTTCAGTCAGGGGCTGAAGTAAAGAAGCCAGGCTCATCAGTCAAGGTATCATGCAAAGCATCTGGCTATACATTTACAGATTACACCATTCACTGGGTGAGGCAAGCTCCCGGTCAAGGTCTCGAGTGGATGGGGTGGATATACCCTCTCAGAGGCTCTATAAATTACGCTCAGAAATTTCAAGGGAGAGTTACAATTACTGCTGATAAAAGTACCAGCACTGCTTATATGGAGCTTTCCTCACTTCGTTCAGAGGACACCGCCGTTTACTTTTGTGCCCGGCATGGTGCCTATTATTCAAATGCCTTCGATTATTGGGGGCAGGGAACTTTGGTCACAGTTTCATCT 308 VL GAGATAGTAATGACTCAGTCTCCCGCTACACTTAGTGTAAGCCCAGGGGAGCGAGCAACCCTCAGTTGCAGAGCATCTGAGAGTGTTGATAATGATGGAATACGTTTTCTCCATTGGTATCAACAAAAACCAGGGCAGGCCCCCAGATTGCTGATCTACCGTGCTTCCAATCGCGAGACTGGCATTCCTGCACGTTTCAGCGGCAGCGGCTCCGGAACCGAGTTTACACTTACTATTAGCTCACTCCAGTCTGAAGACTTCGCTGTGTATTACTGTCAGCAATCCAACAAGGACCCATACACTTTCGGAGGCGGCACTAAGGTTGAGATCAAA 305 2419-0406 vh CAAGTTCAACTTGTCCAAAGTGGGGCTGAAGTTAAAAAACCTGGATCATCAGTCAAGGTTTCATGCAAAGCCAGCGGTTACACATTTACAGACTATACAATACATTGGGTTCGACAGGCTCCCGGGCAAGGGCTCGAATGGATGGGATGGATTTATCCCCTCAGGGGCTCAATTAACTATGCTGAGAAATTTAAGGGTCGTGTAACACTCACCGCCGATAAATCCACCTCAACCGTATATATGGAGCTTTCTTCTCTTCGCTCTGAAGATACCGCCGTCTATTTCTGCGCACGACACGGGGCATACTATTCTAATGCTTTTGACTACTGGGGACAAGGGACACTTGTGACCGTTAGTAGC 309 VL GAGATAGTTATGACTCAGTCTCCCGCCACACTTTCAGTAAGTCCCGGTGAACGCGCCACCCTGTCCTGCCGTGCTTCCGAATCAGTGGATAATGACGGCATTAGGTTTTTGCACTGGTACCAACAAAAGCCCGGACAGGCCCCCCGCCTGCTGATATATCGTGCATCAACACGAGCAACAGGGATCCCCGCTCGATTTAGTGGATCCGGAAGCAGGACCGAATTTACACTTACCATTTCCTCACTTCAGTCAGAAGATTTCGCCGTTTACTACTGTCAGCAGTCAAATAAGGATCCTTACACATTTGGGGGCGGTACAAAAGTCGAGATCAAA 306 2419-0605 vh CAGGTGCAGTTGGTCCAGAGCGGGGCAGAGGTTAAGAAGCCTGGGGCCTCAGTAAAGGTATCCTGCAAGGCTTCTGGGTACACCTTCACAGATTACACTATTCATTGGGTGCGCCAAGCACCTGGTCAAGGCCTTGAATGGATGGGATGGATTTACCCCTTGCGAGGGAGTATTAATTATGCACAGAAGTTCCAGGGAAGGGTTACTCTTACCGCCGACAAGTCCACATCAACCGTTTACATGGAGCTTTCCTCTCTCAGGTCCGAAGACACTGCTGTATATTTCTGCGCTCGGCATGGGGCTTATTACAGCAACGCCTTCGATTACTGGGGTCAGGGTACATTGGTCACAGTGTCCAGT 319 VL GAGATAGTAATGACTCAGTCTCCCGCTACACTTAGTGTAAGCCCAGGGGAGCGAGCAACCCTCAGTTGCAGAGCATCTGAGAGTGTTGATAATGATGGAATACGTTTTCTCCATTGGTATCAACAAAAACCAGGGCAGGCCCCCAGATTGCTGATCTACCGTGCTTCCAATCGCGAGACTGGCATTCCTGCACGTTTCAGCGGCAGCGGCTCCGGAACCGAGTTTACACTTACTATTAGCTCACTCCAGTCTGAAGACTTCGCTGTGTATTACTGTCAGCAATCCAACAAGGACCCATACACTTTCGGAGGCGGCACTAAGGTTGAGATCAAA 305 2419-0805 vh GAGGTCCAGTTGGTCCAGTCAGGAGCCGAAGTCAAGAAGCCTGGGGAAAGCCTGAAAATAAGTTGCAAAGCTAGTGGATATACATTTACAGATTATACCATTCATTGGGTCCGGCAAATGCCAGGAAAAGGCTTGGAGTGGATGGGGTGGATTTATCCCCTCCGAGGCTCAATAAATTATAGTCCTAGTTTTCAGGGGCAGGTAACTATTAGCGCTGATAAAAGTATTTCTACAGTTTATTTGCAGTGGAGTTCATTGAAGGCTAGTGACACCGCTATGTATTTCTGCGCTAGACATGGTGCATATTATTCAAATGCCTTCGACTATTGGGGCCAGGGCACCCTCGTCACTGTGAGTTCC 307 VL GAGATAGTAATGACTCAGTCTCCCGCTACACTTAGTGTAAGCCCAGGGGAGCGAGCAACCCTCAGTTGCAGAGCATCTGAGAGTGTTGATAATGATGGAATACGTTTTCTCCATTGGTATCAACAAAAACCAGGGCAGGCCCCCAGATTGCTGATCTACCGTGCTTCCAATCGCGAGACTGGCATTCCTGCACGTTTCAGCGGCAGCGGCTCCGGAACCGAGTTTACACTTACTATTAGCTCACTCCAGTCTGAAGACTTCGCTGTGTATTACTGTCAGCAATCCAACAAGGACCCATACACTTTCGGAGGCGGCACTAAGGTTGAGATCAAA 305 2419-0105 vh CAAGTGCAGTTGGTCCAGAGTGGAGCAGAGGTGAAGAAGCCTGGTGCTTCCGTCAAGGTGAGTTGCAAGGCATCTGGTTATACTTTCACTGACTACACAATTCATTGGGTCAGGCAGGCCCCTGGACAGGGACTGGAATGGATGGGATGGATCTATCCACTTAGAGGATCAATCAACTATGCTCAAAAGTTCCAGGGTCGTGTAACAATGACCGCAGACAAAAGTATCTCAACTGTATACATGGAATTGTCCCGATTGAGGAGCGACGACACAGCCGTATATTATTGTGCCAGGCACGGAGCCTACTACAGTAATGCCTTCGACTACTGGGGGCAGGGCACCCTTGTTACCGTGTCCAGC 310 VL GAGATAGTAATGACTCAGTCTCCCGCTACACTTAGTGTAAGCCCAGGGGAGCGAGCAACCCTCAGTTGCAGAGCATCTGAGAGTGTTGATAATGATGGAATACGTTTTCTCCATTGGTATCAACAAAAACCAGGGCAGGCCCCCAGATTGCTGATCTACCGTGCTTCCAATCGCGAGACTGGCATTCCTGCACGTTTCAGCGGCAGCGGCTCCGGAACCGAGTTTACACTTACTATTAGCTCACTCCAGTCTGAAGACTTCGCTGTGTATTACTGTCAGCAATCCAACAAGGACCCATACACTTTCGGAGGCGGCACTAAGGTTGAGATCAAA 305 2419-1204 vh CAAGTGCAGCTCGTTCAGTCTGGCGCAGAAGTGAAGAAGCCAGGAGCTTCCGTTAAAGTGTCCTGTAAAGCCTCTGGATATACATTCACAGATTATACAATTCACTGGGTGAGACAAGCAACCGGTCAAGGTCTCGAATGGATGGGCTGGATATACCCCCTCCGAGGTTCCATCAACTACGCTCAAAAATTCCAAGGACGAGTCACTATGACAGCAAACAAGAGTTCCTCCACTGTATATATGGAACTCTCTAGTTTGCGCTCTGAAGACACCGCCGTGTACTTCTGTGCCAGGCACGGCGCATACTATTCTAATGCATTTGACTATTGGGGGCAGGGCACATTGGTAACAGTTAGTTCC 311 VL GAAATTGTAATGACCCAGAGCCCCGCCACCCTTAGTGTGTCCCCAGGCGAGAGGGCCACTCTTTCTTGCCGCGCAAGCGAATCCGTAGACAACGATGGTATAAGATTTTTGCATTGGTATCAGCAAAAGCCAGGCCAGGCACCCCGGCTTCTCATCTACAGAGCTAGCACCCTCGAAACTGGAATCCCCGCTCGTTTTTCAGGATCTGGTAGCGGAACAGAATTTACTTTGACAATTAGTAGTTTGCAGTCAGAGGACTTTGCTGTCTATTATTGCCAGCAGTCTAATAAAGATCCATACACCTTCGGCGGAGGGACCAAAGTAGAGATTAAA 312 2419-1210 vh CAAGTGCAGCTCGTTCAGTCTGGCGCAGAAGTGAAGAAGCCAGGAGCTTCCGTTAAAGTGTCCTGTAAAGCCTCTGGATATACATTCACAGATTATACAATTCACTGGGTGAGACAAGCAACCGGTCAAGGTCTCGAATGGATGGGCTGGATATACCCCCTCCGAGGTTCCATCAACTACGCTCAAAAATTCCAAGGACGAGTCACTATGACAGCAAACAAGAGTTCCTCCACTGTATATATGGAACTCTCTAGTTTGCGCTCTGAAGACACCGCCGTGTACTTCTGTGCCAGGCACGGCGCATACTATTCTAATGCATTTGACTATTGGGGGCAGGGCACATTGGTAACAGTTAGTTCC 311 VL GACATTGTAATGACCCAGTCTCCCGATAGCCTCGCTGTCTCACTCGGAGAACGCGCAACCATCAACTGCAAGTCCTCCCAAAGCGTTGACAATGACGGCATTAGGTTTTTGCACTGGTACCAGCAGAAACCCGGTCAACCTCCTAAGTTGCTCATTTACCGAGCATCTACCCGCGAGTCAGGAGTACCTGATCGCTTTTCCGGTAGCGGTAGTGGAACAGATTTTACTCTGACCATTAGTTCACTCCAGGCAGAAGATGTGGCTGTCTACTACTGCCAACAGTCAAATAAAGACCCTTATACCTTCGGTGGGGGTACCAAAGTAGAGATCAAA 318 2419-1406 vh CAAGTTCAGTTGGTGCAAAGCGGGGCAGAAGTGAAGAAACCTGGTGCTTCTGTGAAAGTTTCCTGCAAGGCCAGCGGCTACACCTTTACTGATTACACAATACACTGGGTACGGCAGGCAACTGGGCAAGGATTGGAATGGATGGGGTGGATATACCCATTGCGAGGGTCTATAAACTACGCACAGAAATTTCAAGGTCGAGTAACAATGACAGCCGACAAATCAATAAGCACCGTTTATATGGAACTCTCATCTCTCAGGAGTGAGGATACCGCCGTGTATTTCTGCGCACGACACGGTGCATATTACTCAAACGCTTTCGACTATTGGGGCCAGGGCACCCTTGTGACTGTTAGTAGC 313 VL GAGATAGTTATGACTCAGTCTCCCGCCACACTTTCAGTAAGTCCCGGTGAACGCGCCACCCTGTCCTGCCGTGCTTCCGAATCAGTGGATAATGACGGCATTAGGTTTTTGCACTGGTACCAACAAAAGCCCGGACAGGCCCCCCGCCTGCTGATATATCGTGCATCAACACGAGCAACAGGGATCCCCGCTCGATTTAGTGGATCCGGAAGCAGGACCGAATTTACACTTACCATTTCCTCACTTCAGTCAGAAGATTTCGCCGTTTACTACTGTCAGCAGTCAAATAAGGATCCTTACACATTTGGGGGCGGTACAAAAGTCGAGATCAAA 306 2419-1205 vh CAAGTGCAGCTCGTTCAGTCTGGCGCAGAAGTGAAGAAGCCAGGAGCTTCCGTTAAAGTGTCCTGTAAAGCCTCTGGATATACATTCACAGATTATACAATTCACTGGGTGAGACAAGCAACCGGTCAAGGTCTCGAATGGATGGGCTGGATATACCCCCTCCGAGGTTCCATCAACTACGCTCAAAAATTCCAAGGACGAGTCACTATGACAGCAAACAAGAGTTCCTCCACTGTATATATGGAACTCTCTAGTTTGCGCTCTGAAGACACCGCCGTGTACTTCTGTGCCAGGCACGGCGCATACTATTCTAATGCATTTGACTATTGGGGGCAGGGCACATTGGTAACAGTTAGTTCC 311 VL GAGATAGTAATGACTCAGTCTCCCGCTACACTTAGTGTAAGCCCAGGGGAGCGAGCAACCCTCAGTTGCAGAGCATCTGAGAGTGTTGATAATGATGGAATACGTTTTCTCCATTGGTATCAACAAAAACCAGGGCAGGCCCCCAGATTGCTGATCTACCGTGCTTCCAATCGCGAGACTGGCATTCCTGCACGTTTCAGCGGCAGCGGCTCCGGAACCGAGTTTACACTTACTATTAGCTCACTCCAGTCTGAAGACTTCGCTGTGTATTACTGTCAGCAATCCAACAAGGACCCATACACTTTCGGAGGCGGCACTAAGGTTGAGATCAAA 305 2419-0206 vh CAGGTGCAACTTGTTCAGTCAGGGGCTGAAGTAAAGAAGCCAGGCTCATCAGTCAAGGTATCATGCAAAGCATCTGGCTATACATTTACAGATTACACCATTCACTGGGTGAGGCAAGCTCCCGGTCAAGGTCTCGAGTGGATGGGGTGGATATACCCTCTCAGAGGCTCTATAAATTACGCTCAGAAATTTCAAGGGAGAGTTACAATTACTGCTGATAAAAGTACCAGCACTGCTTATATGGAGCTTTCCTCACTTCGTTCAGAGGACACCGCCGTTTACTTTTGTGCCCGGCATGGTGCCTATTATTCAAATGCCTTCGATTATTGGGGGCAGGGAACTTTGGTCACAGTTTCATCT 308 VL GAGATAGTTATGACTCAGTCTCCCGCCACACTTTCAGTAAGTCCCGGTGAACGCGCCACCCTGTCCTGCCGTGCTTCCGAATCAGTGGATAATGACGGCATTAGGTTTTTGCACTGGTACCAACAAAAGCCCGGACAGGCCCCCCGCCTGCTGATATATCGTGCATCAACACGAGCAACAGGGATCCCCGCTCGATTTAGTGGATCCGGAAGCAGGACCGAATTTACACTTACCATTTCCTCACTTCAGTCAGAAGATTTCGCCGTTTACTACTGTCAGCAGTCAAATAAGGATCCTTACACATTTGGGGGCGGTACAAAAGTCGAGATCAAA 306 2621 vh GAGGTCCAGCTTCAGCAGTCTGGAGCTGAGCTGGTGAGGCCTGGGTCCTCAGTGAAGATGTCCTGCAAGACTTCTGGATATACTTTCACAAGCTACGGTATAAACTGGGTGAAGCAGAGGCCTGGACAGGGCCTGGAATGGATTGGATATATTTATATTGGAAATGGTTATGCTGAGTACAATGAGAGGTTCAAGGGCAAGGCCACACTGACTTCAGACACATCCTCCAGCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCAATCTATTTCTGTGCACTATACTATCCCTGGTTTACTTACTGGGGCCAGGGGACTCTGGTCACTGTCTCTGCA 75 VL GACATCCAGATGACTCAGTCTCCAGCCTCCCTTTCTGCATCTGTGGGAGATTCTGTCACCATCACATGTCGAGCAAGTGAGAATATTTACAGTTATTTAGCATGGTATCAGCAGAAACAGGGAAAATCTCCTCAGCTCCTGGTCTATAATGCAAAAACCTTAGCTGAAGGTGTGCCATCAAGGTTCAGTGGCAGTGGATCAGGCACACAGTTTTCTCTGAAGATCAACAGCCTGCAGCCTGAAGATTTTGGGAATTATTACTGTCAACATCATTATGATACTCCGTTCACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA 76 2922 vh CAGGTTCAGCTGCACCAGTCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGTTGTCCTGCAAGACTTCTGGCTACACCTTCACAAGCTACGATGTCTTCTGGGTGAAGCAGAGGCCTGGACAGGGACTTGAGTGGATTGGATGGATTTATCCTAGAGATAGTAGTACTAAATACAATGAGAAGTTCAAGGGCAAGGCCACATTGACTGTAGACACATCCTCCAGCACAGCATACATGGAGCTCCACAGCCTGACATCTGAGGACTCTGCGGTCTATTTCTGTGCAAAAGAGGGGTATGATTATGACAAGAGGGGCTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA 77 VL GACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTGTGTCTCTAGGGCAGAGGGCCATCATCTCCTGCAAGGCCAGCCAAAGTGTCAGTTTTGCTGGTACTAATTTAATGCACTGGTACCAACAGAGACCAGGGCAGCAACCCAAACTCCTCATCTATCGTGCATCCAACCTAGAACCTGGGGTTCCTACCAGGTTTAGTGGCAGTGGGTCTAGGACAGACTTCACCCTCAATATCCATCCTGTGGAGGAAGATGATGCTGCAACCTATTACTGTCAGCAAAGTAGGGAATATCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA 78 3125 vh CAGGTTCAACTGCAGCAGTCTGGGGCTGAGCTGGTGAGGCCTGGGGCTTCAGTGACGCTGTCCTGCAAGGCTTCGGGCTACACTTTTACTGACTATGAAATGCACTGGGTGAAGCAGACACCTGTGCATGGCCTGGAATGGATTGGAGCTATTGATCCTGAAACTGGTGGTACTGCCTACAATCAGAGGTTCAAGGGCAAGGCCATACTGACTACAGACAAATCCTCCATCACAGCCTACATGGAGCTCCGCAGCCTGACATCTGAGGACTCTGCCGTCTATTACTGTACAAGATGGAATGATGGCGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA 79 VL GATGTTGTGATGACCCAGACTCCACTGTCTTTGTCGGTTACCATTGGACAACCAGCCTCCATTTCTTGCAAGTCAAGTCAGAGCCTCTTATACAGTAATGGAAAGACATATTTGAATTGGTTTCAACAGAGGCCTGGCCAGTCTCCAAAGCGCCTAATGTATCAGGTGTCCAAACTGGACCCTGGCATCCCTGACAGGTTCAGTGGCAGTGGATCAGAAACAGATTTTACACTTAAAATCAGCAGAGTGGAGGCTGAAGATTTGGGACTTTATTACTGCTTGCAAGGTACATATTATCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA 80 3327 vh GAGGTCCAGCTGCAGCAGTCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATGTCCTGCAAGGCTTCTGGTTACTCCTTTACTGGCTACTTTATGAACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGACGTATTAATCCTTACAATGGTGATACTTTCTACAACCAGAAGTTCAAGGGCAAGGCCACATTGACTGTAGACAAATCCTCTAGCACAGCCCACATGGAGCTCCGGAGCCTGACATCTGAGGACTCTGCACTCTATTATTGTGCAAGCGAAGGTGATGGTTACTACTGGTACTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCA 81 VL GACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTGTGTCTCTAGGGCAGAGGGCCACCATCTCCTGCAGAGCCAGCGAAAGTGTTGATAATTATGGCATTAGTTTTATGAACTGGTTCCAACAGAAACCAGGACAGCCACCCAAACTCCTCATCTATGCTGCATCCAACCAAGGATCCGGGGTCCCTGCCAGGTTTAGTGGCAGTGGGTCTGGGACAGACTTCAGCCTCAACATCCATCCTATGGAGGAGGATGATACTGCAATGTATTTCTGTCAGCAAAGTAAGGAGGTTCCTCGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA 82 3525 vh CAGGTTCAACTGCAGCAGTCTGGGGCTGAGCTGGTGAGGCCTGGGGCTTCAGTGAAGCTGTCCTGCAAGGCTTCGGGCTACACATTTACTGACCATGAAATGCACTGGGTGAGACAGACACCTGTGCATGGCCTGGAATGGATTGGAGTTATTGATCCTGACACTGGTGATACTACCTACAATCAGAAATTCAAGGGCAAGGCCACACTGACTGCAGACAAATCCTCCAGCACAGCCTACATGGACCTCCGCAGCCTGACATCTGAGGACTCTGCCGTCTTTTACTGTACACGGTGGACTGGGGGGGACTACTGGGGCCATGGCACCACTCTCACAGTCTCCTCA 83 VL GATGTTGTGATGACCCAGACTCCACTGTCTTTGTCGGTTACCATTGGACAACCAGCCTCCATTTCTTGCAAGTCAAGTCAGAGCCTCTTATACAGTAATGGAAAGACATATTTGAATTGGTTTCAACAGAGGCCTGGCCAGTCTCCAAAGCGCCTAATGTATCAGGTGTCCAAACTGGACCCTGGCATCCCTGACAGGTTCAGTGGCAGTGGATCAGAAACAGATTTTACACTTAAAATCAGCAGAGTGGAGGCTGAAGATTTGGGACTTTATTACTGCTTGCAAGGTACATATTATCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA 80 3530 vh CAGGTTCAACTGCAGCAGTCTGGGGCTGAGCTGGTGAGGCCTGGGGCTTCAGTGAAGCTGTCCTGCAAGGCTTCGGGCTACACATTTACTGACCATGAAATGCACTGGGTGAGACAGACACCTGTGCATGGCCTGGAATGGATTGGAGTTATTGATCCTGACACTGGTGATACTACCTACAATCAGAAATTCAAGGGCAAGGCCACACTGACTGCAGACAAATCCTCCAGCACAGCCTACATGGACCTCCGCAGCCTGACATCTGAGGACTCTGCCGTCTTTTACTGTACACGGTGGACTGGGGGGGACTACTGGGGCCATGGCACCACTCTCACAGTCTCCTCA 83 VL GATGCTGTGATGACCCAGACTCCACTGTCTTTGTCGGTTACCATTGGACAACCAGCCTCTATCTCTTGCAAGTCGAGTCAGAGCCTCTTATATAGTGATGGAAAGACATATTTGAATTGGTTCCAACAGAGGCCAGGCCAGTCTCCAAAGCGCCTAATGTATCAGGTGTCCAAACTGGACCCTGGCATCCCTGACAGGTTCAGTGGCAGTGGATCAGAGACAGATTTTACACTTAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTACTGCTTGCAAGGTACATATTATCCGTATACGTTCGGATCGGGGACCAAGCTGGAAATAAAA 84 4035 vh CAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTGTCCATCACCTGCACAGTCTCTGGTTTCTCATTAACCATCTATGATGTACACTGGGTTCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGATATGGAGTGATGGAAGCACAGACTATAATGCAGCTTTCATATCTAGACTGAGCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTTAAAATGAACAGTCTGCAAGCTGATGACACAGCCATATACTACTGTGCCAGAAATTGGGTCGACCAGGCCTGGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA 173 VL GACATCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGTGGGAGAAACTATCACCATCACATGTCGAGCAAGTAAGAATATTTACAGTTATTTAGCATGGTATCAGCAGAAACAGGGAAAATCTCCTCAGCTCCTGGTCTATAATGCAAAAACCTTACCAGAAGGTGTGCCATCAAGGTTCAGTGGCAGTGGATCAGGCACACAGTTTTCTCTGAAGATCAACAGCCTGCAGCCTGAAGATTTTGGGAGTTATTACTGTCAACATCATTATGGTACTCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA 174 4035-062 vh CAGGTACAACTCCAGGAATCCGGGCCTGGGCTCGTCAAACCAAGCGAAACACTCTCTCTCACCTGCACCGTTTCTGGGTTTTCTCTTACTATCTATGACGTACATTGGGTAAGGCAACCACCCGGGAAGGGGCTGGAGTGGATCGGTGTAATCTGGTCAGATGGATCTACAGACTACAACCCATCCCTTAAAAGCAGGGTGACCATTTCTAAGGACACTTCCAAGAACCAAGTATCCCTTAAATTGTCCTCTGTAACCGCAGCAGACACCGCAGTTTACTACTGCGCACGAAATTGGGTTGACCAAGCATGGTTTGCATATTGGGGACAGGGAACTCTTGTCACTGTGTCTTCA 299 VL GATATTCAAATGACCCAATCCCCCTCATCACTTTCAGCATCTGTCGGTGATCGGGTCACCATTACTTGCAGAGCCAGTAAGAATATCTACAGCTACCTGGCTTGGTATCAGCAAAAACCTGGTAAGGCCCCTAAACTTCTCGTTTACAATGCTAAGACCCTTCCCGAGGGAGTTCCTTCCAGGTTTTCCGGTAGCGGGAGTGGAACAGATTTCACCTTGACTATTTCTAGCTTGCAGCCCGAGGATTTCGCTACATACTACTGCCAGCATCACTATGGAACCCCCCTGACCTTCGGTCAGGGAACCAAGCTCGAGATCAAA 300 3934 vh CAGGTCCAACTGCAGCAGTCTGGACCTGAGCTGGTGAAGCCTGGAGCTTCAGTGAAGCTGTCCTGCAAGGCTGCTGGCTACATCTTCACTGACTATACTATAAACTGGGTGAAGCAGAGTCCTGGACAGGGACTTGAGTGGATTGGATGGATTTATCCTGGAAGTGGTAATCGTAAATACAATGACAAGTTCAAGGGCAAGGCCACAATGACTGCAGACAAATCCTCCAGCACAGCCTACATGCAGCTCAGCAGCCTGACCTCTGAGGATTCTGCGGTCTATTTCTGTGCAAGAGAGAGTAACTACGTGGGGTACTATGCTATGGACTATTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA 175 VL GATGTTTTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCGTTGTAAATAGTAATGGAAACACCTATTTAGAATGGTACCTGCAGAAACCAGGCCAGTCTCCAAATCTCCTGATCTACAAAGTTTCCAATCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCGGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTACTGTTTTCAAGGTTCACATGTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA 176 3833 vh CAGGTCCAGCTGCAGCAGTCTGGAGCTGAGCTGGTAAGGCCTGGGACTTCAGTGAAGATGTCCTGCAAGGCTGCTGGATACACCTTCACAAACTACTGGATAGGTTGGGTAAAGCAGAGGCCTGGACATGGCCTTGAGTGGATTGGAGATATTTACCCTGGAGGTATAGGAGGTGGTTATACTAAGTACAATGAGAAGTTCAAGGGCAAGGCCACACTGACTGCAGACACATCCTCCAGCACAGCCTACATGCAGCTCGGCAGCCTGACATCTGAGGACTCTGCCATCTATTTCTGTTCAAGATCGGAAACTGGACGGGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA 177 VL GACATCCAGATGACACAGTCTCCATCCTCACTGTCTGCATCTCTGGGAGGCAAAGTCACCATCACTTGCAAGGCAAGCCAAGACATTAATAAGTATATAGCTTGGTACCAACACAAGCCTGGAAAAGGTCCTAGGCTGCTCATACATTACACATCTACATTAAAGCCAGGCATCCCATCAAGGTTCAGTGGAAGTGGGTCTGGGAGAGATTATTCCTTCAGCATCAGTGACCTGGAGCCTGAAGATATTGCAACTTATTATTGTCTACAGTATGATAATCTGAACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA 178 3631 vh GAGATCCAGCTGCAGCAGTCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGGTGTCCTGCAAGGCTTCTGGTTATTCATTCACTGACTACAACATCTACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGATATATTGATCCTTCCAATGGTGGTCCTGGCTACAACCAGAAGTTCAGGGGCAAGGCCACATTGACTGTTGACAAGTCCTCCAGCACAGCCTTCCTGCATCTCAACAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGCAAGAAGGGACAACTACGGCTCGGGGACTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA 179 VL GACATTGTGATGACCCAGTCTCAAAAATTCATGTCCACATCAGTAGGAGACAGGGTCAGCATCACCTGTAAGGCCAGTCAGAATGTGGGTACTGATGTATCCTGGTATCAACAGAAACCAGGGAAATCTCCTAAACCACTGATTTACTGGGCATCAAACCGGTTCACTGGAGTCCCTGATCGCTTCATAGGTAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAATGTGCAGTCTGAAGACTTGGCAGATTATTTCTGTGAGCAATATAGCATCTATCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA 180 3732 vh GAGATCCAGCTGCAGCAGTCTGGACCTGAGCTGGTGAAGCCTGGGGCGTCAGTGAAGGTATCCTGCAAGGCTTCTGGTTACTCATTCACTGACGACAACATGTACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGATATATTGATCCTCTCAATGGTGGTACTGGCTACAACCAGAAATTCAAGGGCAAGGCCACACTGACTGTTGACAAGTCCTCCAGCACAGCCTTCCTGCATCTCAACAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGCAAGAAGGGACAACTACGCCACGGGGACTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA 181 VL GACATTGTGATGACCCAGTCTCAAAAATTCATGTCCACATCAGTAGGAGACAGGGTCAGCATCACCTGCAAGGCCAGTAAGAATGTGGGTACTGATGTATCCTGGTATCAACAGAAACCAGGGAAATCTCCTAAACCACTGATTTACTGGGCATCAAACCGGTTCACTGGAGTCCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAATGTGCAGTCTGAAGACTTGGCAGATTATTTCTGTGAGCAATATAGCAGCTATCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA 182 4338 vh GAGGTCCAGCTGCAGCAGTCTGGCCCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATATCCTGCAAGGCTTCTGGATACACATTCACTGACTACAACATGGACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTTATCCTATCAATGGTTATACTGGCTACAACCAGAGGTTCAAGAACAAGGCCACATTGACTGTAGACAAGTCCTCCAGCACAGCCTACATGGAACTCCACAGCCTGACATCTGAGGACTCTGCGGTCTATTACTGCGCAAGAGATAGTAACTACGTTGGCTGGTACTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCA 183 VL GATGTTGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTGTACACAGTAATGGAAACACCTATTTACATTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACATTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCCTCGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA 184 VL GACATTGTGCTGACACAGTCTCCTGCTTCCTTAACTGTATCTCTGGGGCAGAGGGCCACCTTCTCATGCAGGGCCAGCAAAAGTGTCAGTACATCTGGCTATAGTTATATGCACTGGTACCAACAGAAACCAGGACAGCCACCCAAACTCCTCATCTATTTTACATCCGACCTAGAACCTGGGGTCCCTGCCAGGTTCACTGGCAGTGGGTCTGGGACAGACTTCACCCTCAACATCCATCCTGTGGAGGAGGAGGATGCTGCAACCTATTACTGTCAGCACAGTAGGGAGCTTCCGTACCCCTTCGGAGGGGGGACCAAGTTGGAAATAAAA 185 4540 vh caggtccagctacagcagtctggacctgagctggtgaagcctggggcttcagtgaagatatcctgcaaggcttctggctacaccttcgctgactactatataaactgggtgaagcagaggcctggacagggacttgagtggattggatggatttttcctggaagtggtagtacttactacaatgagaagttcaagggcaaggccacacttactgtagacaaatcctccagcacagcctacatgttgctcagcagcctgacctctgaggactctgcggtctatttctgtgcaagaggggactccggtagggctatggactactggggtcaaggaacctcagtcaccgtctcctca 186 VL gacatccagatgacacagtctccatcctcactgtctgcatctctgggaggcaaagtcaccatcacttgcaaggcaagccaagacattaacaaatatatagcttggtaccaacacaagcctggaaaaggtcctaggctgctcatacattacacatctacattacagtcaggcatcccatcaaggttcagtggaagtgggtctgggagagattattccttcagcatcagcaacctggagcctgaagataatgcaacttattattgtctacagtatgataatcttctcacgttcggtgctgggaccaagctggagctgaaa 187 4540-063 vh CAAGTCCAGCTCGTACAGAGCGGGGCAGAGCTGAAGAAGCCTGGGGCCTCCGTCAAGGTCTCCTGTAAGGCTTCTGGTTACACATTTGCCGACTACTACATGAACTGGGTACGGCAAGCCCCAGGTCAAGGGCTGGAATGGATGGGATGGATTTTTCCAGGGAGCGGCAGCACTTACTACAACCAGAAATTTCAAGGTCGTGTGACAATGACCGTGGATAAAAGCAGCTCTACAGCTTACATGGAGCTTTCCCGCTTGAGGTCCGATGATACTGCCGTATATTATTGTGCCCGTGGTGACTCAGGTAGGGCCATGGACTATTGGGGACAGGGCACCCTCGTGACCGTGTCCAGC 301 VL GATATCCAGATGACACAATCCCCTTCATCCTTGAGCGCATCAGTTGGCGACAGGGTCACCATAACTTGTCAGGCTAGTCAGGATATTAACAAGTACCTGGCTTGGTATCAACACAAGCCTGGAAAGGCCCCCAAATTGCTGATTCACTACACCTCTACATTGGAAACTGGCGTACCCAGTCGCTTTTCTGGGAGTGGAAGCGGAACTGATTTCACTTTCACTATATCCAGTCTTCAGCCAGAAGATATCGCAACTTACTATTGTCTTCAGTATGATAACTTGCTTACTTTCGGAGGAGGGACCAAAGTTGAAATCAAG 302 4540-033 vh CAGGTGCAGTTGGTCCAATCCGGGGCTGAGGTGAAGAAGCCTGGGGCCTCTGTTAAAGTTAGTTGCAAGGCATCAGGCTACACCTTCGCTGACTACTACATCAACTGGGTTAGACAGGCCCCCGGGCAGGGGTTGGAGTGGATGGGTTGGATTTTTCCAGGATCAGGTTCAACATATTACGCACAAAAACTGCAAGGTAGAGTAACCATGACAACTGATACTAGCACCTCCACAGCCTATATGGAACTCCGCTCTCTCAGGAGTGACGATACAGCCGTTTATTACTGCGCCCGTGGGGATTCAGGCCGTGCAATGGATTACTGGGGTCAAGGGACCCTCGTGACCGTAAGTTCA 303 VL GATATCCAGATGACACAATCCCCTTCATCCTTGAGCGCATCAGTTGGCGACAGGGTCACCATAACTTGTCAGGCTAGTCAGGATATTAACAAGTACCTGGCTTGGTATCAACACAAGCCTGGAAAGGCCCCCAAATTGCTGATTCACTACACCTCTACATTGGAAACTGGCGTACCCAGTCGCTTTTCTGGGAGTGGAAGCGGAACTGATTTCACTTTCACTATATCCAGTCTTCAGCCAGAAGATATCGCAACTTACTATTGTCTTCAGTATGATAACTTGCTTACTTTCGGAGGAGGGACCAAAGTTGAAATCAAG 302 4237 vh CAGGCGCACCTGAAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTGTCCATCACCTGCACAGTCTCTGGTTTCTCATTAACCGACTATGATGTACACTGGGTTCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGATATGGAATGATGGAAGCACAGACTATAATACAGCTTTCATATCTAGACTGACCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTTAAAATGAACAGTCTGCAAGCTGATGACACAGCCATATACTACTGTGCCAGAAATTGGTATGGTGGCTACTGGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA 188 VL GACATCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGCGGGAGAAACTGTCACCATCACATGTCGATCAAGTGAGAATATTTACAGTTATTTAGCATGGTATCAGCAGAAACAGGGAAAATCTCCTCAGCTCCTAGTCTATAATGCAAATGCCTTAGCAGAAGGTGTGCCATCGAGGTTCAGTGGCAGTGGATCAGTCACACAGTTTTCTCTGAAGATCAACAGCCTGCAGCCTGAAGATTTTGGGAGTTATTACTGTCAACATCATTATGGTACTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA 189 4439 vh GAGATCCAGCTGCAGCAGTCTGGAGCTGAACTGGTGAAGCCTGGGGCTTCAGTGAAGATATCCTGCAAGGCTTCTGATTACTCATTCACTGGCTACAACATGAACTGGGTGATGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTCATCCTTACTATGGTGGTACTAGCTTCAATCAGAAGTTCATGGGCAAGGCCACATTGACTGCAGACAAATCTTCCAGCACAGCCTACATGCAGCTCAACAGCCTGACATCTGAAGACTCTGCAGTCTATTACTGTGCAAGAGAGAGAAGTAACTTCCATGCTCTGGACTACTGGGGTCAGGGAACCTCAGTCACCGTCTCCTCA 297 VL GACATTGTGCTGACACAGTCTCCTGCTTCCTTAACTGTATCTCTGGGGCAGAGGGCCACCTTCTCATGCAGGGCCAGCAAAAGTGTCAGTACATCTGGCTATAGTTATATGCACTGGTACCAACAGAAACCAGGACAGCCACCCAAACTCCTCATCTATTTTACATCCGACCTAGAACCTGGGGTCCCTGCCAGGTTCACTGGCAGTGGGTCTGGGACAGACTTCACCCTCAACATCCATCCTGTGGAGGAGGAGGATGCTGCAACCTATTACTGTCAGCACAGTAGGGAGCTTCCGTACCCCTTCGGAGGGGGGACCAAGTTGGAAATAAAA 298

Table 5. The amino acid sequences of the heavy chain variable region (VH) and the light chain variable region (VL) of exemplary humanized anti-APRIL antibodies are shown below.

Antibody chain Amino acid sequence SEQID NO >Hu_2218_VH01 QVQLQESGPGLVKPSQTLSLTCTVSGYSITSGYYYWNWIRQHPGKGLEWIGYISYDGYNNYNPSLKNRVTISVDTSKNQFSLKLSSVTAADTAVYYCARYYDYEDWYFGVWGQGTMVTVSS 190 >Hu_2218_VH02 QVQLQESGPGLVKPSQTLSLTCTVSGYSITSGYYWSWIRQHPGKGLEWIGYISYDGYTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARYYDYEDWYFGVWGQGTMVTVSS 191 >Hu_2218_VH03 QVQLQESGPGLVKPSQTLSLTCTVSGYSITSGYYYYWNWIRQHPGKGLEWIGYISYDGYNNYNPSLKSRVTISRDTSKNQFSLKLSSVTAADTAVYYCARYYDYEDWYFGVWGQGTMVTVSS 192 >Hu_2218_VH04 QVQLQQWGAGLLKPSETLSLTCAVYGYSITSGYYWNWIRQPPGKGLEWIGYISYDGYNNYNPSLKNRVTISVDTSKNQFSLKLSSVTAADTAVYYCANYYDYEDWYFGVWGQGTTVTVSS 193 >Hu_2218_VH05 QVQLQQWGAGLVKPSETLSLTCAVYGYSITSGYYWNWIRQPPGKGLEWIGYISYDGYNNYNPSLKNRVTISRDTSKNQFSLKLSSVTAADTAVYYCANYYDYEDWYFGVWGQGTTVTVSS 194 >Hu_2218_VH06 QVQLQESGPGLVKPSETLSLTTCTVSGYSITSGYYYWNWIRQPPGKGLEWIGYISYDGYNNYNPSLKNRVTISVDTSKNQFSLKLSSVTAADTAVYYCANYYDYEDWYFGVWGQGTTVTVSS 195 >Hu_2218_VH07 QVQLQESGPGLVKPSETLSLTTCTVSGYSITSGYYYWNWIRQPPGKGLEWIGYISYDGYNNYNPSLKNRVTISRDTSKNQFSLKLSSVTAADTAVYYCANYYDYEDWYFGVWGQGTTVTVSS 196 >Hu_2218_VH08 QVQLQESGPGLMKPSETLSLTCSVSGYSITSGYYWSWIRKPPGKGLEYIGYVSYDGSTYYNPSLKSRVTISVDTSKNRFSLKLNSVTAADTAVYYCANYYDYEDWYFGYWGQGILVTVSS 197 >Hu_2218_VH09 QVQLQESGPGLMKPSETLSLTCSVSGYSITSGYYWNWIRKPPGKGLEWIGYISYDGYNNYNPSLKSRVTISRDTSKNRFSLKLNSVTAADTAVYYCANYYDYEDWYFGVWGQGILVTVSS 198 >Hu_2218_VH10 EVQLVESGGGLVQPGGSLRLSCAVSGYSITSGYYYWNWIRQAPGKGLEWVASISYDGYNNYNPSVKGRITISRDDSKNTFYLQMNSLRAEDTAVYYCANYYDYEDWYFGVWGQGTLVTVSS 199 >Hu_2218_VH11 EVQLVESGGGLVQPGGSLRLSCAVSGYSITSGYYYWNWIRQAPGKGLEWVAYISYDGYNNYNPSVKGRITISRDTSKNTFYLQMNSLRAEDTAVYYCANYYDYEDWYFGVWGQGTLVTVSS 200 >Hu_2218_VH12 QVQLVESGGGVVQPGRSLRLSCAASGYSITSGYYYWNWVRQAPGKGLEWVAYISYDGYNNYNPSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCANYYDYEDWYFGVWGQGTMVTVSS 201 >Hu_2218_VL01 EIVLTQSPATLSLSPGERATLSCRASESVSIIGTNSIHWYQQKPGQAPRLLIYHASNLETGIPARFSGSGPGTDFTLTISSLEPEDFAVYYCLQSRKIPYTFGQGTKLEIK 202 >Hu_2218_VL02 DIVLTQSPASLAVSPGQRATITCRASESVSIIGTNSIHWYQQKPGQPPKLLIYHASNLETGVPARFSGSGSGTDFTLTINPVEANDTANYYCLQSRKIPYTFGGGTKLEIK 203 >Hu_2218_VL03 EIVMTQSPATLSVSPGERATLSCRASESVSIIGTNSLHWYQQKPGQAPRLLIYHASQSISGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQSRKIPYTFGGGTKVEIK 204 >Hu_2218_VL04 EIVMTQSPATLSVSPGERATLSCRASESVSIIGTNSIHWYQQKPGQAPRLLIYHASNLETGIPARFSGSGSRTEFTLTISSLQSEDFAVYYCLQSRKIPYTFGGGTKVEIK 205 >Hu_2218_VL05 DIQLTQSPSSLSASVGDRVTITCRASESVSIIGTNSMNWYQQKPGKAPKLLIYHASYLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQSRKIPYTFGQGTKVEIK 206 >Hu_2218_VL06 DIQLTQSPSSLSASVGDRVTITCRASESVSIIGTNSMHWYQQKPGKAPKLLIYHASNLESGVPSRFSGSGSRTDFTLTISSLQPEDFATYYCLQSRKIPYTFGQGTKVEIK 207 >Hu_2218_VL07 DIQMTQSPSSLSASVGDRVTITCRASESVSIIGTNSMHWYQQKPGKAPKLLIYHASNLESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCLQSRKIPYTFGQGTKVEIK 208 >Hu_2419_VH01 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYTIHWVRQAPGQGLEWMGWIYPLRGSINYNEKFKDRVTSTRDTSISTAYMELSRLRSDDTVVYYCARHGAYYSNAFDYWGQGTLVTVSS 209 >Hu_2419_VH02 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMHWVRQAPGQGLEWMGRIYPLRGSTNYAQKFQGRVTSTRDTSISTAYMELSRLRSDDTVVYYCARHGAYYSNAFDYWGQGTLVTVSS 210 >Hu_2419_VH03 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYTIHWVRQAPGQGLEWMGWIYPLRGSINYNEKFKDRVTMTADTSSSTAYMELSRLRSDDTVVYYCARHGAYYSNAFDYWGQGTLVTVSS 211 >Hu_2419_VH04 QVQLVQSGAEVKKPGASVKVSCEASGYTFTDYTIHWVRQAPGKGLEWMGWIYPLRGSINYNEKFKDRVTMTADTSTDTAYMELSSLRSKDTAVYYCARHGAYYSNAFDYWGQGTLVTVSS 212 >Hu_2419_VH05 QVQLVQSGAEVVKPGASVKLSCKASGYTFTDYTMYWVKQAPGQGLEWIGEIYPLRGSINFNEKFKSKATLTVDKSASTAYMELSSLRSEDTAVYYCARHGAYYSNAFDYWGQGTLVTVSS 213 >Hu_2419_VH06 QVQLVQSGAEVVKPGASVKLSCKASGYTFTDYTMHWVKQAPGQGLEWIGEIYPLRGSINFNEKFKSKATLTVDKSASTAYMELSSLRSEDTAVYYCARHGAYYSNAFDYWGQGTLVTVSS 214 >Hu_2419_VL01 EIVLTQSPATLSLSPGERATLSCRASESVDNDGIRFMHWYQQKPGQAPRLLIYRASNLESGIPARFSGSGPGTDFTLTISSLEPEDFAVYYCQQSNKDPYTFGQGTKLEIK 215 >Hu_2419_VL02 EIVLTQSPATLSLSPGERATLSCRASESVDNDGIRFMHWYQQKPGQAPRLLIYRASNLESGIPARFSGSGPGTDFTLTISSLEPEDVAVYYCQQSNKDPYTFGQGTKLEIK 216 >Hu_2419_VL03 DIVMTQSPASLAVSLGERATINCRASESVDNDGIRFMHWYQQKPGQPPKLLIYRASNLESGVPDRFSGSGSRTDFTLTISSLQAEDVAVYYCQQSNKDPYTFGGGTKVEIK 217 >Hu_2419_VL04 DIVMTQSPASLAVSLGERATINCRASESVDNDGIRFMHWYQQKPGQPPKLLIYRASNLESGVPDRFSGSGSRTDFTLTINSLQAEDVAVYYCQQSNKDPYTFGGGTKVELK 218 >Hu_2419_VL05 DIVLTQSPATLSVSPGERATISCRASESVDNDGIRFMHWYQQKPGQPPKLLIYRASNLESGVPARFSGSGSRTDFTLTISSVEPEDFATYYCQHSWEIPPTFGGGTKLEIK 219 >hu_4035_VH01 QVQLVESGGGVVQPGRSLRLSCAASGFSLTIYDVHWVRQAPGKGLEWVAVIWSDGSTDYNAAFISRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNWVDQAWFAYWGQGTLVTVSS 220 >hu_4035_VH02 QVQLVESGGGVVQPGRSLRLSCAASGFSLTIYDVHWVRQAPGKGLEWVGVIWSDGSTDYNAAFISRFTISKDNSKNTLYLQMNSLRAEDTAVYYCARNWVDQAWFAYWGQGTLVTVSS 221 >hu_4035_VH03 QVQLVESGGGVVQPGRSLRLSCAASGFSLTIYDVHWVRQAPGKGLEWVAVIWSDGSTDYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCARNWVDQAWFAYWGQGTLVTVSS 222 >hu_4035_VH04 QVQLVESGGGVVQPGRSLRLSCAVSGFSLTIYDVHWVRQAPGKGLEWVGVIWSDGSTDYADSVKGRFTISKDNSKNTVYLQMNSLRAEDTAVYYCARNWVDQAWFAYWGQGTLVTVSS 223 >hu_4035_VH05 QVQLQESGPGLVKPSETLSLTCTVSGFSLTIYDVHWIRQPPGKGLEWIGVIWSDGSTDYNAAFISRVTISVDTSKNQFSLKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS 224 >hu_4035_VH06 QVQLQESGPGLVKPSETLSLTCTVSGFSLTIYDVHWVRQPPGKGLEWIGVIWSDGSTDYNPSLKSRVTISKDTSKNQVSLKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS 225 >hu_4035_VH07 QVQLQESGPGLMKPSETLSLTCSVSGDSITIYDWHWIRQPPGKGLEWIGVVWSDGSTDYNPSLKSRVTISVDTSKNRFSLKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS 226 >hu_4035_VH07 QVQLQESGPGLVKPSETLSLTCTVSGFSLTIYDVHWIRQPPGKGLEWIGVIWSDGSTDYNPSLKSRVTISKDNSKNQFSLKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS 227 >hu_4035_VH09 QVQLQESGPGLVKPSETLSLTCTVSGFSLTIYDVHWIRQPPGKGLEWIGVIWSDGSTDYNPSLKSRVTISKDTSKNQVSLKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS 262 >hu_4035_VH10 QVQLQESGPGLVKPSETLSLTCTVSGGSITIYDWHWVRQPPGKGLEWIGVIWSDGSTDYNPSLKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS 263 >hu_4035_VH11 QVQLQESGPGLVKPSETLSLTCTVSGGSITIYDWHWVRQPPGKGLEWIGVIWSDGSTDYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS 264 >hu_4035_VH12 QVQLQESGPGLVKPSETLSLTCTVSGGSITIYDWHWIRQPPGKGLEWIGVIWSDGSTDYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS 265 >hu_4035_VL01 DIQMTQSPSSLSASVGDRVTITCRASKNIYSYLAWYQQKPGKAPKLLIYNAKTLPEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHHYGTPLTFGQGTKLEIK 228 >hu_4035_VL02 DIQMTQSPSSLSASVGDRVTITCRASKNIYSYLAWYQQKPGKAPKLLVYNAKTLPEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHHYGTPLTFGQGTKLEIK 229 >hu_4035_VL03 EIVLTQSPATLSLSPGERATLSCRASKNIYSYLAWYQQKPGQAPRLLIYNAKTRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHHYGTPLTFGQGTKLEIK 230 >hu_4035_VL04 EIVLTQSPATLSLSPGERATLSCRASKNIYSYLAWYQQKPGQAPRLLVYNAKTLPEGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHHYGTPLTFGQGTKLEIK 231 >hu_4035_VL05 EIVMTQSPATLSVSPGERATLSCRASKNIYSYLAWYQQKPGQAPRLLIYNAKTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQHHYGTPLTFGGGTKVEIK 232 >hu_4035_VL06 DIQLTQSPSFLSASVGDRVTITCRASKNIYSYLAWYQQKPGKAPKLLIYNAKSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHHYGTPLTFGGGTKLEIK 233 >hu_4035_VL07 DIQLTQSPSFLSASVGDRVTITCRASKNIYSYLAWYQQKPGKAPKLLIYNAKSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHHYGTPLTFGGGTKLEIK 234 >hu_4237_VH01 QLQLQESGSGLVKPSQTLSLTCAVSGFSLTDYDVHWVRQPPGKGLEWIGVIWNDGSTDYNPSLISRVTISKDNSKNQVSLKLSSVTAADTAVYYCARNWYGGYWFAYWGQGTLVTVSS 235 >hu_4237_VH02 QLQLQESGSGLVKPSQTLSLTCAVSGGSITDYDWHWVRQPPGKGLEWIGVIWNDGSTDYNPSLISRVTISVDNSKNQFSLKLSSVTAADTAVYYCARNWYGGYWFAYWGQGTLVTVSS 236 >hu_4237_VH03 QVQLVESGGGVVQPGRSLRLSCAASGFSFTDYDMHWVRQAPGKGLEWVAVIWNDGSTDYATSVIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNWYGGYWFAYWGQGTLVTVSS 237 >hu_4237_VH04 QVQLVESGGGVVQPGRSLRLSCAASGFSFTDYDMHWVRQAPGKGLEWVGVIWNDGSTDYATSVIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNWYGGYWFAYWGQGTLVTVSS 238 >hu_4237_VH05 QVQLQESGPGLMKPSETLSLTCSVSGGSITDYDWHWIRQPPGKGLEWIGVVWNDGSTDYNPSLKSRVTISVDTSKNRFSLKLNSVTAADTAVYYCARNWYGGYWFAYWGQGILVTVSS 239 >hu_4237_VH06 QVTLKESGPALVKPTQTLTLTCTFSGFSLTDYDVHWIRQPPGKALEWLAVIWNDGSTDYSPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARNWYGGYWFAYWGQGTLVTVSS 240 >hu_4237_VL01 DIQMTQSPSSLSASVGDRVTITCRSSENIYSYLAWYQQKPGKAPKLLVYNANALAEGVPSRFSGSGSVTDFTLTISSLQPEDFATYYCQHHYGTPFTFGQGTKLEIK 241 >hu_4237_VL02 DIQMTQSPSTLSASVGDRVTITCRSSENIYSYLAWYQQKPGKAPKLLVYNANALAEGVPSRFSGSGSVTEFTLTISSLQPDDFATYYCQHHYGTPFTFGQGTKLEIK 242 >hu_4237_VL03 EIVMTQSPATLSVSPGERATLSCRASENIYSYLAWYQQKPGQAPRLLIYNANASAEGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQHYGTPFTFGGGTKVEIK 243 >hu_4237_VL04 DIQMTQSPSSLSASVGDRVTITCRASENIYSYLAWYQQKPGKAPKLLLYNANRLESGVPSRFSGSGSGTDFTLTISSLQPEDFASYYCQHHYGTPFTFGSGTKLEIK 244 >hu_4237_VL05 DIQMTQSPSSLSASVGDRVTITCRASENIYSYLAWYQQKPGKAPKLLLYNANRLESGVPSRFSGSGSGTDYTLTISSLQPEDFASYYCQHHYGTPFTFGSGTKLEIK 245 >hu_3833_VH01 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPGGIGGGYTKYNEKFKGRVTMTADTSTSTAYMELRSLRSDDTAVYYCSRSETGRAMDYWGQGTLVTVSS 246 >hu_3833_VH02 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPGGIGGGYTKYAQKLQGRVTMTADTSTSTAYMELRSLRSDDTAVYYCSRSETGRAMDYWGQGTLVTVSS 247 >hu_3833_VH03 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPGGIGGGYTKYAQKFQGRVTMTADTSTSTAYMELSSLRSEDTAVYYCSRSETGRAMDYWGQGTLVTVSS 248 >hu_3833_VH04 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPGGIGGGYTKYNEKFKGRVTMTADTSTSTAYMELSSLRSEDTAVYFCSRSETGRAMDYWGQGTLVTVSS 249 >hu_3833_VH05 QVQLVQSGAELKRPGASVKVSCKASGYTFTNYWMGWVKQAPGQGLEWMGDIYPGGIGGGYTNYAQKFKGKATMTADTSSSTAYMQLSRLRSEDTAVYYCSRSETGRAMDYWGQGTLVTVSS 250 >hu_3833_VL01 DIQMTQSPSSLSASVGDRVTITCQASQDINKYLAWYQQKPGKAPKLLIHYTSTLKPGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCLQYDNLNTFGGGTKLEIK 251 >hu_3833_VL02 DIQMTQSPSSLSASVGDRVTITCKASQDINKYIAWYQQKPGKAPKLLIHYTSTLKPGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCLQYDNLNTFGGGTKLEIK 252 >hu_3833_VL03 DIQMTQSPSSLSASVGDRVTITCQASQDINKYLAWYQQKPGKAPKLLIYYTSTLETGVPSRFSGSGSGTDFTFSISSLQPEDIATYYCLQYDNLNTFGGGTKLEIK 253 >hu_4540_VH01 QVQLVQSGAEVKKPGASVKVSCKASGYTFADYYINWVRQAPGKGLEWMGWIFPGSGSTYYNEKFKGRVTMTVDKSTSTAYMELSSLRSEDTAVYFCARGDSGRAMDYWGQGTLVTVSS 254 >hu_4540_VH02 QVQLVQSGAEVKKPGASVKVSCKASGYTFADYYMNWVRQAPGQGLEWMGWIFPGSGSTYYAEKFKGRVTSTRDTSISTAYMELSRLRSDDTVVYYCARGDSGRAMDYWGQGTLVTVSS 255 >hu_4540_VH03 QVQLVQSGAEVKKPGASVKVSCKASGYTFADYYINWVRQAPGQGLEWMGWIFPGSGSTYYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARGDSGRAMDYWGQGTLVTVSS 256 >hu_4540_VH04 QVQLVQSGAEVKKPGASVKVSCKASGYTFADYYINWVRQAPGQGLEWMGWIFPGSGSTYYAQKLQGRVTMTVDKSSSTAYMELRSLRSDDTAVYYCARGDSGRAMDYWGQGTLVTVSS 257 >hu_4540_VH05 QVQLVQSGAELKKPGASVKVSCKASGYTFADYYMNWVRQAPGQGLEWMGWIFPGSGSTYYNQKFQGRVTMTVDKSSSTAYMELSRLRSDDTAVYYCARGDSGRAMDYWGQGTLVTVSS 258 >hu_4540_VL01 DIQMTQSPSSLSASVGDRVTITCKASQDINKYIAWYQQKPGKAPKLLIHYTSTLQSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCLQYDNLLTFGQGTKLEIK 259 >hu_4540_VL02 DIQMTQSPSSLSASVGDRVTITCKASQDINKYIAWYQHKPGKAPKLLIHYTSTLQSGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCLQYDNLLTFGQGTKLEIK 260 >hu_4540_VL03 DIQMTQSPSSLSASVGDRVTITCQASQDINKYLAWYQHKPGKAPKLLIHYTSTLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCLQYDNLLTFGGGTKVEIK 261

In one embodiment, the antibody molecule contains one, two, or three CDRs of the VH region of the antibody molecule described herein, such as in Table 1 or 5 (for example, any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206 2419-0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, 4439, or Chothia definitions) In one embodiment, the antibody molecule contains one, two, or three CDRs of the VL region of the antibody molecule described herein, such as in Table 1 or 5 (for example, any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206 2419-0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, 4439, or Chothia definitions) In one embodiment, the antibody molecule comprises one or more (e.g., two or three) VH region CDRs and/or one or more (e.g., two or three) VL region CDRs of the antibody molecule described herein, e.g., in Table 1 or 5 (for example, any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 3327 3530 3525 3125 2621 4035 4035-062 3934 3833 363.4 4540-063, 4540-033, 4439, 4439 or 4237) using the definitions of CDR Kabat or Chothia.

In one embodiment, the antibody molecule contains one, two, or three VH CDRs described in Table 1 or 5. In one embodiment, the antibody molecule contains one, two, or three VL CDRs described in Table 1 or 5. In one embodiment, the antibody molecule contains one or more (e.g., two or three) VH CDRs and/or one or more (e.g., two or three) VL CDRs described in Table 1 or 5.

In one embodiment, an antibody molecule contains one, two, three, or four VH framework regions of an antibody molecule described in Table 1 or 5 (e.g., any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419 -0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 , 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, 4439 or 4237). In one embodiment, the antibody molecule contains one, two, three, or four VL framework regions of the antibody molecule described in Table 1 or 5 (e.g., any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419 -0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 , 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, 4439 or 4237). In one embodiment, the antibody molecule contains one or more (e.g., two, three, or four) VH framework regions and/or one or more (e.g., two, three, or four) VL framework regions of the antibody molecule described in Table 1 or 5 ( for example, any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-12 2419-1305 2419-1306 2419-1310 2419-1406 2922 3327 3530 3525 3125 2621 4035 4035-062 3934 3833 3631 3732 4308 43.0 4540-033, 4439 or 4237).

In one embodiment, the antibody molecule contains the heavy chain variable region of the antibody molecule described herein, for example, in Table 1 or 5 (for example, any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419 -0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 , 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439 or 4237). In one embodiment, the antibody molecule comprises the light chain variable region of the antibody molecule described herein, e.g., in Table 1 or 5 (e.g., any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419 -0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 2419-1406 2922 , 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439 or 4237). In one embodiment, an antibody molecule comprises a heavy chain variable region and a light chain variable region of an antibody molecule described herein, e.g., in Table 1 or 5 (e.g., any of the monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206 2419-0406 2419-0605 2419-0805 2419-0806 2419-1204 2419-1205 2419-1210 2419-1305 2419-1306 2419-1310 3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439 or 4237).

In one embodiment, the antibody molecule contains a heavy chain variable region having the amino acid sequence described in Table 1 or 5, or an amino acid sequence substantially identical to it. In one embodiment, the antibody molecule contains a light chain variable region having the amino acid sequence described in Table 1 or 5, or an amino acid sequence substantially identical to it. In one embodiment, the antibody molecule contains a heavy chain variable region having the amino acid sequence described in Table 1 or 5 (or its amino acid sequence substantially identical to it) and a light chain variable region having the amino acid sequences described in Table 1 or 5 ( or an amino acid sequence substantially identical to them).

In one embodiment, the antibody molecule contains a heavy chain variable region encoded by the nucleotide sequence described in Table 2, or a nucleotide sequence substantially identical to it. In one embodiment, the antibody molecule contains a light chain variable region encoded by the nucleotide sequence described in Table 2, or a nucleotide sequence substantially identical to it. In one embodiment, the antibody molecule comprises a heavy chain variable region encoded by the nucleotide sequence described in Table 2 (or a nucleotide sequence substantially identical thereto) and a light chain variable region encoded by the nucleotide sequence described in Table 2 (or a nucleotide sequence essentially identical).

In one embodiment, the antibody molecule further comprises a heavy chain constant region. In one embodiment, the heavy chain constant region is an IgG1 constant region, eg, any of SEQ ID NOs: 320-322 or a functional portion thereof. In another embodiment, the heavy chain constant region is an IgG2 constant region, eg, any of SEQ ID NOs: 323-326 or a functional portion thereof. In one embodiment, the antibody molecule further comprises a light chain constant region. In one embodiment, the antibody molecule further comprises a heavy chain constant region and a light chain constant region. In one embodiment, the antibody molecule comprises a heavy chain constant region, a light chain constant region, and the heavy and light chain variable regions of the antibody molecules described in Table 1 or 5. In some embodiments, the antibody molecule comprises a heavy chain constant region, a light chain constant region, and variable regions that contain one, two, three, four, five, or six CDRs of the antibody molecule described in Table 1 or 5.

Exemplary heavy chain constant regions are described below.

Exemplary IgG1 Constant Regions

>IGHG1*01

STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP (SEQ ID NO: 320)

>IGHG1*03

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP (SEQ ID NO: 321)

>IGHG1*04

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNHYTQKSLSLSP (SEQ ID NO: 322)

Exemplary IgG2 Constant Regions

>IGHG2*01

STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP (SEQ ID NO: 323)

>IGG2*02

STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP (SEQ ID NO: 324)

>IGG2*04

STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP (SEQ ID NO: 325)

>IGG2*06

STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP (SEQ ID NO: 326)

In one embodiment, the antibody molecule contains one or both of the following:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 11; HCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 12; or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of SEQ ID NO: 13, or

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the LCDR1 amino acid sequence of SEQ ID NO: 280; LCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 285; or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues, or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 16.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein the heavy chain variable region comprises: HCDR1 comprising the amino acid sequence of SEQ ID NO: 11; HCDR2 containing the amino acid sequence of SEQ ID NO: 12; and HCDR3 containing the amino acid sequence of SEQ ID NO: 13 and

(ii) a light chain variable region (VL) wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of LCDR1 SEQ ID NO: 280 ; LCDR2 containing the amino acid sequence of SEQ ID NO: 285; or an LCDR3 containing the amino acid sequence of SEQ ID NO: 16.

In one embodiment, the antibody molecule contains one or both of the following:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 17; HCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 282; or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of SEQ ID NO: 13, or

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 280; LCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 285; or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues, or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 16.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein the heavy chain variable region comprises: HCDR1 comprising the amino acid sequence of SEQ ID NO: 17; HCDR2 containing the amino acid sequence of SEQ ID NO: 282; and HCDR3 containing the amino acid sequence of SEQ ID NO: 13 and

(ii) a light chain variable region (VL) wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of SEQ ID NO: 280; LCDR2 containing the amino acid sequence of SEQ ID NO: 285; or an LCDR3 containing the amino acid sequence of SEQ ID NO: 16.

In one embodiment, the antibody molecule contains a VH containing the amino acid sequence of SEQ ID NO: 296. In one embodiment, the antibody molecule contains a VL containing the amino acid sequence of SEQ ID NO: 286. In one embodiment, the antibody molecule contains a VH containing the amino acid sequence of SEQ ID NO: 296 and VL containing the amino acid sequence of SEQ ID NO: 286.

In one embodiment, the antibody molecule contains a VH encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 313. In one embodiment, the antibody molecule contains a VL encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 306. In one embodiment, the antibody molecule contains a VH encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 313 and a VL encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 306.

In one embodiment, the antibody molecule further comprises an IgG2 heavy chain constant region, eg, any of SEQ ID NOs: 323-326.

In one embodiment, the antibody molecule contains one or both of the following:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 11; HCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 12; or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of SEQ ID NO: 13, or

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the LCDR1 amino acid sequence of SEQ ID NO: 280; LCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 285; or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues, or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 16.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein the heavy chain variable region comprises: HCDR1 comprising the amino acid sequence of SEQ ID NO: 11; HCDR2 containing the amino acid sequence of SEQ ID NO: 12; and HCDR3 containing the amino acid sequence of SEQ ID NO: 13 and

(ii) a light chain variable region (VL) wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of LCDR1 SEQ ID NO: 280 ; LCDR2 containing the amino acid sequence of SEQ ID NO: 285; or an LCDR3 containing the amino acid sequence of SEQ ID NO: 16.

In one embodiment, the antibody molecule contains one or both of the following:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 17; HCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 282; or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of SEQ ID NO: 13, or

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 280; LCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 285; or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues, or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 16.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein the heavy chain variable region comprises: HCDR1 comprising the amino acid sequence of SEQ ID NO: 17; HCDR2 containing the amino acid sequence of SEQ ID NO: 282; and HCDR3 containing the amino acid sequence of SEQ ID NO: 13 and

(ii) a light chain variable region (VL) wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of SEQ ID NO: 280; LCDR2 containing the amino acid sequence of SEQ ID NO: 285; or an LCDR3 containing the amino acid sequence of SEQ ID NO: 16.

In one embodiment, the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 289. In one embodiment, the antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 286. In one embodiment, the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 289. NO: 289 and VL containing the amino acid sequence of SEQ ID NO: 286.

In one embodiment, the antibody molecule contains a VH encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 308. In one embodiment, the antibody molecule contains a VL encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 305. In one embodiment, the antibody molecule contains a VH encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 308 and a VL encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 306.

In one embodiment, the antibody molecule further comprises an IgG2 heavy chain constant region, eg, any of SEQ ID NOs: 323-326.

In one embodiment, the antibody molecule contains one or both of the following:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 11; HCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 12; or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of SEQ ID NO: 13, or

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the LCDR1 amino acid sequence of SEQ ID NO: 280; LCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 281; or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues, or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 16.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein the heavy chain variable region comprises: HCDR1 comprising the amino acid sequence of SEQ ID NO: 11; HCDR2 containing the amino acid sequence of SEQ ID NO: 12; and HCDR3 containing the amino acid sequence of SEQ ID NO: 13 and

(ii) a light chain variable region (VL) wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of LCDR1 SEQ ID NO: 280 ; LCDR2 containing the amino acid sequence of SEQ ID NO: 281; or an LCDR3 containing the amino acid sequence of SEQ ID NO: 16.

In one embodiment, the antibody molecule contains one or both of the following:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 17; HCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 282; or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of SEQ ID NO: 13, or

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 280; LCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 281; or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues, or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 16.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein the heavy chain variable region comprises: HCDR1 comprising the amino acid sequence of SEQ ID NO: 17; HCDR2 containing the amino acid sequence of SEQ ID NO: 282; and HCDR3 containing the amino acid sequence of SEQ ID NO: 13 and

(ii) a light chain variable region (VL) wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of SEQ ID NO: 280; LCDR2 containing the amino acid sequence of SEQ ID NO: 281; or an LCDR3 containing the amino acid sequence of SEQ ID NO: 16.

In one embodiment, the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 289. In one embodiment, the antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 284. In one embodiment, the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 289 and VL containing the amino acid sequence of SEQ ID NO: 284.

In one embodiment, the antibody molecule contains a VH encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 308. In one embodiment, the antibody molecule contains a VL encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 305. In one embodiment, the antibody molecule contains a VH encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 308 and a VL encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 305.

In one embodiment, the antibody molecule further comprises an IgG2 heavy chain constant region, eg, any of SEQ ID NOs: 323-326.

In one embodiment, the antibody molecule contains one or both of the following:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 93; HCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 94; or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of SEQ ID NO: 95, or

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the LCDR1 amino acid sequence of SEQ ID NO: 96; LCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 97; or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of SEQ ID NO: 98.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein the heavy chain variable region comprises: HCDR1 comprising the amino acid sequence of SEQ ID NO: 93; HCDR2 containing the amino acid sequence of SEQ ID NO: 94; and HCDR3 containing the amino acid sequence of SEQ ID NO: 95 and

(ii) a light chain variable region (VL) wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of LCDR1 SEQ ID NO: 96 ; LCDR2 containing the amino acid sequence of SEQ ID NO: 97; or an LCDR3 containing the amino acid sequence of SEQ ID NO: 98.

In one embodiment, the antibody molecule contains one or both of the following:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: HCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 99; HCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 273; or HCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of SEQ ID NO: 95, or

(ii) a light chain variable region (VL), wherein the light chain variable region contains three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), where the light chain variable region contains one, two, or all of the following: an LCDR1 containing an amino acid a sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 96; LCDR2 containing an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or has at least 85%, 90%, 95%, 99% or 100% homology with the amino acid sequence of SEQ ID NO: 97; or an LCDR3 containing an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues, or has at least 85%, 90, 95, 99, or 100% homology with the amino acid sequence of SEQ ID NO: 98.

In one embodiment, the antibody molecule contains:

(i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein the heavy chain variable region comprises: HCDR1 comprising the amino acid sequence of SEQ ID NO: 99; HCDR2 containing the amino acid sequence of SEQ ID NO: 273; and HCDR3 containing the amino acid sequence of SEQ ID NO: 95 and

(ii) a light chain variable region (VL) wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of SEQ ID NO: 96; LCDR2 containing the amino acid sequence of SEQ ID NO: 97; or an LCDR3 containing the amino acid sequence of SEQ ID NO: 98.

In one embodiment, the antibody molecule contains a VH containing the amino acid sequence of SEQ ID NO: 225. In one embodiment, the antibody molecule contains a VL containing the amino acid sequence of SEQ ID NO: 229. In one embodiment, the antibody molecule contains a VH containing the amino acid sequence of SEQ ID NO: 225 and VL containing the amino acid sequence of SEQ ID NO: 229.

In one embodiment, the antibody molecule contains a VH encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 299. In one embodiment, the antibody molecule contains a VL encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 300. In one embodiment, the antibody molecule contains a VH encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 299 and a VL encoded by a nucleic acid containing the nucleotide sequence of SEQ ID NO: 300.

In one embodiment, the antibody molecule further comprises an IgG1 heavy chain constant region, eg, any of SEQ ID NOs: 320-322.

In one embodiment, an antibody molecule described herein has one or more (eg, 2, 3, 4, 5, or all) of the following properties: (a) is a humanized antibody molecule; (b) binds to human APRIL at an EC ₅₀ of 60 pM or less as determined by ELISA; (c) inhibits the binding of human APRIL to TACI, eg in vitro, with an IC ₅₀ of 0.5 nM or less; (d) inhibits the binding of human APRIL to BCMI, eg in vitro, with an IC ₅₀ of 0.6 nM or less; (e) is n IgG2κ; or (f) has an Fc region engineered to reduce complement activation. light chain regions, or one or both of the heavy chain or light chain of any of the antibody molecules 2419-1406, 2419-0205, or 2419-0206. In one embodiment, the antibody molecule is suitable for use in the treatment of a disorder in the kidney, for example, IgA nephropathy. In another embodiment, the antibody molecule is suitable for use in the treatment of cancer, such as multiple myeloma.

In one embodiment, an antibody molecule described herein has one or more (eg, 2, 3, 4, 5, or all) of the following properties: (a) is a humanized antibody molecule; (b) binds to human APRIL at an EC50 of 50 pM or less, as determined by ELISA; (c) inhibits the binding of human APRIL to TACI, eg in vitro, with an IC ₅₀ of 0.3 nM or less; (d) inhibits the binding of human APRIL to BCMA, eg in vitro, with an IC ₅₀ of 0.2 nM or less; (e) is IgG1κ; or (f) has a higher BCMA neutralizing activity, e.g., has an IC _{50 of} 0.1 nM or less. In one embodiment, the antibody molecule contains one or more (e.g., 2, 3, 4, 5 or all) CDRs, one or both of the heavy chain variable region or the light chain variable region, or one or both of the heavy chain or light chain of the 4035-062 antibody molecule. In one embodiment, the antibody molecule is suitable for use in the treatment of cancer or an autoimmune disorder.

The antibody molecules described herein may have several advantageous properties. For example, antibody molecules can be used to effectively treat, prevent, or diagnose a disorder associated with APRIL, such as the disorder described herein, such as IgA nephropathy.

In one embodiment, the antibody molecule is capable of binding or substantially binding to human APRIL and mouse APRIL. In one embodiment, the antibody molecule is able to bind or substantially bind to human APRIL, but cannot or substantially cannot bind to murine APRIL. In one embodiment, the antibody molecule binds to APRIL with high affinity, e.g., a dissociation constant (KD) of less than about 100 nM, typically about 10 nM, and more typically about 10-0.001 nM, about 10-0.01 nM, about 10-0.01 nM, about 5-0.01 nM, about 3-0.05 nM, about 1-0.1 nM, or greater, e.g., less than about 80, 70, 60, 50, 40, 30 , 20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005 or 0.001 nM. In one embodiment, the antibody molecule binds to APRIL with a Koff slower than 1×10 ^-4 , 5×10 ^-5 , or 1×10 ^-5 s ^-1 . In one embodiment, the antibody molecule binds to APRIL with Kon faster than 1×10 ⁴ , 5×10 ⁴ , 1×10 ⁵ , or 5×10 ⁵ M ^-1 s ^-1 .

In one embodiment, the antibody molecule is capable of inhibiting or substantially inhibiting the binding of human APRIL to TACI. In one embodiment, the antibody molecule is capable of inhibiting or substantially inhibiting the binding of human APRIL to TACI. In one embodiment, the antibody molecule is capable of inhibiting or substantially inhibiting the binding of human APRIL to BCMA. In one embodiment, the antibody molecule is capable of inhibiting or substantially inhibiting the binding of human APRIL to TACI and BCMA. In one embodiment, the antibody molecule is capable of inhibiting or substantially inhibiting the binding of human APRIL to TACI, but is not capable of inhibiting or substantially inhibiting the binding of human APRIL to BCMA. In one embodiment, the antibody molecule is capable of inhibiting or substantially inhibiting the binding of human APRIL to BCMA, but is not capable of inhibiting or substantially inhibiting the binding of human APRIL to TACI.

In one embodiment, the antibody molecule inhibits the binding of human APRIL to human TACI by 50% or more, e.g., 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% as determined by the method described herein (eg, normalized without antibody control).

In one embodiment, the antibody molecule inhibits the binding of human APRIL to human BCMA by 30% or more, e.g., 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100% as determined by the method described herein (eg, normalized without antibody control).

In one embodiment, the antibody molecule does not substantially inhibit the binding of human APRIL to human BCMA, e.g., inhibits the binding of human APRIL to human BCMA by less than 10%, as determined by the method described herein (e.g., normalized without antibody control).

In one embodiment, the antibody molecule binds to a linear or conformational epitope on APRIL. In one embodiment, the antibody molecule binds to an epitope conserved between human APRIL and murine APRIL. In one embodiment, the antibody molecule binds to the epitope described herein. In one embodiment, the antibody molecule binds or substantially binds to the same, similar or overlapping epitope on APRIL as the second antibody molecule (eg, the monoclonal antibody described in Table 1 or 5). In one embodiment, the antibody molecule competes with a second antibody molecule (eg, the monoclonal antibody described in Table 1 or 5) for binding to APRIL.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more residues within the APRIL region as defined in Table 3. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 , 25, or all human APRIL residues from Table 3. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 3. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains APRIL residues from two monomers, for example one or more residues from monomer A and monomer B, as shown in Table 3.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more residues in the APRIL region as defined in Table 4. In one in an embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the human APRIL residues from Table 4. In in one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 4. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains one or more residues APRIL from loop C-D (eg, loop connecting β-sheets C and D), loop G-H (eg, loop connecting β-sheets G and H), or both.

In one embodiment, the antibody molecule binds or substantially binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues of human APRIL positions 105-114 and/or one or more than (eg, 2, 3, 4, 5, 6, 7, 8, 9 or all) residues of murine APRIL positions 96-105.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or more than residues within the APRIL region as defined in Table 7. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more, e.g., 2, 3, 4, 5, 6, 7 , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all human APRIL residues from Table 7. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 7.

In one embodiment, the antibody molecule binds or substantially binds to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more residues within the APRIL region as defined in Table 8. In one embodiment, the antibody molecule binds or substantially binds to an epitope that contains or consists of one or more, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 , 25, or all human APRIL residues from Table 8. In one embodiment, the antibody molecule binds or substantially binds to an epitope that overlaps an epitope that contains or consists of all human APRIL residues from Table 8.

In an embodiment, the epitope is a conformational epitope.

In one embodiment, the antibody molecule does not or substantially does not bind to one, two or all of the Asp129, Arg233 or His203 of human APRIL.

In one embodiment, binding of the antibody molecule to APRIL (eg, human APRIL) inhibits or substantially inhibits the binding of the CRD2 domain of TACI (eg, human TACI) to APRIL (eg, human APRIL). In another embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits binding of human TACI to one or more of, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all of the APRIL residues from Table 3. In another embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits the binding of human TACI with one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the human APRIL residues from Table 4. In yet another embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits binding of human TACI to one or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all of the human APRIL residues from the Table 7. In yet another embodiment, binding of the antibody molecule to human APRIL inhibits or substantially inhibits binding of human TACI to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or with all human APRIL residues from Table 8.

Animal models

The antibody molecules described herein can be evaluated in vivo , for example, using various animal models. For example, an animal model can be used to test the efficacy of an antibody molecule described herein in inhibiting APRIL and/or in treating or preventing a disorder as described herein, such as IgA nephropathy. Animal models can also be used, for example, to study side effects, measure the concentration of antibody molecules in situ , demonstrate the correlation between APRIL function and the disorder described herein (eg, IgA nephropathy).

Exemplary animal models for IgA nephropathy that can be used to evaluate the antibody molecule described herein include, but are not limited to, the ddY mouse model for spontaneous IgA nephritis (Imai et al. Kidney Int. 1985; 27 (5 ): 756-761); a mouse model using inert proteins or a common viral pathogen as stimulus antigen (Emancipator et al. Curr. Protoc. Immunol. 2001 May; Chapter 15: Unit 15.11), a rat model with non-infectious protein antigens (Emancipator et al. Curr. Protoc. Immunol 2001 May;Chapter 15: Unit 15.11); chronic mouse model of immune complex associated IgA nephropathy (Montinaro et al. Nephrol. Dial. Transplant. 1995; 10(11): 2035-2042); mouse Gne M712T as a model of human glomerulopathy (Kakani et al. Am. J. Pathol. 2012; 180 (4): 1431-1440); mouse IgA nephropathy with MBP-20 fusion protein (Zhang et al. Anat. Rec. (Hoboken). 2010; 293 (10): 1729-1737); and a mouse model for IgA nephritis associated with the immune complex (Rifai et al. J Exp Med. 1979; 150 (5): 1161-1173). Other animal models for IgA nephropathy are described, for example, in Tomino et al. J. Nephrol. 2008; 21(4):463-467; Endo Ren. fail. 1997; 19(3):347-371; and Rifai Kidney Int. 1987; 31(1):1-7.

Illustrative animal models for the other disorders described herein are also known in the art. Illustrative animal types that can be used to evaluate the antibody molecules described herein include, but are not limited to, mice, rats, rabbits, guinea pigs, and monkeys.

Pharmaceutical compositions and kits

In some aspects, the present disclosure comprises compositions, eg, pharmaceutically acceptable compositions, that comprise an antibody molecule described herein (eg, a humanized antibody molecule described herein) formulated with a pharmaceutically acceptable carrier.

Used in the present description, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, isotonic and retarding absorption agents, and the like, which are physiologically compatible. The carrier may be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, dorsal, or epidermal administration (eg, by injection or infusion). In some embodiments, less than about 5%, such as less than about 4%, 3%, 2%, or 1% of the antibody molecules in the pharmaceutical composition are present as aggregates. In other embodiments, at least about 95%, such as at least about 96%, 97%, 98%, 98.5%, 99%, 99.5%, 99.8%, or more of the antibody molecules in the pharmaceutical the compositions are present as monomers. In some embodiments, the level of aggregates or monomers is determined by chromatography, such as high performance size exclusion chromatography (HP-SEC).

The compositions presented in the present description, can be presented in various forms. These include, for example, liquid, semi-solid and solid dosage forms such as liquid solutions (eg solutions for injection and infusion), dispersions or suspensions, liposomes and suppositories. The appropriate form depends on the intended route of administration and therapeutic application. Typical suitable compositions are in the form of injection or infusion solutions. One suitable route of administration is parenteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular). In some embodiments, the antibody molecule is administered by intravenous infusion or injection. In some embodiments, the antibody is administered intramuscularly or subcutaneously.

As used herein, the expressions "parenteral administration" and "parenteral administration" mean methods of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal , intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intraarticular injection and infusion.

Therapeutic compositions generally must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for high antibody concentrations. Sterile injectable solutions can be prepared by incorporating the active compound (ie, antibody or antibody portion) in the required amount in a suitable solvent with one or more of the ingredients listed above, followed by filtered sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which produces a powder of the active ingredient, together with any additional target ingredient, from a previously sterile-filtered solution. The correct fluidity of the solution can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by using surfactants. Long-term absorption of injectable compositions can be achieved by including an agent that delays absorption, for example, monostearate salts and gelatin.

The antibody molecules described herein can be administered in a variety of ways. Some of these are known in the art, and for many therapeutic, prophylactic, or diagnostic applications, intravenous injection or infusion is a suitable route/mode of administration. For example, antibody molecules can be administered by intravenous infusion at a rate of less than 10 mg/min; preferably less than or equal to 5 mg/min, up to a dose of about 1-100 mg/m ² , preferably about 5 to 50 mg/m 2 , about 7 to 25 mg/m ² , and more preferably about 10 mg/m ² . As will be appreciated by one of skill in the art, the route and/or route of administration will vary depending on the intended results. In some embodiments, the active compound may be formulated with a carrier that will protect the compound from rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Many methods for preparing such compositions are patented or known to those skilled in the art. See, for example, Sustained and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978.

In some embodiments, the implementation of the antibody molecule can be administered orally, for example, using an inert diluent or assimilable edible carrier. The antibody molecule (and other ingredients, if appropriate) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or included directly in the subject's diet. For oral therapeutic administration, the antibody molecule can be administered with excipients and used as ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like. For administration of an antibody molecule other than parenteral administration, it may be necessary to coat the compound or co-administer the compound with the material to prevent its inactivation. Therapeutic, prophylactic, or diagnostic compositions can also be administered via medical devices, some of which are known in the art.

Dosing regimens are adjusted to provide a targeted response (eg, therapeutic, prophylactic, or diagnostic response). For example, a single bolus may be administered, multiple divided doses may be administered over time, or the dose may be proportionally reduced or increased as required by the therapeutic situation. It is particularly advantageous to formulate parenteral compositions in a single dosage form for ease of administration and dosage uniformity. As used herein, a single dosage form refers to physically discrete units suitable as unit doses for patients to be treated; each unit contains a predetermined amount of the active compound, calculated to obtain the desired therapeutic effect in combination with the required pharmaceutical carrier. The specification of unit dosage forms is dictated by and directly dependent on (a) the unique characteristics of the antibody molecule and the particular therapeutic, prophylactic, or diagnostic effect to be achieved, and (b) the limitations inherent in methods of mixing such an antibody molecule to treat sensitivity in individuals.

A typical non-limiting range for a therapeutically, prophylactically, or diagnostically effective amount of an antibody molecule is about 0.1-50 mg/kg of patient body weight, e.g., about 0.1-30 mg/kg, e.g., about 1-30, 1-15, 1-10, 1-5, 5-10 or 1-3 mg/kg, e.g. about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40 or 50 mg/kg. The antibody molecule can be administered by intravenous infusion at a rate of less than 10 mg/min, such as less than or equal to 5 mg/min, to reach a dose of about 1 to 100 mg/m ² , such as about 5 to 50 mg/m ² . from about 7 to 25 mg/m ² , for example about 10 mg/m ² . It should be noted that dosage values may vary depending on the type and severity of the condition to be alleviated. It should also be understood that for any given patient, specific dosage regimens will need to be adjusted over time according to individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges given herein are illustrative only and are not intended to be limiting. scope or practical application of the claimed compositions.

Pharmaceutical compositions of the present description may include a "therapeutically effective amount", "prophylactically effective amount" or "diagnostic effective amount" of the antibody molecule described herein.

"Therapeutically effective amount" refers to an amount effective at dosages and for periods of time necessary to achieve the desired therapeutic result. A therapeutically effective amount of an antibody molecule may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody moiety or antibody to elicit a targeted response in the individual. A therapeutically effective amount is also one in which any toxic or deleterious effects of the antibody molecule are outweighed by the therapeutically beneficial effects. A "therapeutically effective dose" typically inhibits the measured parameter by at least about 20%, such as at least 40%, at least 60%, or at least 80%, relative to untreated patients. The measured parameter can be, for example, hematuria, colored urine, foamy urine, pain, swelling (edema) in the arms and legs, or high blood pressure. The ability of an antibody molecule to inhibit a measurable parameter can be assessed in an animal model system predictive of efficacy in treating or preventing IgA nephropathy. Alternatively, this property of the composition can be assessed by examining the ability of the antibody molecule to inhibit APRIL, for example, using an in vitro assay.

A "prophylactically effective amount" refers to an amount effective at dosages and for periods of time necessary to achieve the desired prophylactic result. Generally, since a prophylactic dose is used in patients before or at an earlier stage of the disease, the prophylactically effective amount will be less than the therapeutically effective amount.

"Diagnostically effective amount" refers to an amount effective at dosages and for periods of time necessary to achieve the desired diagnostic result. Typically, a diagnostically effective amount is one in which the disorder, eg, the disorder described herein, eg, IgA nephropathy, can be diagnosed in vitro, ex vivo, or in vivo .

Also provided in this disclosure is a kit that contains the antibody molecule described herein. The kit may include one or more other items, including: instructions for use; other reagents, for example a label, a therapeutic agent or an agent suitable for chelation or other binding, a labeled antibody molecule or a therapeutic agent, or a radioprotective composition; devices or other materials for obtaining an antibody molecule for administration; pharmaceutically acceptable carriers; and devices or other materials for administration to a patient.

Nucleic acids

The present disclosure also includes nucleic acids containing nucleotide sequences that encode antibody molecules (eg, heavy and light chain variable regions and CDRs of antibody molecules) as described herein.

For example, the present disclosure includes first and second nucleic acids encoding the heavy and light chain variable regions, respectively, of an antibody molecule selected from one or more of the antibody molecules described herein, such as an antibody molecule of Table 1 or 5, or a portion antibody molecules, such as the variable regions of Table 2. A nucleic acid may comprise a nucleotide sequence encoding any of the amino acid sequences in the Tables provided herein, or a sequence substantially identical to it (for example, a sequence that is at least about 85%, 90 %, 95%, 99% or more identical to it, or which differs by no more than 3, 6, 15, 30 or 45 nucleotides from the sequences presented in the Tables herein).

In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs from a heavy chain variable region having the amino acid sequence shown in the tables herein, or a sequence substantially homologous to it (e.g., a sequence that is at least about 85%, 90%, 95%, 99% or more identical to them and/or having one or more substitutions, eg conservative substitutions). In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs from a light chain variable region having the amino acid sequence shown in the tables herein, or a sequence substantially homologous thereto (e.g., the sequence at least about 85%, 90%, 95%, 99% or more identical to them and/or having one or more substitutions, eg conservative substitutions). In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs from the heavy and light chain variable regions having the amino acid sequence shown in the tables herein, or a sequence substantially homologous to it (eg, sequence at least 85%, 90%, 95%, 99% or more identical to it and/or with one or more substitutions, for example, conservative substitutions).

In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs from a heavy chain variable region having the nucleotide sequence shown in Table 2, a sequence substantially homologous thereto (e.g., a sequence of at least about 85%, 90%, 95%, 99% or more identical to it and/or capable of hybridizing under the stringency conditions described herein). In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs from a light chain variable region having the nucleotide sequence shown in Table 2, or a sequence substantially homologous thereto (e.g., a sequence of at least , about 85%, 90%, 95%, 99% or more identical to it and/or capable of hybridization under the stringency conditions described herein). In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs from the heavy and light chain variable regions having the nucleotide sequence shown in Table 2, or a sequence essentially homologous to them (eg, sequence at least 85%, 90%, 95%, 99% or more identical to them and/or capable of hybridizing under the stringent conditions described herein).

In some embodiments, the nucleic acid comprises the nucleotide sequence shown in Table 2, or a sequence substantially homologous to it (e.g., a sequence at least about 85, 90, 95, 99 or more identical to it and/or capable of hybridizing into stringency conditions described in this document). In some embodiments, the nucleic acid comprises a portion of the nucleotide sequence shown in Table 2, or a sequence substantially homologous to it (e.g., a sequence at least about 85, 90, 95, 99 or more identical to it, and/or capable of hybridization under the stringency conditions described herein). The portion may encode, for example, a variable region (eg, VH or VL); one, two or three or more CDRs; or one, two, three or four or more wireframe regions.

The nucleic acids described herein include deoxyribonucleotides or ribonucleotides or their analogs. The polynucleotide can be either single stranded or double stranded, and if single stranded, it can be a coding strand or a non-coding (antisense) strand. The polynucleotide may contain modified nucleotides such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides can be interrupted by non-nucleotide components. The polynucleotide may be further modified after polymerization, for example by conjugation with a labeled moiety. The nucleic acid may be a recombinant polynucleotide or polynucleotide of genomic, cDNA, semi-synthetic or synthetic origin, which is either not found in nature or linked to another polynucleotide in an artificial environment.

In some aspects, the use includes host cells and vectors containing the nucleic acids described herein. The nucleic acids may be present in a single vector or separate vectors present in the same host cell or a separate host cell, as described in more detail below.

Vectors

Further in the present description are vectors that contain nucleotide sequences encoding the antibody molecule described in this document.

In one embodiment, the vector contains a nucleotide encoding an antibody molecule described herein, for example, as described in Table 1 or 5. In another embodiment, the vector contains a nucleotide sequence described herein, for example, in Table 2. Vectors include, but not limited to, a viral, plasmid, cosmid, lambda phage vector, or from an artificial yeast chromosome (YAC).

Many vector systems can be used. For example, one class of vectors uses DNA elements that are derived from animal viruses such as, for example, bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, baculovirus, retroviruses (Rous sarcoma virus, MMTV or MOMLV) or SV40 virus. Another class of vectors uses RNA elements derived from RNA viruses such as Semliki forest virus, eastern equine encephalitis virus, and flaviviruses.

In addition, cells that have stably integrated DNA in their chromosomes can be selected by introducing one or more markers that allow selection of transfected host cells. The marker can provide, for example, prototropy in an auxotrophic host, resistance to biocides (eg antibiotics) or resistance to heavy metals such as copper, or the like. The selection marker gene can either be directly linked to the DNA sequences to be expressed, or introduced into the same cell by co-transformation. Additional elements may be required for optimal mRNA synthesis. These elements may include splicing signals as well as transcription promoters, enhancers, and transcription termination signals.

Once the expression vector or DNA sequence containing the constructs has been obtained for expression, the expression vectors can be transfected or introduced into an appropriate host cell. Various methods can be used to achieve this, such as, for example, protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, virus transfection, gene gun, lipid-based transfection, or other conventional methods. In the case of protoplast fusion, cells are grown in media and screened for appropriate activity.

Methods and conditions for culturing the resulting transfected cells and for recovering the antibody molecule produced are known to those skilled in the art and may vary or be optimized depending on the particular expression vector and mammalian host cell used based on the present disclosure.

Cells

The present disclosure also provides cells (eg, host cells) containing a nucleic acid encoding an antibody molecule as described herein. For example, host cells may contain a nucleic acid molecule having the nucleotide sequence described in Table 2, a sequence substantially homologous to it (e.g., a sequence of at least about 85%, 90%, 95%, 99% or more identical to it and/or capable of hybridization under the stringency conditions described herein), or a part of one of the specified nucleic acids. In addition, host cells may contain a nucleic acid molecule encoding an amino acid sequence from Table 1 or substantially homologous to it (eg, sequence at least about 80%, 85%, 90%, 95%, 99% or more identical to it) or part of one of these sequences.

In some embodiments, the host cells are genetically modified to contain nucleic acids encoding the antibody molecule described herein.

In some embodiments, the host cells are genetically engineered using an expression cassette. The expression "expression cassette" refers to nucleotide sequences that are capable of influencing gene expression in hosts that are compatible with such sequences. Such cassettes may include a promoter, an open reading frame with or without introns, and a termination signal. Additional factors necessary or useful for effecting expression may also be used, such as, for example, an inducible promoter.

The disclosure also provides host cells containing the vectors described herein.

The cell may be, but is not limited to, a eukaryotic cell, a bacterial cell, an insect cell, or a human cell. Suitable eukaryotic cells include, but are not limited to, Vero cells, HeLa cells, COS cells, CHO cells, HEK293 cells, BHK cells, and MDCKII cells. Suitable insect cells include, but are not limited to, Sf9 cells. In one embodiment, the cell (eg, host cell) is an isolated cell.

Applications of antibody molecules

The antibody molecules described herein, as well as the pharmaceutical compositions disclosed herein, have in vitro, ex vivo and in vivo therapeutic, prophylactic and/or diagnostic uses.

In one embodiment, the antibody molecule reduces (eg, inhibits, blocks or neutralizes) one or more biological activities of APRIL. For example, these antibody molecules can be administered to cells in culture, in vitro or ex vivo , or to a patient, such as a human, such as in vivo , to reduce (eg, inhibit, block, or neutralize) one or more biological activities of APRIL. In one embodiment, the antibody molecule inhibits or substantially inhibits the binding of APRIL, eg human APRIL, to TACI, BCMA, or both. Accordingly, in one aspect, the disclosure provides a method of treating, preventing, or diagnosing a disorder, such as the disorder described herein (e.g., IgA nephropathy) in a patient, the method comprising administering to the patient an antibody molecule described herein such that the disorder is subjected to treated, prevented or diagnosed. For example, the disclosure provides a method comprising contacting an antibody molecule described herein with cells in culture, such as in vitro or ex vivo , or administering an antibody molecule described herein to a patient, such as in vivo , to treat, prevent, or diagnose disorders, eg, an APRIL-associated disorder (eg, IgA nephropathy).

As used herein, the term "patient" is intended to include non-human humans and animals. In some embodiments, the patient is a human, such as a human suffering from the disorder described herein (eg, IgA nephropathy) or at risk of developing the disorder described herein (eg, IgA nephropathy). The term "non-human animals" includes mammals and non-mammals such as non-human primates. In some embodiments, the patient is a human. The methods and compositions described herein are suitable for the treatment of a disorder described herein (eg, IgA nephropathy) in human patients. Patients suffering from the disorder described herein (eg, IgA nephropathy) include patients who have developed the disorder described herein (eg, IgA nephropathy) but are (at least temporarily) asymptomatic, patients who have who exhibited a symptom of the disorder described herein (eg, IgA nephropathy) or patients suffering from a disorder associated with or related to the disorder described herein (eg, IgA nephropathy).

Ways to treat or prevent disorders

The antibody molecules described herein can be used to treat or prevent disorders associated with APRIL or their symptoms.

Characteristic disorders or conditions that may be associated with APRIL include, but are not limited to, IgA nephropathy, diabetic nephropathy, malignancy (e.g., hematologic cancer (e.g., B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, multiple myeloma (eg, colon cancer, breast cancer (eg, breast carcinoma), esophageal cancer (eg, esophageal adenocarcinoma), brain cancer (eg, glioblastoma), and kidney cancer (eg, renal cell carcinoma)), immunoproliferative disorders (eg, monoclonal IgA hypergammaglobulinemia), vasculitis (eg, renal vasculitis, Henoch-Schonlein purpura (IgA-associated vasculitis), and post-streptococcal glomerulonephritis), autoimmune disorders (eg, rheumatoid arthritis, systemic lupus erythematosus, linear IgA-mediated bullous disease/linear immunoglobulin A (IgA)-mediated dermatosis and IgA-mediated acquired epidermolysis bullosa), IgA pemphigus, celiac disease, and alcoholic cirrhosis. In one embodiment, the disorder is associated with aberrant IgA expression. In one embodiment, the antibody molecule is used to treat a patient who has the disorder described herein or who is at risk of developing the disorder described herein.

The antibody molecules described herein are typically administered at a rate that maintains a therapeutically effective level of antibody molecules in the patient's system until the patient recovers. For example, antibody molecules can be administered at a frequency that reaches a serum concentration sufficient for at least about 1, 2, 5, 10, 20, 30, or 40 antibody molecules to bind to each APRIL molecule. In one embodiment, antibody molecules are administered every 1, 2, 3, 4, 5, 6, or 7 days, every 1, 2, 3, 4, 5, or 6 weeks, or every 1, 2, 3, 4, 5, or 6 months .

Methods for administering various antibody molecules are known in the art and are described below. Suitable doses of antibody molecules to be used will depend on the age and weight of the patient and the particular drug used.

In one embodiment, the antibody molecule is administered to a patient (eg, human) intravenously. In one embodiment, the antibody molecule is administered to a patient at a dose of 0.1 to 50 mg/kg, e.g., 0.2 to 25 mg/kg, 0.5 mg/kg to 10 mg/kg, 0.5 mg /kg to 5 mg/kg, from 0.5 mg/kg to 3 mg/kg, from 0.5 mg/kg and 2.5 mg/kg, from 0.5 mg/kg and 2 mg/kg, from 0.5 mg/kg and 1.5 mg/kg, 0.5 mg/kg to 1 mg/kg, 1 mg/kg to 1.5 mg/kg, 1 mg/kg to 2 mg/kg , 1 mg/kg to 2.5 mg/kg, 1 mg/kg to 3 mg/kg, 1 mg/kg to 2.5 mg/kg, or 1 mg/kg to 5 mg/kg. In one embodiment, the antibody molecule is administered to a patient at a fixed dose of 10 to 1000 mg, e.g., 10 to 500 mg, 10 to 250 mg, 10 to 150 mg, 10 mg to 100 mg, 10 to 50 mg, 250 to 500 mg 150 to 500 mg 100 to 500 mg 50 to 500 mg 25 to 250 mg 50 to 150 mg mg 50 to 100 mg 100 to 150 mg 100 mg to 200 mg or 150 mg to 250 mg. In one embodiment, the antibody molecule is administered once a week, twice a week, every two weeks, every three weeks, every four weeks, once every eight weeks, once a month, once every two months, or once at three months. In one embodiment, the antibody molecule is administered at a concentration of 0.5 mg/kg to 3 mg/kg or 50 to 150 mg once a week, twice a week, every other week, or every four weeks.

The antibody molecules can be used alone or conjugated to a second agent, such as a bacterial agent, toxin, or protein, such as a second anti-APRIL antibody molecule. This method includes: administering an antibody molecule, alone or conjugated to a second agent, to a patient in need of such treatment. Antibody molecules can be used to deliver various therapeutic agents, such as a toxin, or mixtures thereof.

IgG nephropathy

IgG nephropathy (also known as Berger's disease, Berger's syndrome, Berger's syndrome, nephritis, IgAN, or synpharyngitis glomerulonephritis) is the most common chronic glomerular disease worldwide. Conservative epidemiological estimates indicate a global incidence of approximately 5-50 cases/million (children) and 10-40 cases/million (adults). This incidence has a regional shift with a higher prevalence in Asia and the Americas with a particularly high disease burden in Japan and regions of China. Biopsy confirmed cases of IgA nephropathy in Japan with a prognosis of approximately 350,000 cases. In the United States, this prognosis is approximately 100,000 - as such, it is the most commonly diagnosed glomerular disease in adults. Despite a relatively slow onset, IgA nephropathy results in end-stage renal disease (ESRD), i.e. kidney failure in 20-50% of patients within 20-30 years. These figures are probably grossly underestimated given the need to confirm the disease with a kidney biopsy, a protocol that can be applied in a variety of clinical settings. The disease has a complex pathogenesis with genetic, epidemiological, and potentially environmental components for the etiology, pathology, and progression of the disease. It also has a variable clinical presentation ranging from asymptomatic to ending in renal failure (ESRD). Currently, there are no specific disease-specific therapies to treat the primary disease or progression.

The etiology of this disease is established, as its name suggests. Briefly, the disease is caused by the deposition of IgA, usually in the form of immune complexes, in the mesangium of the kidney. Molecular characterization of these specific immunoglobulins has been carried out. These IgA are of the A1 subclass (IgA1 vs. IgA2), predominantly polymeric (with J-chain mediated bonds) and appear to be differentially o-glycosylated at the hinge region, which is located between the CH1 and CH2 domains. In particular, these -glycans heterogeneously lack β1,3 galactose bonds and as such are commonly referred to as galactose-deficient IgA1 (or gdIgA1). Since the pathogenesis of this dysfunction may involve a polygenic, multi-hit mechanism for inducing renal pathology and aberrant physiology, IgA1 can be considered as a so-called self-antigen representing this first critical "hit" in the multi-hit model for IgA nephropathy. A set of autoantibodies to this disease has also been defined. and refers to immunoglobulins (predominantly IgG) that specifically recognize this differentiated glycosylated epitope and promote the formation of immune complexes (representing the so-called "hit 2"). It should also be noted that IgA itself is susceptible to aggregation due to misassembly, conformational changes, and potential changes in the N-glycosylation state of the CH2/CH3 glycans.

Regardless of theory, it is believed that in one embodiment, the level of aberrantly glycosylated IgA1 correlates with disease and clinical outcome in IgA nephropathy. Aberrantly glycosylated IgA1 has been characterized directly from kidney biopsies, and increased production of aberrantly glycosylated IgA1 has been observed in B cells (tonsillar, PBMC) in patients with IgA nephropathy. Serum levels of galactose-deficient IgA1 in patients with IgA nephropathy are associated with disease progression (Zhao et al. Kidney Int. 2012; 82 (7): 790-6). Differential staining of lectins has demonstrated increased levels of aberrantly glycosylated IgA1 in the serum and glomeruli of patients with IgA nephropathy compared to healthy controls (Allen et al. Kidney Int. 2001; 60 (3): 969-73).

Based on this evolving disease model, IgA nephropathy can properly be considered an autoimmune disease with strong and critical extrarenal involvement. It is assumed that the identification and validation of selected targets based on the immune system plays a critical role in the pathogenesis of the disease, namely, the production of IgA and the subsequent production of autoreactive antibodies to this target, represent a logical therapeutic strategy for treatment. For this reason, APRIL (TNFSF13) has received special attention. Additional justification for targeting APRIL is new genetic evidence based on multiple genome-wide studies (GWAS) along with IgA-associated genetic disorders, such as IgG hypogammaglobulinemia associated with the common variable immunoglobulin deficiency (CVID), whose loci are mapped with defects. in TNFRSF13B (TACI) with direct implications for the role of APRIL-TACI interactions in the regulation of IgA synthesis.

IgA nephropathy often does not cause symptoms in the early stages. The disease can go unnoticed for years and is sometimes first diagnosed when routine tests show protein and red blood cells in the urine that cannot be seen without a microscope (microscopic hematuria). Signs and symptoms of IgA nephropathy when kidney function is impaired include, for example, cola-colored or tea-colored urine (caused by red blood cells in the urine); recurring episodes of cola or tea-colored urine, sometimes even visible blood in the urine, usually during or after an upper respiratory infection or other type back pain below the ribs (lateral side); foam in toilet water due to protein in the urine; swelling (edema) in the hands and feet; and high blood pressure. In one embodiment, the sign or symptom includes, for example, one or more of hematuria, proteinuria, albuminuria, hypertension, or early stage kidney disease (eg, requiring dialysis or transplantation). In an embodiment, the sign or symptom is associated with, for example, one or more of aberrantly glycosylated IgA1, formation of autoantibodies, deposition of nephritogenic immune complexes in the kidney, or inflammation and loss of kidney function.

The classic presentation (in about 40-50% of cases, more common in younger people) of IgA nephropathy is episodic hematuria that usually starts after a day or two due to a non-specific upper respiratory tract infection (hence synpharyngitis). Less often, a gastrointestinal or urinary infection may be the stimulating agent. All of these infections share a common activation of mucosal defenses and hence the production of IgA antibodies. These episodes may occur on an irregular basis every few months and eventually subside in most patients. Renal function usually remains normal, although rarely, acute renal failure may occur.

A smaller proportion (about 20-30% of cases, usually elderly) of patients with IgA nephropathy have microscopic hematuria and proteinuria (less than 2 grams per day). These patients may not have any symptoms that are only discovered clinically if the doctor decides to take a urine sample. Consequently, the disease is more often diagnosed in situations where urinalysis is mandatory, such as schoolchildren in Japan.

Some (approximately 5%) patients with IgA nephropathy present with: nephrotic syndrome (eg, 3–3.5 g loss of protein in the urine, associated with worse prognosis); acute renal failure (for example, as a complication of overt hematuria, when it usually recovers, or due to rapidly progressive glomerulonephritis, which often leads to chronic renal failure); chronic renal failure (eg, no previous symptoms, no anemia, hypertension, and other symptoms of kidney failure in people who are likely to have had long-term undetected microscopic hematuria and/or proteinuria).

A variety of systemic diseases can be associated with IgA nephropathy, such as liver failure, celiac disease, rheumatoid arthritis, reactive arthritis, ankylosing spondylitis, and HIV. The diagnosis of IgA nephropathy and the search for any associated disease sometimes reveals such a serious systemic disease. Sometimes there are simultaneous symptoms of Henoch-Schonlein purpura. Several HLA alleles are suspected, along with complement phenotypes, as genetic factors.

IgG nephropathy can be diagnosed by a variety of tests, such as urinalysis, blood tests (eg, increased creatinine levels in waste products), iothalamate clearance test, renal imaging (eg, ultrasound, X-ray, or cystoscopy), kidney biopsy or a combination of them.

For an adult patient with isolated hematuria, tests such as renal ultrasound and cystoscopy are usually performed to determine the source of bleeding. These tests would rule out kidney stones and bladder cancer, two other common urological causes of hematuria. In children and young adults, a history and association with a respiratory infection may raise suspicion of IgA nephropathy. A kidney biopsy is often needed to confirm the diagnosis. The biopsy specimen demonstrates mesangium proliferation with IgA deposition on immunofluorescence and electron microscopy. However, patients with isolated microscopic hematuria (i.e., without associated proteinuria and with normal renal function) are not usually biopsied because it is associated with an excellent prognosis. Urinalysis will show red blood cells, usually in the form of erythrocyte renal casts. Proteinuria, usually less than 2 grams per day, may also be present. Other renal causes of isolated hematuria include, for example, thin basement membrane disease and Alport's syndrome, the latter being an inherited disorder associated with hearing loss and eye problems. Other blood tests done to make a diagnosis include CRP or ESR, complement levels, ANA, and LDH. Protein electrophoresis and immunoglobulin levels can show an increase in IgA in 50% of all patients.

Treatment with a number of drugs can slow the progression of the disease and help manage symptoms such as high blood pressure, protein in the urine (proteinuria), and swelling (edema) in the arms and legs. Exemplary treatments for IgA nephropathy include, for example, high blood pressure drugs (eg, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)), omega-3 fatty acids, immunosuppressants (eg, corticosteroid drugs such as prednisone ), statin therapy, mycophenolate mofetil, cyclosporine, mizoribine, cyclophosphamide (eg, in combination with antiplatelet/anticoagulants or in combination with steroids and azathioprine), renal dialysis, or kidney transplantation. Exemplary therapies for IgA nephropathy are also described in Floege and Eitner J. Am. soc. Nephrol. 22: 1785-1794, 2011. Other exemplary therapies for IgA nephropathy are described in the Combination Therapy section of this specification.

Regardless of theory, it is believed that in one embodiment, targeting APRIL selectively reduces IgA. APRIL -/- mice have normal T and B lymphocyte development, normal T and B cell proliferation in vitro , but have reduced serum IgA levels (Castigli et al. Proc Natl Acad Sci US A. 2004; 101(11):3903- 8). The discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against enteric pathogens (Kiryluk et al. Nat Genet. 2014; 46 (11): 1187-96). Serum levels and B cell production of APRIL are elevated in patients with IgA nephropathy and correlate with aberrantly glycosylated IgA levels (Zhai et al. Medicine (Baltimore). 2016; 95(11):e3099). Plasma levels of APRIL (TNFSF13) correlate with chronic kidney disease progression in IgA nephropathy (Han et al. J Am Soc Nephrol. 2016; 27 (2): 439-53). Treatment with anti-APRIL antibodies results in a decrease in serum IgA, clearance of renal mesangium, and reduction in inflammatory cell infiltration and glomerular lesions in mice (Kim et al. PLoS One. 2015; 10(9):e0137044). Anti-APRIL antibody maintains immune cell homeostasis in bone marrow and spleen (Kim et al. PLoS One. 2015; 10(9):e0137044).

APRIL (TNFSF13) is a logical biological and therapeutic target for the treatment of IgA nephropathy. Regardless of theory, it is believed that in one embodiment, the effectiveness of the antibody molecules described herein, in relation to the targeted modulation of APRIL-mediated immunobiolial mechanisms, is directly related to the treatment of IgA nephropathy. The anti-APRIL antibody molecules described herein (eg, humanized anti-APRIL antibody molecules), eg, with high biological efficacy and/or low complement activation, can be used to treat IgA nephropathy. In one embodiment, the antibody molecule has picomolar APRIL binding affinity and subnanomolar receptor blocking activity for both TACI and BCMA, eg in vitro . In another embodiment, the antibody molecule functionally interferes with APRIL-mediated downstream cell signaling, eg, via the canonical NFκB activation pathway. In one embodiment, the antibody molecule is designed, for example, as an IgG2 subtype for the purposes of clinical mitigation against an antibody-dependent complement recruitment exacerbation, for example, in the kidneys of patients with IgA nephropathy. In one embodiment, an antibody molecule described herein may have an improved safety profile compared to more effective B cell depletion therapeutic approaches, e.g., due to less perturbations in B and T cell homeostasis, as shown in mouse models (Kim et al., PLoS One. 2015;10(9):e0137044).

The antibody molecules described herein can be used to treat or prevent various stages of IgA nephropathy. In one embodiment, the antibody molecule is used to treat a symptom associated with IgA nephropathy, such as hematuria, proteinuria, albuminuria, hypertension, early stage kidney disease (eg, requiring dialysis or transplantation), or a combination thereof. In one embodiment, the antibody molecule reduces aberrantly glycosylated IgA1, autoantibody formation, nephritogenic immune complex deposition in the kidney, inflammation, and loss of kidney function, or a combination thereof. In one embodiment, the patient is at low risk, eg, has minor bladder abnormalities (eg, microhematuria), normal glomerular filtration rate (GFR), and/or no hypertension. In another embodiment, the patient is at moderate or high risk, eg, has proteinuria greater than 0.5-1 g/day and/or reduced GFR (eg, below 30-50 ml/min) and/or hypertension. In yet another embodiment, the patient has an acute or rapid loss of GFR, such as with nephrotic syndrome or rapidly progressive glomerulonephritis (RPGN) or acute renal failure (AKI) due to gross hematuria or another common cause. In one embodiment, the patient has proteinuria greater than 0.5 g/day, for example, 0.5 to 1 g/day, or greater than 1 g/day. In an embodiment, a patient treated for IgA nephropathy has a glomerular filtration rate (GFR) of less than 50 ml/min, such as less than 30 ml/min. In one embodiment, the antibody molecule does not significantly alter (eg, is able to maintain) immune cell homeostasis. In another embodiment, the antibody molecule results in a reduction in IgA rather than complete ablation of IgA.

diabetic nephropathy

The antibody molecule described herein can be used to treat or prevent diabetic nephropathy. Diabetic nephropathy (or known as diabetic kidney disease) is a progressive kidney disease caused, for example, by damage to the capillaries in the glomeruli of the kidneys. It is usually characterized by nephrotic syndrome and diffuse scarring of the glomeruli. It is often associated with long-term diabetes mellitus and is the leading cause of dialysis. It is classified as a complication of diabetes associated with small blood vessels.

Illustrative symptoms of diabetic nephropathy include, but are not limited to, extreme fatigue, headaches, a general feeling of illness, nausea, vomiting, frequent urination, lack of appetite, itchy skin, or swollen feet. The cause of diabetic nephropathy may be, for example, high blood sugar levels, increased formation of the end product of glycation. Cytokines may be involved in the development of diabetic nephropathy.

Diabetes can cause a number of changes in the body's metabolism and circulation, which likely combine to produce excess reactive oxygen species. These changes damage the glomeruli of the kidneys, resulting in the hallmark of albuminuria (Cao and Cooper J Diabetes Investig. 2011; 2 (4): 243-247). As diabetic nephropathy progresses, the glomerular filtration barrier (GFB), consisting of fenestrated endothelium, glomerular basement membrane and epithelial podocytes, is enlarged damaged (Mora-Fernández et al. J. Physiol. (Lond.) 2014; 592 (Pt 18): 3997-4012). Damage to the glomerular basement membrane allows proteins in the blood to leak out, leading to accumulation in Bowman's space as isolated nodules that are positive for iodic acid-Schiff (Kimmelstiel-Wilson nodes).

Diagnosis of diabetic nephropathy may be based on measurement of high urinary albumin or evidence of decreased kidney function (Lewis and Maxwell Practitioner. 2014; 258 (1768): 13-7, 2). Albumin measurements can be defined as follows: normal albuminuria: urinary albumin excretion <30 mg/24 hours; microalbuminuria: urinary albumin excretion in the range of 30-299 mg/day; clinical (overt) albuminuria: urinary albumin excretion ≥300 mg/24 h. To test kidney function, the patient's glomerular filtration rate (eGFR) measured from a blood sample is assessed. The normal eGFR value is 90 to 120 ml/min/1.73 m2.

Other therapies that can be used in combination with an antibody molecule described herein to treat diabetic nephropathy include, for example, an angiotensin-converting enzyme (ACE) inhibitor (eg, captopril, enalapril, lisinopril, or ramipril), an angiotensin II receptor blocker (ARB) (eg, candesartan cilexetil, irbesartan, losartan, or telmisartan), calcium channel blocker (eg, amlodipine, diltiazem, or verapamil), diuretic (eg, chlorthalidone, hydrochlorothiazide, or spironolactone), beta-blocker (eg, atenolol, carvedilol or metoprolol) and diabetic therapy (eg, control of high blood pressure or blood sugar, or reduction of dietary salt intake).

malignant neoplasm

The antibody molecule described herein can be used to treat or prevent cancer. Illustrative cancers that can be treated or prevented by the antibody molecules described herein include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-associated Kaposi's sarcoma lymphoma, primary central nervous system (CNS) lymphoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (eg, Ewing's sarcoma or osteosarcoma, and malignant fibrous histiocytoma ), brain tumor (eg, astrocytoma, cerebral glioma, atypical teratoid/rhabdoid tumor of the central nervous system, embryonic tumor of the central nervous system, germ cell tumor of the central nervous system, craniopharyngioma, or ependymoma), breast cancer, bronchial tumor, Burkitt's lymphoma , carcinoid tumor (eg, gastrointestinal carcinoid tumor), cardiac (heart) tumor, fetal tumor, germ cell tumor, lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye malignancy (eg, intraocular melanoma or retinoblastoma), fallopian tube cancer, fibrous histiocytoma of bone, osteosarcoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor (eg, central nervous system tumor, extracranial tumor, extragonadal tumor, ovarian or testicular cancer), gestational trophoblastic disease, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor , pancreatic neuroendocrine tumor, Kaposi's sarcoma, kidney cancer (eg, renal cell carcinoma or Wilms' tumor), Langerhans cell histiocytosis (LCH), laryngeal cancer, leukemia (eg, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), or hairy cell leukemia), lip and mouth cancer, liver cancer, lung cancer (eg, non-small cell lung cancer (NSCLC) or small cell lung cancer), lymphoma (eg, AIDS-related Burkitt's lymphoma , cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or lymphoma of the central nervous system), Waldenström's macroglobulinemia, male breast cancer, malignant fibrous bone histiocytoma and osteosarcoma, melanoma (eg, intraocular (ocular) melanoma), Merkel cell carcinoma, mesothelioma , metastatic squamous cell carcinoma, median tract carcinoma, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myelomas/plasmacyte neoplasms, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, chronic myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer , neuroblastoma, cancer of the oral cavity, cancer of the lip and mouth, cancer of the oropharynx, osteosarcoma and malignant fibrous histiocytoma of the bone, ovarian cancer (eg, epithelial ovarian cancer or germ cell tumor of the ovary), pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors ), papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, peritoneal cancer, prostate cancer, rectal cancer, retinoblastoma, rhabdomyosarcoma, sarcoma salivary gland (Ewing's sarcoma, Kaposi's sarcoma, osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, or uterine sarcoma), Cesari's syndrome, skin cancer (eg, melanoma, Merkel carcinoma, or non-melanoma skin cancer), small intestine cancer, squamous cell carcinoma, testicular cancer, cancer throat, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureters, urethral cancer, endometrial cancer, vaginal cancer, vulvar cancer or their metastatic lesion.

In one embodiment, the cancer is a hematologic cancer, e.g., lymphoma or leukemia, e.g., selected from non-Hodgkin's B-cell lymphoma, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, multiple myeloma, Waldenström's macroglobulinemia, or lymphoplasmic lymphoma. In one embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is a solid tumor selected from, for example, colorectal cancer, breast cancer (eg, breast carcinoma), esophageal cancer (eg, esophageal adenocarcinoma), brain cancer (eg, glioblastoma), or kidney cancer. (eg, renal carcinoma).

In one embodiment, the antibody molecule is used to treat lymphoma. Other therapies that can be used in combination with the antibody molecule described herein for the treatment of lymphoma include, for example, chemotherapy, immunotherapy, targeted drug therapy, radiation therapy, and stem cell transplantation. Exemplary targeted drug therapy includes a CD20 inhibitor (eg, rituximab (RITUXAN® or ibritumomab tiuxetan (ZEVALIN®)).

In one embodiment, the antibody molecule is used to treat leukemia. Other treatments that can be used in combination with the antibody molecule described herein for the treatment of leukemia include, for example, chemotherapy, immunotherapy, targeted drug therapy, radiation therapy, and stem cell transplantation. Illustrative targeted drug therapy includes a tyrosine kinase inhibitor (eg, imatinib (GLEEVEC®).

In one embodiment, the antibody molecule is used to treat multiple myeloma. Other therapies that can be used in combination with the antibody molecule described herein for the treatment of multiple myeloma include, for example, chemotherapy, corticosteroids, immunotherapy, targeted drug therapy, radiation therapy, and stem cell transplantation. Exemplary targeted drug therapy includes, for example, a thalidomide analog (eg, thalidomide (THALOMID®), lenalidomide (REVLIMID®), or pomalidomide (POMALYST®)).

In one embodiment, the antibody molecule is used to treat Waldenstrom's macroglobulinemia. Other therapies that can be used in combination with the antibody molecule described herein to treat Waldenström's macroglobulinemia include, for example, plasmapheresis, chemotherapy, immunotherapy, targeted drug therapy, and stem cell transplantation.

In one embodiment, the antibody molecule is used to treat colorectal cancer. Other treatments that can be used in combination with the antibody molecule described herein for the treatment of colorectal cancer include, for example, surgery, chemotherapy, radiation therapy, immunotherapy, and targeted drug therapy. Illustrative targeted drug therapy includes, for example, a VEGF inhibitor (eg, bevacizumab (AVASTIN®)), an EGFR inhibitor (eg, cetuximab (ERBITUX®), panitumumab (VECTIBIX®)) and a VEGFR2-TIE2 dual tyrosine kinase inhibitor (eg, regorafenib (STIVARGA ®)).

In one embodiment, the antibody molecule is used to treat breast cancer, such as breast carcinoma. Other treatments that can be used in combination with the antibody molecule described herein for the treatment of breast cancer include, for example, surgery, chemotherapy, radiation therapy, hormonal therapy, immunotherapy, and targeted drug therapy. Illustrative targeted drug therapy includes, for example, a HER2 inhibitor (eg, trastuzumab (HERCEPTIN®), pertuzumab (PERJETA®), ado-trastuzumab (KADCYLA®), or lapatinib (TYKERB®)) or a VEGF inhibitor (eg, bevacizumab (Avastin®) ).

In one embodiment, the antibody molecule is used to treat cancer of the esophagus, such as esophageal adenocarcinoma. Other treatments that can be used in combination with the antibody molecule described herein for the treatment of esophageal cancer include, for example, surgery, chemotherapy, radiation therapy, and immunotherapy.

In one embodiment, the antibody molecule is used to treat brain cancer, such as glioblastoma. Other treatments that can be used in combination with the antibody molecule described herein for the treatment of brain cancer include, for example, surgery, chemotherapy, radiation therapy, radiosurgery, immunotherapy, and targeted drug therapy. Exemplary targeted drug therapy includes, for example, a VEGF inhibitor (eg, bevacizumab (AVASTIN®)).

In one embodiment, the antibody molecule is used to treat kidney cancer, such as renal carcinoma. Other therapies that can be used in combination with the antibody molecule described herein for the treatment of kidney cancer include, for example, surgery, cryosurgery, radiofrequency ablation, radiation therapy, immunotherapy, and targeted drug therapy. Illustrative targeted drug therapy includes, for example, a VEGF inhibitor (eg, bevacizumab (AVASTIN®)), a tyrosine kinase inhibitor (eg, axitinib (INLYTA®), pazopanib (VOTRIENT®), sorafenib (NEXAVAR®), or sunitinib (SUTENT®), or an inhibitor mTOR (eg, temsirolimus (TORISEL®) or everolimus (AFINITOR®).

Immunoproliferative Disorders

The antibody molecule described herein can be used to treat or prevent an immunoproliferative disorder. Immunoproliferative disorders (also known as immunoproliferative diseases or immunoproliferative neoplasms) are immune system disorders characterized by abnormal proliferation of primary cells of the immune system (eg, B cells, T cells, and natural killer (NK) cells) or excessive production of immunoglobulins (eg. , antibodies).

Typical immunoproliferative disorders include, but are not limited to, lymphoproliferative disorders (LPD), hypergammaglobulinemia, and paraproteinemia. Lymphoproliferative disorders include several pathological conditions in which lymphocytes are overproduced. They usually occur in patients who have compromised the immune system. Hypergammaglobulinemia is often characterized by elevated serum immunoglobulin levels. Paraproteinemia or monoclonal gammopathy is the presence of an excess of one monoclonal gammaglobulin (eg, paraprotein) in the blood. In one embodiment, the antibody molecule is used to treat monoclonal IgA hypergammaglobulinemia.

Vasculitis

The antibody molecule described herein can be used to treat or prevent vasculitis. Vasculitis is a group of disorders that destroy blood vessels when they become inflamed. Vasculitis is mainly caused by leukocyte migration and consequent damage. Illustrative types of vasculitis include, but are not limited to, microscopic polyarteritis (polyangiitis), Wegener's granulomatosis, Henoch-Schonlein purpura, and polyarteritis nodosa.

In one embodiment, the antibody molecule is used to treat Henoch-Schonlein purpura (IgA-associated vasculitis).

Henoch-Schonlein purpura (HSP, also known as anaphylactoid purpura, rheumatic purpura, or Henoch-Schonlein purpura) is a skin and other organ disease that most commonly affects children. HSP is a systemic vasculitis (inflammation of the blood vessels) and is characterized by the deposition of immune complexes of IgA and complement component 3 (C3) on arterioles, capillaries and venules. In the skin, the disease causes palpable purpura (small hemorrhages); often with joint and abdominal pain. With kidney damage, there may be loss of small amounts of blood and protein in the urine; in a small number of cases, kidney involvement progresses to chronic kidney disease even with irreversible kidney damage. HSP is often preceded by an infection, such as a throat infection.

Symptoms of Henoch-Schonlein purpura include, for example, a rash (purpura), swollen or painful joints (arthritis), gastrointestinal symptoms (such as abdominal pain, nausea, vomiting, or bloody stools), and kidney damage (such as protein or blood in urine). The level of IgA in the serum of patients with HSP is high.

Standards for defining Henoch-Schonlein purpura include, for example, the 1990 American College of Rheumatology (ACR) classification (Mills et al. (1990). Arthritis and Rheumatism 33 (8): 1114-21), the 1994 Chapel Hill Consensus Conference ( CHCC) (Jennette et al. (1994) Arthritis and Rheumatism 37 (2): 187-92), as well as the 2006 European League Against Rheumatism (EULAR) and Society for Pediatric Rheumatology (PRES) classification, which include a mandatory criterion for palpation purpura with at least one of the following findings: diffuse abdominal pain, predominant IgA deposition (confirmed by skin biopsy), acute arthritis in any joint, and renal failure (as evidenced by the presence of blood and/or protein in the urine) (Ozen et al (2006) Annals of Rheumatic Diseases 65 (7): 936-41).

Other therapies that can be used in combination with the antibody molecule described herein for the treatment of Henoch-Schonlein purpura include, for example, analgesics for abdominal and joint pain, steroids (for example, oral steroids, or a combination of intravenous methylprednisolone (a steroid ), cyclophosphamide and dipyridamole followed by prednisone). Other regimens also include, for example, steroids/azathioprine and steroids/cyclophosphamide (with or without heparin and warfarin) or intravenous immunoglobulin (IVIG).

In another embodiment, the antibody molecule is used to treat acute proliferative glomerulonephritis, such as after streptococcal glomerulonephritis.

Acute proliferative glomerulonephritis is a disorder of the glomeruli (glomerulonephritis) or small blood vessels in the kidney. It is a common complication of bacterial infections, typically skin infections with streptococcal bacteria types 12, 4, and 1 (impetigo), and after strep pharyngitis, for which it is also known as post-infectious or post-streptococcal glomerulonephritis. The infection causes blood vessels to form in the inflamed kidneys, which interferes with the ability of the kidney organs to filter urine.

The pathophysiology of this disorder is consistent with an immune complex mediated mechanism. This disorder produces proteins that have different antigenic determinants, which in turn have affinity for sites in the glomerulus. As soon as binding to the glomerulus occurs through interaction with properdin, complement is activated. Complement fixation induces the generation of additional inflammatory mediators.

Symptoms of acute proliferative glomerulonephritis include, for example, hematuria, oliguria, edema, hypertension, fever, headache, malaise, anorexia, and nausea.

Other therapies that can be used in combination with the antibody molecule described herein to treat acute proliferative glomerulonephritis include, for example, blood pressure (BP) control and potassium control in individuals with an acute phase of oliguric kidney injury.

Autoimmune disorders

The antibody molecule described herein can be used to treat or prevent an autoimmune disorder. Exemplary autoimmune disorders that can be treated or prevented with the antibody molecule described herein include, without limitation, acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia, amyloidosis, ankylosing spondylitis, anti -GBIM/анти-TBM нефрит, антифосфолипидный синдром (APS), аутоиммунную ангиодистрофию, аутоиммунную апластическую анемию, аутоиммунную дисфункцию, аутоиммунный гепатит, аутоиммунную гиперлипидемию, аутоиммунный иммунодефицит, аутоиммунную болезнь внутреннего уха (AIED), аутоиммунный миокардит, аутоиммунный оофорит, аутоиммунный панкреатит, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal and neural neuropathies, Balo's disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory polyneuropathia (CIDP), chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, scarring pemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie's myocarditis, CREST disease, essential mixed cryoglobulinemia, demyelinating neuropathies, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis opticoneuritis), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrous alveolitis, giant cell arteritis (temporal arteritis) myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangitis (formerly called Wegener's granulomatosis), Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP) , IgA nephropathy, IgG4-related sclerosing disease, immunoregulatory lipoproteins, myositis with inclusion bodies, interstitial cystitis, juvenile arthritis, juvenile diabetes (type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, arborescent conjunctivitis, linear IgA dermatosis (LAD), lupus erythematosus (SLE), Lyme disease, chronic diseases, Meniere's disease, microscopic polyangitis, mixed connective tissue disease (MCTD), Moray's ulcer, Fly-Habermann's disease, multiple sclerosis, myasthenia gravis gravis, myositis, narcolepsy, neuromyelitis optica (Devika), neutropenia, ocular scarring pemphigoid, optoneuritis, palindromic rheumatism, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, Parsonage-Turner syndrome, Pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, autoimmune polyglandular syndromes type I, II and III, polymyalgia, rheumatism, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, prioderma gangrenosum, aplasia vera, Raynaud's disease, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, recurrent polychondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, sclerosis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff man syndrome, subacute septic endocarditis (SBE), Susak's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis/giant cell arteritis , thrombocytopenic purpura (TTP), Tholos-Hunt syndrome, transverse myelitis, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vesiculobullous dermatosis, vitiligo, Wegener's granulomatosis (also known as granulomatosis with polyangitis (GPA ).

In one embodiment, the autoimmune disorder is rheumatoid arthritis, systemic lupus erythematosus, linear IgA bullous dermatosis (eg, linear immunoglobulin A (IgA) dermatosis), or IgA-mediated acquired epidermolysis bullosa.

In one embodiment, the antibody molecule is used to treat rheumatoid arthritis. Other therapies that can be used in combination with an antibody molecule described herein for the treatment of rheumatoid arthritis include, for example, an NSAID, a steroid (e.g., a corticosteroid), a disease-modifying antirheumatic drug (DMARD) (e.g., methotrexate (TREXALL®), leflunomide (ARAVA®), hydroxychloroquine (PLAQUENIL®), or sulfasalazine (AZULFIDINE®), biological response modifier (eg, abatacept (ORENCIA®), adalimumab (HUMIRa®), anakin (KINERET®), sertolizumab (CIMZIA ®), etanercept (ENBREL®), golimumab (SIMPONI®), infliximab (REMICADE®), rituximab (RITUXAN®), and tocilizumab (ACTEMRA®), or tofacitinib (XELJANZ®)), or surgery.

In one embodiment, the antibody molecule is used to treat systemic lupus erythematosus. Other treatments that can be used in combination with an antibody molecule described herein for the treatment of rheumatoid arthritis include, for example, an NSAID, an antimalarial drug (eg, hydroxychloroquine (PLAQUENIL®), a corticosteroid (eg, prednisone), an immunosuppressant (eg, azathioprine (IMURAN®, AZASAN®), mycophenolate (CELLCEPT®), leflunomide (ARAVA®), or methotrexate (TREXALL®)) or a BAFF inhibitor (eg, belimumab (BENLYSTA®).

In one embodiment, the antibody molecule is used to treat linear IgA bullous disease (eg, linear immunoglobulin A (IgA) dermatosis). Other therapies that can be used in combination with an antibody molecule described herein to treat linear IgA bullous disease (eg, linear immunoglobulin A (IgA) dermatosis) include, for example, corticosteroids (eg, prednisone or prednisolone ), an antibiotic (eg, tetracycline, erythromycin, sulfapyridine), colchicine, or mycophenolate mofetil.

In one embodiment, the antibody molecule is used to treat IgA-mediated acquired epidermolysis bullosa. Other treatments that can be used in combination with the antibody molecule described herein for the treatment of IgA-mediated epidermolysis bullosa acquisita include, for example, an antibiotic, an anti-inflammatory drug (eg, a corticosteroid), or surgery.

Other disorders

The antibody molecule described herein can be used to treat or prevent other disorders such as IgA pemphigus, celiac disease, or alcoholic cirrhosis.

In one embodiment, the antibody molecule is used to treat or prevent IgA pemphigus. Other therapies that can be used in combination with the antibody molecule described herein to treat IgA pemphigus include, for example, a corticosteroid, an immunosuppressant (eg, azathioprine (IMURAN®), methotrexate (TREXALL®), or mycophenolate mofetil ( CELLCEPT®)), a CD-20 inhibitor (eg, rituximab (RITUXAN®), an antibiotic, antiviral, or antifungal agent.

In one embodiment, the antibody molecule is used to treat or prevent celiac disease. Other treatments that can be used in combination with the antibody molecule described herein for the treatment of celiac disease include, for example, a gluten-free diet, vitamin or mineral supplement, or steroid.

In one embodiment, the antibody molecule is used to treat or prevent alcoholic cirrhosis. Other treatments that can be used in combination with the antibody molecule described herein for the treatment of alcoholic cirrhosis include, for example, an immunosuppressant (eg, azathioprine, prednisone, azathioprine, cyclosporine, or methotrexate) or liver transplantation.

Combination Therapies

Antibody molecules can be used in combination with other therapies. For example, a combination therapy may include an antibody molecule co-formulated and/or co-administered with one or more additional therapeutic agents, such as one or more additional therapeutic agents described herein. In other embodiments, the antibody molecules are administered in combination with other forms of therapeutic treatment, such as other forms of therapeutic treatment described herein. Such combination therapy may advantageously use lower doses of administered therapeutic agents, thus avoiding the possible toxic effects or complications associated with various monotherapies.

As used herein, the term administered "in combination" means that two (or more) different treatments are delivered to a patient before or during the patient's illness. In one embodiment, two or more treatments are delivered prophylactically, for example, before the subject becomes ill or is diagnosed with a disorder. In another embodiment, two or more treatments are delivered to a patient after the disorder has developed or been diagnosed. In some embodiments, delivery of one treatment is still in progress when delivery of the second begins so that they overlap. This is sometimes referred to as "simultaneous" or "parallel delivery". In other embodiments, delivery of one treatment ends before another treatment begins. In some embodiments, the implementation of both cases, the treatment is more effective due to the combined introduction. For example, the second treatment is more effective, e.g., an equivalent effect is observed with a lower degree of the second treatment, or the symptoms are reduced more with the second treatment than would be observed if the second treatment was carried out in the absence of the first treatment, or a similar situation is observed with the first treatment. In some embodiments, the delivery is such that the reduction in a symptom or other parameter associated with the disorder is greater than what would be observed with one treatment received in the absence of the other. The effect of the two treatments may be partially additive, fully additive, or more than additive. The delivery may be such that the effect of the first delivered treatment is still detectable when the second treatment is delivered.

In some embodiments, the additional agent is a second antibody molecule, such as an antibody molecule other than the first antibody molecule. Illustrative antibody molecules that may be used in combination include, but are not limited to, any combination of the antibody molecules listed in Table 1 or 5.

In one embodiment, the antibody molecule is administered in combination with a second therapy to treat or prevent IgA nephropathy.

In one embodiment, the antibody molecule is administered in combination with an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB).

In one embodiment, the antibody molecule is administered in combination with a decoy Fc receptor, such as a soluble Fc receptor. In one embodiment, the soluble Fc receptor is a soluble Fc gamma IIB receptor. In one embodiment, the soluble Fc receptor is SM101/BAX 1810 (Baxalta). In one embodiment, the soluble Fc receptor is administered at a dose of 1 mg/kg to 50 mg/kg, such as 5 mg/kg to 15 mg/kg, 12 mg/kg to 24 mg/kg, or 20 mg/kg to 30 mg/kg.

In one embodiment, the antibody molecule is administered in combination with long acting corticotropin (ACTHAR®). Long-acting corticotropin is an analogue of adrenocorticotropic hormone (ACTH). In one embodiment, long acting corticotropin is administered at a dose of 50U to 150U, eg 80U to 120U, by subcutaneous injection two or three times per week. In an embodiment, long acting corticotropin is administered at a dose of 120 IU by subcutaneous injection, for example once, twice or three times per week.

In one embodiment, the antibody molecule is administered in combination with mycophenolate mofetil (MMF). Mycophenolate mofetil is mycophenolic acid 2-morpholinoethyl ester (MPA), an immunosuppressant and an inhibitor of indosine monophosphate dehydrogenase (IMPDH). In one embodiment, mycophenolate mofetil is administered at a dose of 0.5 g to 2 g, such as 1 g to 1.5 g or 1.5 g to 2 g, orally or intravenously, such as once, twice, or three times a day. day.

In one embodiment, the antibody molecule is administered in combination with bortezomib (VELCADE®). Bortezomib, also known as [(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boric acid, is a proteasome inhibitor. In one embodiment, bortezomib is administered at a dose of 0.5 mg/m2 to 2.5 mg/m2, such as 1 mg/m2 to 1.5 mg/m2, such as every three days or every week.

In one embodiment, the antibody molecule is administered in combination with allopurinol (ZYLOPRIM®). Allopurinol, also known as 1H-pyrazolo[3,4-d]pyrimidin-4(2H)-one, is a purine analogue. In an embodiment, allopurinol is administered at a dose of about 50 to 1000 mg, eg, 100 mg to 600 mg or 200 to 300 mg, orally, eg, once a day or once every other day.

In one embodiment, the antibody molecule is administered in combination with prednisone and/or cyclophosphamide. In one embodiment, prednisone is administered at a dose of 0.2 to 2 mg/kg, eg 0.5 to 1 mg/kg, eg, once a day. In one embodiment, cyclophosphamide is administered at a dose of 0.2 to 2 g, eg 0.5 to 1 g, eg, once a day.

In one embodiment, the antibody molecule is administered in combination with rituximab (RITUXAN®). Rituximab is a chimeric anti-CD20 monoclonal antibody. In one embodiment, rituximab is administered at a dose of 100 mg/m2 to 500 mg/m2, such as 200 mg/m2 to 450 mg/m2 or 300 mg/m2 to 400 mg/m2 intravenously, such as once a week , once every two weeks, once every four weeks, or once every eight weeks.

In one embodiment, the antibody molecule is administered in combination with blisibimod. Blisibimod, also known as A-623 or AMG 623, is a selective B-cell activating factor (BAFF, also known as B-lymphocyte stimulator or BLyS) antagonist.

In one embodiment, the antibody molecule is administered together with budesonide. In one embodiment, budesonide is NEFECON®, an oral composition that releases budesonide.

In one embodiment, the antibody molecule is administered together with valsartan and/or probucol. In one embodiment, valsartan is administered at a dose of 50 mg/day to 200 mg/day, such as 80 mg/day to 160 mg/day. In one embodiment, probucol is administered at a dose of 500 mg/day to 1000 mg/day, such as 700 mg/day to 800 mg/day.

In one embodiment, the antibody molecule is administered in combination with OPL-CCL2-LPM. OPL-CCL2-LPM is a recombinant fusion protein consisting of the human chemokine CCL2 (monocyte chemoattractant protein-1) fused to a truncated form of the enzymatically active A1 domain of Shigella dysenteriae holocytoxin (SA1). In one embodiment, OPL-CCL2-LPM is administered at a dose of 0.001 to 1 mg/kg, such as 0.01 mg/kg to 0.5 mg/kg or 0.05 mg/kg to 0.1 mg/kg. kg, for example, intravenously.

In one embodiment, the antibody molecule is administered in combination with methylprednisolone. In one embodiment, methylprednisolone is administered at a dose of 0.1 mg/kg to 2 mg/kg/day, such as 0.2 mg/kg/day to 1.5 mg/kg/day or 0.5 mg/kg/day kg/day up to 1 mg/kg/day, for example, orally.

In one embodiment, the antibody molecule is administered in combination with sirolimus. Sirolimus, also known as rapamycin, can inhibit IL-2 and other cytokine receptor dependent signal transduction mechanisms by acting on mTOR and thereby blocking T and B cell activation. In one embodiment, sirolimus is administered at a dose of 0.2 mg/day to 2 mg/day, such as 0.5 mg/day to 1 mg/day.

In one embodiment, the antibody molecule is administered in combination with a renin-angiotensin system (RAS) blocker. For example, the RAS blocker may be an angiotensin-converting enzyme (ACE) inhibitor or an AT1 receptor blocker (ARB). Exemplary ACE inhibitors that can be used in combination with an antibody molecule described herein include, for example, benazepril (LOTENSIN®), captopril, enalapril (VASOTEC®), fosinopril, lisinopril (ZESTRIL®), moexipril (UNIVASC®) , perindopril (ACEON®), quinapril (ACCUPRIL®), ramipril (ALTACE®) or trandolapril (MAVIK®). Exemplary AT1 receptor blockers that can be used in combination with the antibody molecule described herein include, for example, candesartan (ATACAND®), eprosartan (TEVETEN®), irbesartan (AVAPRO®), losartan (COZAAR®), olmesartan (BENICAR®) telmisartan (MICARDIS®) or valsartan (DIOVAN®).

In one embodiment, the antibody molecule is administered in combination with fostamatinib. Fostamatinib is a prodrug of the active compound tamatinib (R-406), which is an inhibitor of the spleen tyrosine kinase (Syk) enzyme. In one embodiment, fostamatinib is administered at a dose of about 50 to 200 mg, eg, 100 mg to 150 mg, eg, orally, eg, every day.

In one embodiment, the antibody molecule is administered in combination with paricalcitol. In one embodiment, paricalcitol is administered at a dose of about 0.2 to 2 mg, eg 0.5 mg to 1 mg, eg, every day.

In one embodiment, the antibody molecule is administered in combination with ramipril. In one embodiment, ramipril is administered at a dose of about 0.5 to 5 mg, such as 1 mg to 4 mg or 2 mg to 3 mg, such as every day.

In one embodiment, the antibody molecule is administered in combination with an angiotensin converting enzyme (ACE) inhibitor. In one embodiment, the ACE inhibitor is enalapril (VASOTEC®).

In one embodiment, the antibody molecule is administered in combination with an immunosuppressant. In one embodiment, the immunosuppressant is tacrolimus. Tacrolimus, also known as FK-506 or fujimycin, is a macrolide calcineurin inhibitor.

In one embodiment, the antibody molecule is administered in combination with omega-3 fatty acids.

In one embodiment, the antibody molecule is administered in combination with CCX168. CCX168 is an oral C5aR inhibitor.

Exemplary therapies that can be used in combination with an antibody molecule or composition described herein to treat or prevent other disorders are also described in the Methods for Treating or Preventing Diseases section of this specification.

Diagnostic methods

In some aspects, the present disclosure provides a diagnostic method for detecting the presence of APRIL in vitro (eg, in a biological sample, such as a biopsy or blood sample) or in vivo (eg, in vivo imaging in a patient). The method includes: (i) contacting a sample with an antibody molecule as described herein, or administering an antibody molecule to a patient; (optionally) (ii) contacting a control sample, such as a control sample (eg, a biological control sample, such as a biopsy or a blood sample) or a patient control, with an antibody molecule described herein; and (iii) detecting the formation of a complex between the antibody molecule and APRIL in the sample or in the patient or in the control sample or in the control patient, where a change, for example, a statistically significant change, in the formation of the complex in the sample or in the patient relative to the control sample or patient is indicative of availability of APRIL in the sample. An antibody molecule may be labeled directly or indirectly with a detectable substance to facilitate detection of bound or unbound antibody. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent substances, luminescent substances and radioactive substances, as described above and described in more detail below.

The term "sample" when referring to samples used to detect a polypeptide (e.g., APRIL) or a nucleic acid encoding a polypeptide includes, but is not limited to, cells, cell lysates, proteins or membrane extracts of cells, biological fluids such as blood, or tissue samples such as biopsies.

The formation of a complex between an antibody molecule and APRIL can be detected by measuring or visualizing either the antibody molecule bound to APRIL or the unbound antibody molecule. Any suitable detection assays can be used, and common detection assays include enzyme-linked immunosorbent assays (ELISA), radioimmunoassay (RIA), or tissue immunohistochemistry. As an alternative to labeling an antibody molecule, the presence of APRIL can be analyzed in a sample using a competitive immunoassay using detectable labeled standards and an unlabeled antibody molecule. In this assay, a biological sample, labeled standards, and an antibody molecule are combined and the amount of labeled standard bound to an unlabeled binding molecule is determined. The amount of APRIL in a sample is inversely proportional to the amount of labeled standard bound to the antibody molecule.

The antibody molecules described herein can be used to diagnose disorders that can be treated or prevented using the antibody molecules described herein. The detection or diagnostic methods described herein may be used in combination with other methods described herein to treat or prevent the disorder described herein.

EXAMPLES

Example 1 Immunization and selection of antibodies against APRIL.

Female CD-1 IGS mice (outbred) (weighing 20-25 g), aged 7-8 weeks, were immunized intraperitoneally (ip) with 10 μg of recombinant oligomeric FLAG-ACRP30 headless APRIL, referred to here as FLAG-ACR-APRIL. For the purposes of potentially generating a cross-species anti-APRIL (mouse and human) antibody response, both autologous and heterologous immunizations were performed and included the use of human and/or murine APRIL as immunogens. FLAG-labeled APRIL immunogens were prepared in a 200 µl volume consisting of 100 µl sterile PBS and 100 µl RIBI emulsified adjuvant system (Sigma Aldrich) consisting of a defined mixture of monophosphorylpyridic acid A (MPL isolated from Salmonella minnesota ) and synthetic trehalose dicorinomycolate ( TDM, an analog of trehalose dimycolate from tubercle bacillus cordofactor). 3 mice per group were immunized twice a week for four weeks. Anti-APRIL serum antibody titers were then detected by indirect ELISA using FLAG-GCN4 APRIL, R&D Systems. Briefly, 50 ng of FLAG-GCN4 hAPRIL (105-250) or FLAG-GCN4 mAPRIL (96-241) in PBS was coated on 96-well Maxisorp flat bottom plates (NUNC # 439454) overnight at 4°C. The coated plates were blocked in 1x blocking buffer containing 5% BLOTTO™ in PBS and 0.05% Tween-20 (PBST) for 1 hour at room temperature. All subsequent incubation steps were followed by an intermediate washing step 3 times in PBST. Anti-APRIL antibody titers were determined from fold dilutions of mouse sera (in PBS) starting at 1:1000 followed by incubation with 1:5000 HRP-conjugated rabbit anti-mouse IgG (Jackson Immunoresearch Laboratories) for 1 hour at room temperature. Ig reactivity against APRIL was visualized using 100 μl/well of freshly prepared TMB substrate (KPL). Colorimetric development was carried out for 10 minutes at room temperature before the enzymatic reaction was suppressed by adding 100 μl of 1N sulfuric acid and quantified by absorbance at 450 nm. Mice with strong seropositive titers against the primary immunogen (human or mouse APRIL) were challenged by tail vein injection three days prior to sacrifice, spleen removal and splenocyte fusion isolation. Mice with preferential cross-species cross-reactivity based on serum profiling have been noted.

P3X63Ag8.653 plasmacytomas (ATCC # CRL-1580), referred to herein as P3X cells, were used as a source of fusion partner myeloma. B cells isolated from the spleen were immortalized using published modified methods. Briefly, P3X cells were cultured for at least 1 week prior to use and maintained in logarithmic phase to achieve target cell densities of 6×10 ⁵ and 1.2×10 ⁶ cells/mL and with 95% viability the day before. subsequent fusion of splenocytes. Spleen cells were isolated from 2-3 mice per immunization group after euthanasia and cardiac puncture and harvested in DMEM+1% antibiotic (penicillin/streptomycin) and then gently washed by centrifugation (2X) until tissue debris formed and the suspended splenocytes were clarified. The splenocytes were then pelleted by centrifugation for 10 min at 400xg at 4° C. and the erythrocytes were lysed at room temperature for 5 minutes after the cell pellet was carefully resuspended in 1X erythrocyte lysis buffer. Splenocytes were harvested by centrifugation (2X) after dilution with ice-cold DMEM. P3X cells were also washed 3 times in DMEM before confluence.

Mouse splenocytes were fused with P3X cells in fusion medium (50% PEG 1450, Sigma Aldrich)) at a ratio of 3:1 according to established methods. Briefly, pre-warmed PEG was gradually added to the precipitated mixture of splenocytes and P3X cells (37° C. with gentle resuspension) followed by gradual addition of pre-warmed DMEM. The fused cells were harvested by low speed centrifugation and resuspended in hybridoma selective media (hypoxanthine-aminopterin-thymidine, Sigma Aldrich) followed by incubation at 37° C. for 30 minutes. The fused cells were seeded in a 96-well plate at a density of approximately 2×10 ⁶ spleen cells per plate (20,000 cells per well).

Hybridoma supernatants were screened by ELISA on day 14 post-fusion as described (Example 2). Briefly, conditioned medium supernatants were quantified for total IgG by bioinferometry using the AMC Mouse IgG Quantification Kit (Pall Biosciences). Supernatants from hybridoma conditioned media were normalized to 10 μg/ml when possible and analyzed for APRIL reactivity for both FLAG-GCN4-hAPRIL and FLAG GCN4-mAPRIL as described. To exclude clones with strong immunoreactivity to specific FLAG or ACRP30 epitopes (optional epitopes present in the parent immunogen), an intermediate screen using a non-APRIL FLAG-tagged protein (FLAG-ACR30-myc-his) was also included. APRIL-positive hybridomas (human APRIL or mouse) were screened for receptor blocking activity by ELISA as described in Example 3. Briefly, recombinant TACI-Fc was coated on Maxisorp 96-well plates at 100 ng/well at 0 1 M carbonate-bicarbonate buffer (pH 9.6) overnight at 4°C. The plates were blocked with 1% BSA in 1xPBS for 1 hour at 37°C and then washed 3 times in 1x PBST (with 0.025% Tween). Recombinant FLAG-labeled APRIL (mouse or human) at 50 ng/mL was premixed in binding buffer with supernatant from hybridoma media normalized to 10 μg/mL IgG when possible. Anti-APRIL antibody was preincubated for 1 hour at 30°C with shaking prior to addition to TACI-Fc coated plates, followed by 1 hour incubation also at 30°C. Detection of TACI-Fc bound FLAG-APRIL was quantified using an HRP-conjugated anti-FLAG M2 antibody (Sigma Aldrich) used at a 1:10,000 dilution as described in Example 3. APRIL-immunoreactive hybrids that also showed inhibition at least 10% for either human APRIL or mouse APRIL, subcloned by limited dilution and reassessed for APRIL binding and blocking activity and IgG titer by ELISA as described herein. Hybridomas with positive activity but low IgG titer were further isotyped to identify potential IgM-producing clones. Positive hybridomas were selected for culture scale-up, antibody purification and further characterization as described in Example 2.

Example 2 Purification and characterization of anti-APRIL antibodies derived from mouse hybridomas

Thirteen hybridoma clones from Example 1 were cultured sequentially on a larger scale from 96-well plates to 24-well plates and then into T150 flasks (20 ml volume). Prior to purification, cells were transferred from HAT selective media to predetermined low Ig media. Supernatants were collected 3-5 days after medium transfer and clarified by centrifugation followed by sterile filtration through 0.22 μm PES membranes (Corning). IgG titers were confirmed by bioinferometry as described herein. Supernatants were diluted 1:1 using 2x Protein G binding buffer (1 M glycine, 2 M NaCl, pH 9). Antibodies were purified by Protein G affinity chromatography using 1 ml Protein G HiTrap columns (GE Health Care) at a flow rate of 1 ml/min and according to the manufacturer's recommendations. IgG was eluted from the Protein G column by lowering the pH using 0.1 M glycine buffer, pH 2.8 followed by immediate neutralization using 2 M TRIS, pH 8.5. Purified antibodies were re-prepared by dialysis in 1x PBS, pH 7.4 followed by concentration by ultrafiltration using an AMICON Ultra-30 filtration device with a molecular weight cutoff of 30 kDa. The final concentration of antibodies was determined spectrophotometrically using NanoDrop using the generalized optical density coefficient for mouse antibodies (IgG1). The purity and integrity of the antibodies was confirmed by SDS-PAGE under both reducing and non-reducing conditions. The isotype of the antibody was determined using a Rapid ELISA mouse mAb isotyping kit (Pierce/Thermofisher Scientific) in combination with preliminary sequence analysis (see Example 3). All purified antibodies were determined to be predominantly of IgG1 and G2a distribution; the light chains were determined to be of the kappa class. A relatively smaller subset of anti-APRIL immunoreactive antibodies derived from B-002/B-003 mice (e.g., 02-009, 02-016, 046, FIG. 1A-1B) was determined to be IgM and was not tolerated for the cleaning.

Purified antibodies were further characterized for APRIL binding, APRIL cross-species cross-reactivity (human APRIL vs mouse APRIL), and receptor blocking activity using TACI-Fc. For binding, an indirect APRIL-based ELISA was used to determine, as a first approximation, the relative affinity of purified anti-APRIL antibodies for human APRIL or mouse APRIL. The ELISA method was generally the same as described above. Briefly, HA-GCN4 hAPRIL (amino acid residues 105-250) and HA-GCN4 mAPRIL (amino acid residues 96-241) were coated at a density of 50 ng/well. The blocking and washing steps were performed as described herein. The binding of anti-APRIL antibodies to APRIL was quantified using an 8-point dilution of test antibody that spanned four log scales. Antibody binding to APRIL was detected using rabbit anti-mouse IgG (H+L)-HRP conjugate (Jackson ImmunoResearch Laboratories). Antibody binding data were analyzed by non-linear regression analysis using a three-parameter fit to determine maximum binding and apparent EC ₅₀ values. The results are shown in FIG. 3. Human specific monoclonal antibodies against APRIL h01A (described, for example, in Guadagnoli, M. et al. Blood 117, 6856-6865 (2011)), described here as mAb 1313 and A019C11 (described, for example, in Jagessar S. et al J Neuroimmune Pharmacol 7: 557-570 (2012)), referred to herein as mAb 0201, was used as a positive control for binding to human APRIL and for comparative purposes. Apry-1-1 mouse specific antibody (Adipogen) was also used to quantify antibody binding to mouse APRIL.

Anti-APRIL antibody receptor blocking activity was also measured by ELISA using recombinant TACI or BCMA (extracellular domain(s)) expressed and purified as Fc fusion proteins in a competition-based binding experiment. For this experiment, recombinant TACI-Fc or BCMA-Fc was generated in HEK 293 cells after transient transfection of these cells using the pc-tPA-Fc Fc expression vector. Briefly, this vector was constructed from the parental mammalian expression vector pcDNA3.1 (Life Technologies) using standard molecular cloning techniques. The vector was designed to include the 5' Kozak consensus translation initiation sequence and then the N-terminal tPA signal sequence for processing and optimized secretion of the recombinant protein into the medium as a soluble protein. The C-terminus of the extracellular APRIL-binding domains of human TACI or human BCMA were fused in-frame to the Fc portion of human IgG1 starting at position E98 in CH1. DNA sequences were synthesized according to codon optimization for mammalian expression and initially cloned into pcDNA3.1, typically as a Bam H1-Xba cassette. The receptor variants were cloned into the resulting vector as Asc1-Bbs1 or Asc1-Not1 DNA fragments depending on the construction and cloning strategy. TACI-Fc contains the human TACI 29-110 sequences, which include both the CRD1 and CRD2 domains, and generally corresponds to the TacI-Fc decoy receptor. This sequence is described herein as HuTACI-Fc-001 (or more commonly as TACI-Fc unless otherwise noted). The TACI variant, also expressed as an Fc fusion protein, includes only CRD2. TACI may include a C-terminal region (or so-called "stalk") from amino acids 110 to about 166, which immediately precedes the transmembrane domain. BCMA-Fc contains an extracellular cytokine binding domain (amino acid residues 1-54) and is described herein as HuBCMA-Fc-001 (or more commonly as BCMA-Fc unless otherwise noted).

Recombinant TACI-Fc or BCMA-Fc was coated on 96-well plates in 0.1 M carbonate-bicarbonate buffer (pH 9.6) overnight at 4°C. The plates were washed three times with 1xPBST (PBS+0.025% Tween 20) followed by blocking with 1% BSA in 1xPBS, 37°C for 1 hour. All subsequent washing steps were performed with 1xPBST. To assess antibody blocking, either 15 ng/mL or 50 ng/mL HA-GCN4-huAPRIL was pre-incubated with various antibody concentrations ranging from 0.03 to 30 μg/mL in a binding buffer consisting of 1% BSA and 0.025% Tween -20 in 1X PBS. Pre-incubation was carried out at 30°C for 1 hour with stirring. The anti-APRIL antibody premix with 50 ng/ml APRIL or 15 ng/ml APRIL was then added to TACI-Fc or BCMA-Fc coated plates, respectively, and incubated for another hour at 30°C. HA-labeled APRIL binding to any receptor was quantified using a goat polyclonal anti-HA HRP-labeled antibody (Abcam) added at a 1:10,000 dilution followed by colorimetric development using 100 µl/well of freshly prepared TMB substrate (KPL) for 30 minutes at room temperature before suppressing the enzymatic reaction by adding 1N sulfuric acid. The ELISA signal was quantified by absorbance at 450 nm. The results are shown in FIG. 2A-2B and FIG. 3. ELISA data were analyzed by non-linear regression. IC ₅₀ values were calculated based on four parameter fitting of antibody titration curves. Where appropriate, % inhibition is calculated based on data normalization with no antibody control (0% inhibition) against background (no APRIL) set to 100% inhibition. Human antibodies mAb 1313 and mAb 0201 were used as positive controls and for comparative purposes. Aprly-1 or Aprly-5 non-blocking antibodies (Enzo Biosciences) were used as a negative control. The mouse-specific blocking antibody aprily-1-1 (Adipogen) was commonly used as a positive control in experiments using mouse APRIL (HA-GCN4-mAPRIL).

The functional activity of anti-APRIL antibodies was also assessed using a cellular receptor signal transduction assay. In this assay, APRIL binding to either TACI or BCMA results in receptor activation, which in turn leads to subsequent activation of NF-κB, a transcription factor that ultimately mediates programmed changes in B cell gene expression and phenotype. The use of known NF-κB reporter cell lines for this purpose has been described in the literature. The use of heterologous (non-lymphoid) cell lines lacking TACI or BCMA expression, but where TACI or BCMA can be introduced exogenously via transfection, allows for a controlled receptor-mediated assay of APRIL signaling and inhibition of this signal by anti-APRIL antibodies. For this purpose, a commercial NF-κB reporter cell line derived from 293TN cells, NF-κB/293/GFP-LucTM (System Biosciences) was chosen. These cells were stably transfected with both GFP and firefly luciferase genes, arranged in tandem with transcriptional control of the CMV minimal promoter (mCMV) and multiple copies of the NF-κB recognition element.

NF-κB/293/GFP-LucTM cells were maintained and grown in 293TN cell growth medium (DMEM base medium supplemented with GlutaMAX and FBS) according to the manufacturer's instructions. The expression plasmids pcMV6-XL4/TACI and pcMV6-XL4/BCMA (Origene) were used for transfections. These plasmids encode full-length human TACI (TNFRSF13B, registration number NM_012452) or BCMA (TNFRSF17, registration number NM_001192) 293TN reporter cells were transfected at a density of approximately 6×10 ⁵ cells/ml (>90% viability) using PEI-MAX as follows: For pcMV6-XL4/TACI, 10.4 ng/mL (~ 1 ng/well); for cell culture pcMV6-XL4/BCMA 83 ng/ml (~ 8 ng/well). The total plasmid concentration was kept constant at 1.67 μg/ml culture volume (167 ng/well) using the empty pcMV6-XL4 vector as needed to maintain constant amounts of plasmid for each transfection. Transfections were scaled appropriately based on the number of plates needed. 100 μl of the transfection mixture was transferred to each well. The plates were transferred to a 37°C incubator at 5% CO ₂ for 20-24 hours.

On the second day, recombinant APRIL (HA-GCN4-APRIL) was preincubated with serially diluted antibody in complete 293TN culture medium before being added to the cells. Briefly, for APRIL-mediated activation of TACI signal transduction, 40 ng/ml APRIL (2X concentration of targets) was mixed 1:1 with serially diluted antibody (also diluted in culture medium) in a 96-well plate; for APRIL-mediated activation of BCMA signal transduction, 200 ng/ml APRIL (target concentration 2X) was also mixed 1:1. The antibody-APRIL mixture was incubated for 1 hour at 37° C. with shaking. 40 μl of the preincubated mixture was added to the transfected cell culture after the spent culture media were removed. Cells were incubated at 37°C, as above, for an additional 20-24 hours. NF-κB-driven luciferase activity was then quantified using the ONE-Glo™ Luciferase Kit (Promeg a), essentially following the manufacturer's protocol but with minor modifications. Relative fluorescent units (RLU) were measured on opaque white 96-well plates using a plate reader with a luminometer. The results are presented in FIG.4. Data were normalized to no Ab control after correction for assay background signal (without APRIL). IC ₅₀ values were obtained from non-linear regression analysis of antibody titration curves for a four-parameter fit. Antibodies 1313 and 0201 were commonly used as positive controls. In the case of using recombinant mouse APRIL, apry1-1 was used as a positive control. Non-neutralizing antibodies Aprily-1 or Aprily-5 against human APRIL were commonly used as negative controls.

Example 3 Determination and molecular cloning of anti-APRIL immunoglobulin sequences.

Mouse antibody VH and VL gene sequences derived from hybridoma screening were initially determined by reverse transcription PCR of B cell RNA using a pool of predetermined primer sets specific for mouse Ig sequences of varying degeneracy. The 5' primer design for VH sequencing was based on a comprehensive analysis of the mouse immunoglobulin database with appropriate alignments to variable leader sequences. From this analysis, VH leader sequences were grouped (or sorted based on sequence relatedness and germline "family"representation); a unique set of primers were designed, each predicted to anneal more specifically to these sorted families of VH sequences, and used as a cocktail in the RT-PCR reaction. The 3' primers were designed to anneal in the heavy chain constant region. This primer set was naturally less complex and matched the unique sequences in CH1 that define the four known mouse IgG constant regions (IgG1, IgG2a, IgG2b and IgG3). IgM-bound VH sequences were amplified as described above, but with the 3' primer substitution for the IgM isotype. Similarly, the so-called "pool primer" for RT-PCR was used to amplify the corresponding VL sequences from mouse hybridoma RNA. Similarly, a systematic query of all known mouse VL leader sequences was performed. Because both kappa and lambda light chains do not share constant and variable region sequences, separate primer sets (kappa-specific and lambda-specific) were designed. The 3' primers were designed based on an isotype-specific (kappa vs. lambda) light chain constant region in a manner similar to that described above for the heavy chain sequences. RT-PCR amplification of hybridoma gene sequences from B-cell RNA was performed using other known methods. Briefly, RNA was extracted from 0.5-2×10 ⁶ cells using the RNeasy kit (Life Technologies) according to the manufacturer's instructions. Cell lysis was facilitated using Qiashredder or a related method for the initial extraction of nucleic acids. Purified RNA was quantified by UV absorbance. cDNA synthesis and subsequent PCR amplification (using Platinum Taq polymerase and primer mixtures described above) were performed in tandem using a Superscript III One Step RT-PCR kit (Life Technologies). PCR amplicons were purified using a Qiaquick PCR purification kit (Life Technologies) and quantified by UV absorption at 260 and 280 nm using a Nanodrop spectrophotometer. The PCR products were also analyzed by agarose gel electrophoresis to confirm the predicted size and purified from the gel as needed. The sequences of the VH and VL genes were determined by direct sequencing of PCR products using nested primers. Ambiguous sequence data was followed by re-amplification of cellular RNA by RT-PCR as described above, but with protocol modification and subsets of shorter primers; if necessary, the PCR products were cloned by TA cloning into an intermediate vector) and transformed into TOP10 (Life Technologies) or DH5α (New England Biolabs) chemically competent cells according to the manufacturer's protocols. DNA sequence data were analyzed using public databases (eg, International Immunogenetics Information System (IMGT), VBase, or NCBI Ig-Blast) to evaluate germline usage, identify CDR sequences, and evaluate putative isotype when possible. Overall, the sequencing strategy resulted in the identification of unique VH sequences for each hybridoma of interest; several clones led to the identification of many light chains.

The resulting VH and VL Ig sequences were amplified by PCR and cloned separately into the mammalian expression vectors o-pcMG2 and o-pcMK2, respectively, for recombinant production in HEK293 cells as paired mouse IgG2 (HC) and kappa (LC) isotyped antibodies. Gene-specific primers were designed based on the VH and VL sequences identified as described above. The primer design included 18-23 overlapping nucleotides complementary to the respective framework regions of the variable domain gene sequences, in addition to vector complementary sequences designed to allow recombination-based cloning with a modified Gibson assembly, fused in-frame to the variable region sequences by DNA ligation as described below. Primer design was performed using NEB Builder (New England Biolabs) or Primer3 software. An additional primer design contained the inclusion of restriction endonuclease recognition sequences at the appropriate 5' ends for subcloning, if necessary. In the case of ambiguous variable sequences, primer design included the use of moderately degenerate nucleotide sequences (at positions 1-2) or surrogate ("best guess") codons, based on knowledge of the predicted germline framework sequences identified in the original VH and VL sequence analysis.

For molecular cloning by RT-PCR, RNA was extracted from hybridomas, essentially as described. First strand cDNA was synthesized using Superscript III First Strand Synthesis Supermix (Life Technologies) according to the manufacturer's protocol. 2.5 μl cDNA template DNA was amplified by PCR using high fidelity DNA polymerase Q5 (New England BioLabs). Amplification included a total of 35 cycles with "sensor" PCR using first a three-step amplification for 10 cycles followed by 25 cycles of two-step amplification (annealing and pulling at 72°C). PCR amplicons were evaluated by agarose gel electrophoresis to confirm purity, correct size, and approximate amounts. Gel purification of PCR products was performed, if necessary, using a Qiaquick gel purification kit (Qiagen). Expression vectors HC and LC Ig were linearized and prepared for cloning by double digestion with restriction endonuclease. The 5' ends of the hydrolyzed vectors were then dephosphorylated with shrimp alkaline phosphatase, followed by heat inactivation of the enzymes. PCR products were ligated into 50 ng of linearized vector (purified from gel) using NEB Builder (New England Biolabs) at a 2:1 molar ratio of insert:vector. 2 μl of the ligation mixture was transformed into chemically competent E. coli cells (DH5α, New England Biolabs) and plated on LB with antibiotic. Recombinant clones were selected by colony DNA sequencing followed by 200 ml scale E. coli plasmid purification of positive clones using Purelink Maxiprep low endotoxin kits (Life Technologies) according to manufacturer's protocols.

For the production of recombinant antibodies, approximately 225 μg of each of the purified Ig expression vectors (HC and LC) were used to transiently transfect HEK 293F cells. Approximately 2×10 ⁶ cells/ml were transfected using PEI-Max based transfection reagent and cultured in Freestyle 293 medium for a total of 5-7 days. Antibody titers were quantified by bioinferometry using immobilized Protein A biosensors (Biosensors Pall).

Recombinant antibodies were purified from the culture supernatant after clarification by low speed centrifugation and sterile filtration through 0.22 μm PES membrane followed by the addition of a protease inhibitor cocktail (Cocktail III, Thermofisher) to attenuate the damage of proteolysis. Antibodies were purified by Protein A affinity chromatography using a 1 ml Hitrap Protein A column (GE Healthcare) eluting at low pH as described followed by neutralization with TRIS, pH 8.5. Antibodies were reprepared and concentrated in 1xPBS, pH 7.4 by tandem dialysis and ultrafiltration using Amicon-Ultra 30 centrifugal concentrators.

Example 4 In Vitro Anti-APRIL Antibody Receptor Binding and Blocking Activities

Recombinant anti-APRIL antibodies have been characterized for both APRIL binding activity and receptor blocking using both ELISA-based and cell signaling methods as described herein. As shown in FIG. 5-6, the first indirect ELISA binding approach to human APRIL revealed several antibodies with low and subnanomolar binding affinities for the target cytokine based on EC ₅₀ values extrapolated from non-linear regression analyzes of antibody titration curves. Antibodies 2218, 2419 and 2621 in particular bind to human APRIL with an apparent target binding affinity of less than 0.2 nM; antibodies 3530 and 2922 bound human APRIL with an apparent target binding affinity of 0.2 nM to 1 nM. 3125 bound to human APRIL with lower apparent affinity (> 1 nM). A similar analysis of the binding of monoclonal antibodies to the murine APRIL homologue revealed only mAb 3530 with significant cross-species binding to the target (data not shown). Functional analysis of antibody blocking activity was assessed by competitive ELISA using the Fc receptor as the capture ligand APRIL in a 96-well format as described herein. This analysis included the use of both biologically relevant APRIL TNFR-related receptors (human TACI and human BCMA) to evaluate any selectivity for antibody-mediated APRIL receptor antagonism interactions. As shown in FIG. 9, antibody IC ₅₀ values were calculated from non-linear analysis of antibody titration curves. Blocking antibodies 1313 and 0201 against human proteins were used as positive controls and for comparative purposes. Aprily-5 non-neutralizing antibody (Enzo Biosciences) was used as a negative control. Based on in vitro data, all recombinant antibodies demonstrated at least partial blocking of human APRIL with human TACI-Fc. As shown in FIG. 7, monoclonal antibodies 2218, 2419, 2621, 3327 and 3530 blocked the binding of APRIL-TACI with corresponding IC ₅₀ values in the low or subnanomolar range. mAbs 3125 and 2922 appear to block with slightly less efficiency, with IC ₅₀ values greater than 10 nM. As shown in FIG. 8, a similar evaluation of receptor blocking using BCMA-Fc indicates that antibodies 2218, 2419 and 3327 are also capable of blocking BCMA binding with low or subnanomolar activity. mAb 3530 appears to be relatively selective in blocking APRIL binding to TACI-Fc over BCMA-Fc; thus, this antibody can be considered as "TACI-selective". mAb 2621 does not appear to block APRIL binding to BCMA-Fc as assessed in this assay; mAb 2621 itself can be considered as a potentially "TACI-specific" antibody.

Functional (receptor antagonism) activity of anti-APRIL antibodies was further assessed using an orthogonal, cellular NF-κB transcription reporter assay to assess inhibition of APRIL-mediated receptor signal activation. This assay included heterologous expression of full-length (transmembrane) TACI or BCMA by transient plasmid transfection into HEK293 and an engineered HEK293 cell line containing a stably transfected NF-κB transcriptionally activated luciferase reporter gene. The assay was generally performed as described herein using recombinant Hu APRIL as the exogenous source of the cytokine activating receptor. The data was normalized to no antibody control after background signal subtraction (no APRIL or Ab). The data are summarized in FIG. 11A-11B. Based on these data, the effective receptor blocking activity of monoclonal antibodies 2218 and 2419 was further confirmed in a dose dependent antibody manner. These activities included blocking both BCMA and TACI receptors. Monoclonal antibodies 2922 and 3125 were qualitatively less active, consistent with their relatively lower activity in receptor-Fc blocking ELISA (ie compared to mAbs 2218 and 2419). Apparent discrepancies between the two assays may be due to different levels of receptor expression, protein turnover, or other biological factors not present in less complex ELISA-based binding assays. However, these data taken together demonstrate a clear functional activity of recombinant anti-APRIL antibodies in relation to the antagonism of APRIL activity described herein.

Additional experimental data include, for example, the following. The binding of exemplary anti-APRIL antibodies to human APRIL is shown in FIG. 16. Relative binding affinities of exemplary anti-APRIL antibodies are shown in FIG. 17. Antibody inhibition of APRIL-mediated receptor signaling is shown in FIG. 18A-18B. Antibody inhibition of APRIL binding to TNFSF TACI and BCMA receptors is shown in FIG. 19A-19B. Antibody inhibition of APRIL binding to human TACI-Fc and human BCMA-Fc is summarized in the table in FIG. 20.

Example 5: Cross-species cross-reactivity of antibodies against APRIL

In addition to demonstrating the functional activity of several anti-APRIL antibodies, the cross-reactivity of these antibodies to bind and block both murine and human APRIL was also assessed. For this characterization, the same set of in vitro assays was used as described, but with the inclusion of similar mouse HA-labeled APRIL (R&D Systems). For illustrative purposes, a subset of data from a receptor-Fc blocking ELISA (both TACI-Fc and BCMA-Fc) was included. In this assay, mAb 3530 was compared with antibodies 1313 (human specific blocking antibody against APRIL), Apry-1-1 (mouse specific blocking antibody against APRIL), and non-neutralizing antibody Aprly-5 (negative control). Data on blocking activity of the receptor with antibody titration are summarized in FIG. 10A-10B to block APRIL binding to human TACI-Fc and human BCMA-Fc, respectively. Consistent with other data, mAb 3530 appears to be a "TACI-selective" antibody based on its relative neutralization profile (TACI vs. BCMA). In addition, this antibody is able to clearly block the binding of both murine and human APRIL to TACI-Fc with comparable potency (apparent IC ₅₀ values). To the best of our knowledge, this is the first example of cross-species cross-reactivity of an anti-APRIL antibody with both implications both for epitope specificity and for use in preclinical development of this antibody using appropriate (isogenic) rodent models.

The cross-blocking activity of APRIL anti-APRIL antibodies is also shown in FIG. 21A-21B.

Example 6 Functional activity of an anti-APRIL antibody to reduce serum IgA in vivo

In addition to its role in promoting tumor growth, the cytokine APRIL plays several critical roles in the regulation of adaptive and mucosal immunity in relation to the modulation of B and T cell function. This immunological activity includes the induction of IgA production in B cells through receptor-mediated induction of Ig class switching, B cell proliferation and survival of IgA+ bound plasma cells. This central role of APRIL in IgA production leads to its potential as a therapeutic target for diseases associated with dysregulated IgA production and/or formation of IgA-containing immune complexes. Such diseases include, but are not limited to, IgA nephropathy, IgA-associated vasculitis (e.g. Henoch-Schonlein purpura), SLE, IgA-associated monoclonal gammopathy, alcoholic liver disease, etc. Thus, the biological activity of a therapeutic antibody against APRIL can be assessed in vivo directly by the reduction in serum IgA levels following administration of such an antibody to a laboratory rodent model. To this end, the mouse APRIL-specific blocking antibody Apry-1-1 (Adipogen) used as a control for evaluating the activity of an anti-APRIL antibody in vitro as described herein was also used as a test article. Age group male B6C3F1 mice (6-10 weeks) were injected with 20 mg/kg antibody twice a week via IP injection for 8 weeks. Saline injection was used as a negative control (vehicle). Serum levels of isotype-specific immunoglobulin (IgG, IgM and IgA) were monitored individually by ELISA approximately every 12 days. Body weight was monitored 3 times a week, general and biochemical blood tests and the general condition of the animals were monitored on a regular basis. Blood sampling was performed before dosing (Day 0, before blood sampling). Survival after blood sampling was observed at the end of 2 weeks (end of phase I) at 4 weeks and 6 weeks. Terminal blood sampling was performed at the end of 8 weeks. The results are shown in FIG. 12A-12B.

In this study, chronic administration of a functional anti-APRIL antibody with in vitro proven blocking activity resulted in a decrease in serum IgA levels below 50%. A decrease was observed by day 24 and was maintained during antibody treatment. Anti-mouse APRIL treatment had no statistically significant effect on total serum Ig levels compared to controls; general and biochemical blood tests were also not affected.

Example 7: Epitope Mapping

Variants of human APRIL with site-directed mutations were used for epitope mapping. As shown in FIG. 22, APRIL is shown as a trimer (cyan, green and magenta). A typical epitope containing a high affinity binding site for the CRD2 receptor is depicted in dark blue. Amino acid change positions are marked by the preceding wild-type amino acid number and subsequent mutation (eg, R233G represents a mutation of arginine at position 233 to glycine).

Epitope mapping of exemplary antibodies 4035, 2419, and 3833 was performed. Antibody binding to human and mouse variants was assessed by ELISA. Comparison was made with reference antibody 1313. FLAG-labeled APRIL was captured from the culture medium using an anti-FLAG antibody. The results are shown in FIG. 23A-23B, 24A-24B and 25A-25B. Differentiated epitope mapping of exemplary anti-APRIL antibodies was performed using site-directed mutagenesis. Primary characterization of the human APRIL binding site was performed by site-directed mutagenesis of selected amino acid positions in APRIL followed by evaluation of antibody binding to these variants by ELISA. Illustrative data for three antibodies against APRIL 4035 (solid circles), 2419 (solid squares) and 1313 (open triangles) are shown in FIG. 26 for illustrative purposes.

Differential binding profiles of exemplary anti-APRIL antibodies are shown in Table 6. Exemplary amino acid residues that bind to the anti-APRIL antibody molecules described herein are provided. One or more of these residues form at least a portion of the binding region on APRIL. Exemplary residues in the binding region that are predicted to affect binding (eg, based on site-directed mutagenesis studies described herein) are marked with an "X". Illustrative residues predicted to have little or no effect on binding (eg, based on the site-directed mutagenesis studies described herein) are marked "N" for comparative purposes.

Table 6. Differential binding profiles of exemplary anti-APRIL antibodies (Table discloses SEQ ID NOs: 338-341, respectively, in order of appearance)

1313 4035 3833 2419 Influence No influence Influence No influence Influence No influence Influence No influence AK position AK 129 asp 130 asp 131 Ser 132 asp X 170 Leu 174 Val N X X 175 Thr 176 Phe X X N X 177 Thr 178 Met 179 gly 180 Gln 181 Val X N N X 190 Gln X X N X 192 Thr 195 Arg X X 196 Cys 197 ile 200 Met 201 Pro 202 Ser 203 His 205 asp 206 Arg N X X 208 Tyr X X X N 226 Ser N 228 ile N N X 230 Pro 231 Arg 232 Ala 233 Arg 237 Asn X N N N 241 His

Example 8 Humanization of Mouse Anti-APRIL Antibodies

Selected anti-APRIL antibodies were obtained after mouse immunization as described herein. The variable regions of the selected antibodies, namely 2419, 4035 and 4540, were subsequently humanized for potential therapeutic use and reduced immunogenicity. Briefly, humanization was performed by identifying human germlines proximal to the murine heavy (VH) and light (VL) chain variable regions. Once identified, complementarity determining regions (CDRs) from mAb2419 VH and VL were transplanted into human germline matrices VH and VL, respectively, using a structure-oriented design. Additional mutations (including backmutations to the parent residue in the mouse mAb) were selectively introduced based on visual inspection of the structural model. Humanized antibody constructs were recombinantly produced in HEK293 cells after transient transfection with separate heavy and light chain expression vectors. Recombinant antibodies were purified by Protein A affinity chromatography using standard methods. The humanized antibodies were then tested for APRIL binding, functional receptor blocking (TACI-APRIL and BCMA-APRIL interactions), and thermal stability using protein denaturation differential scanning fluorescence assay. Relative activity and stability profiles were compared with parental mouse antibodies based on humanization.

Example 9: In Vitro Receptor Binding and Blocking Activities of Humanized Anti-APRIL Antibodies

The relative binding of exemplary anti-APRIL antibodies was measured by indirect ELISA. Binding of humanized mouse antibody variants 4035 and 2419 to human APRIL is shown in FIG. 27A-27B, respectively. Binding of a humanized variant of the human-mouse cross-reactive antibody 4540-063 to both human and mouse APRIL is shown in FIG. 28A-28B, respectively. Comparison of humanized anti-APRIL antibodies with parental (non-humanized) mouse antibodies was performed for comparative purposes. The extrapolated EC ₅₀ values are summarized in FIG. 29A-29B. Exemplary antibody molecules bind to APRIL with picomolar affinity.

The apparent binding affinity of antibodies 2419-1406 and 4035-062 to trimeric human APRIL was also measured by ELISA. The APRIL trimer was stabilized by the N-terminal fusion of APRIL with the isoleucine zipper oligomerization domain (GCN4). The binding of APRIL to human TACI-Fc is shown for comparative purposes. The results of ELISA binding are shown in FIG. 29C. Picomolar EC ₅₀ values obtained from the binding curves depicted in FIG. 29C are summarized in FIG. 29D. The antibody showed picomolar (pM) binding to trimeric human APRIL, which was measured by ELISA. A higher binding affinity of 2419-1406 and 4035-062 to APRIL was observed relative to the binding of APRIL to its own receptor (TACI-Fc).

Inhibition of APRIL binding to TNFSF TACI and BCMA receptors was measured using humanized IgG2κ variants of parental mouse antibody 2419. The assay is based on receptor blocking ELISA using recombinant human APRIL (R&D Systems) and human TACI-Fc (FIG. 30A) or BCMA -Fc (FIG. 30B). The parental chimeric 2419 (mouse VH-VL grafted to human IgG1κ constant regions) was included for comparative purposes, as was the chimeric anti-human APRIL antibody 4035. Inhibition was analyzed by non-linear regression using a four-parameter fitted curve after normalization to 100% activity (no antibody control). The IC ₅₀ values are summarized in FIG. 33.

The inhibition of APRIL binding to TNFSF receptors TACI (FIG. 31A) and BCMA (FIG. 31B) was measured with additional humanized variants 2419 (IgG2κ) 2419-0205 and 2419-1406 and humanized version (4035-062) of parental antibody 4035. Humanized 4035-062 belongs to the IgG1κ subtype. Chimeric, non-humanized versions of mouse antibodies 4035 and 2419, and 1313c were included for comparative purposes. mAb1313 is a control antibody against APRIL. TACI-Fc and BCMA-Fc were used. The IC ₅₀ values are summarized in FIG. 33.

The inhibition of APRIL binding to the TNFSF receptors TACI (FIG. 32A) and BCMA (FIG. 32B) was measured with humanized variants of the mouse/human APRIL cross-neutralizing antibody 4540. The humanized antibody 4540 is of the IgG1κ subtype. Parental 4540 (non-humanized chimera) and humanized 4035-062 (FIGS. 30A-30B) were included for comparative purposes. Inhibition was analyzed by non-linear regression using a four-parameter fitted curve as described for FIG. 29A-29B and FIG. 30A-30B. IC ₅₀ values are also summarized in FIG. 33. Subnanomolar blocking of APRIL receptor binding was observed for most of the antibodies tested.

These results reveal that humanization and reformatting (eg, as IgG2) usually, if not always, results in comparable retention of receptor blocking activity.

Antibody inhibition of APRIL-mediated receptor signaling was assessed. Inhibition of APRIL receptor-mediated intracellular NFκB signaling was assessed using the HEK 293 NFκB reporter cell line after transient transfection with either the full-length human TNF receptor family TACI or BCMA cDNA expression vectors. Data were normalized to no antibody control (100%). Inhibition of TACI- and BCMA-mediated NFκB signaling is shown in FIG. 34A-34B, respectively.

FIG. 35 depicts approximate IC ₅₀ values for antibody inhibition of APRIL-mediated receptor signaling. Data extrapolated from FIG. 34A-34B based on non-linear regression analysis using variable slope, three-parameter anti-response antibody concentration fitting. Negative antibody control (no APRIL binding) showed no activity in this assay (data not shown). These results reveal effective inhibition of the APRIL-mediated NFκB-dependent signaling pathway (low or sub-nanomolar IC ₅₀ ) by an exemplary anti-APRIL antibody molecule. Blocking occurs with both the TACI receptor and BCMA.

Example 10 Evaluation of Anti-APRIL Antibody Binding Specificity to APRIL

Selected anti-APRIL antibodies were evaluated for potential cross-reactivity with other members of the TNFa superfamily (TNFSF) of the cytokine family, including: human TNFα (TNFSF2, Adipogen), human CD40 (TNFSF4, Adipogen), human FasL (TNFSF6, Adipogen), human TRAIL ( TNFSF10, Adipogen), human RANKL (TNFSF11, Adipogen), human Tweak (TNFSF12, Abcam), human and mouse BAFF (TNFSF13B, AB Biosciences and Adipogen, respectively), and human LIGHT (TNFSF14, Adipogen). These cytokines share a common degree of sequence variability as well as higher order structural homology. Among them, BAFF appears to be most closely related to APRIL, with 29% identity and 53% amino acid sequence similarity.

Binding was assessed by an indirect ELISA protocol using similar methods as described for assessing APRIL binding; cytokines were immobilized on an ELISA plate at 50 ng per well and then exposed to a solution of each of the tested antibodies at a fixed concentration of 10 μg/ml. Anti-human or mouse Ig-HRP polyclonal antibody conjugates (Jackson Laboratories) were used to detect antibody binding. The results shown in FIG. 36 revealed that eleven of the twelve antibodies tested in this assay bind specifically to APRIL in the absence of any measurable cross-reactivity with other TNFSF members, substantially above assay background. Antibody 4338 showed detectable binding to both human and mouse versions of BAFF and was used as an analytical control.

mAb 2419-1406 and 4035-062 showed minimal or no extraneous protein cross-reactivity in a vast array of over 4500 human membrane proteins (RETROGENIX™). An example of a protein expression array construct is shown in FIG. 37A. Confirmatory/secondary screening was performed on 12 proteins (FIGS. 37B-37C). Binding to Fc receptors was observed for both 2419-1406 and 4035-062 as predicted. Weaker binding to FcγR1 was observed for antibody 2419-1406, consistent with being of the IGg2 isotype. Slight binding to PDGFR was also detected for 2419-1406. Binding of antibodies 4035-062 to any other membrane targets, except those described, was not observed.

Example 11: Identification of a target epitope for maximum efficacy of anti-APRIL antibodies

The epitope of an exemplary anti-APRIL antibody molecule, mAb 2419, was mapped using a combination of empirical and computational tools and data. These methods and the resulting data included 1) low resolution crystallography of mAb 2419 Fab complexed with human APRIL (amino acids 115-250) coupled with 2) structural modeling (FIG. 38A) and 3) saturation mutagenesis of APRIL at selected positions within the surface of APRIL performed in combination with APRIL surface display in yeast (FIG. 38B). As shown in both FIGS. 38A-38B, the antibody molecule targets a non-linear quaternary epitope spanning two different APRIL monomers within a more complex trimeric complex. The 2419 epitope also overlaps significantly with the APRIL region corresponding to the high affinity receptor binding site (CRD2 site) critical for blocking both the TACI receptor and BCMA (FIG. 38B). A secondary receptor binding site (CRD1 site) also overlaps with the 2419 epitope, implying blocking of TACI-APRIL interactions. Based on this analysis, the positions in APRIL that define epitope 2419 include V133, V181, E185, Q187, G188, R189, Q190, E191, T192, R195, H218, L219, H220, S226, I228, P230 (located in the monomer A); V121, I123, Q139, P140, A141, L142, N237, S239, P240 and H241 (located in monomer B).

More targeted analysis of this epitope by mutagenesis of selected surface accessible positions of APRIL indicates a subset of positions in the larger epitope 2419 (depicted structurally in FIG. 38A) that appear to be particularly critical for antibody binding. These so-called "hot residues", ie. those residues that are critical for the interaction between APRIL and mAb 2419 have been empirically defined) using a combination of the methods described above) as those positions where a mutation from the wild-type sequence to almost any other amino acid residue results in a significant loss of 2419 binding to APRIL. Examples of such positions include V181, Q190, T192, and I228 on one monomer, and A141 and H241 on an adjacent monomer.

Table 8 Exemplary amino acid residues of human APRIL that bind to mAb 2419 (amino acid numbering based on SEQ ID NO: 85)

Position Monomer hot residue Human V133 A V181 A Y E185 A Q187 A G188 A R189 A Q190 A Y E191 A T192 A Y R195 A H218 A L219 A H220 A S226 A I228 A Y P230 A V121 B I123 B Q139 B P140 B A141 B Y L142 B N237 B S239 B P240 B H241 B Y

Thus, the epitope overlaps predicted regions for maximum receptor blocking and targets a non-linear quaternary epitope spanning two different APRIL monomers, implying neutralization of the biologically most active form of APRIL (trimer).

Example 12 Pharmaceutical Properties of Anti-APRIL Antibodies.

Thermal stability of exemplary anti-APRIL antibody molecules, 2419-1406 and 4035-062, was measured using the Sypro-Orange® fluorescent scan assay (FIG. 39A). Thermal melt temperatures (Tm values) for 2419-1406 and 4035-062 are shown in FIG. 3. mAb 2419-1406 and mAb 4035-062 show high thermal stability.

The tg32 mouse model was used as a surrogate for PK prediction of antibody pharmacokinetics (PK) in humans. The PK of a control antibody (IgG1) with a preset PK of approximately 25 days (in humans) was also evaluated in this study for comparative purposes. As shown in FIG. 40A-40B, a favorable PK profile of the exemplary anti-APRIL antibody molecule, 2419-1406 and 4035-062, was observed in the tg32 transgenic mouse line carrying the humanized FcRn.

Example 13 Cross-species cross-reactive anti-APRIL antibodies effectively reduce serum IgA levels in mice

Mouse mAb 4540 is a cross-species (mouse and human) anti-APRIL antibody with receptor neutralizing activity. mAb 4540 targets the overlapping APRIL epitope with mAb 2419-1406. mAb4540 was used as a surrogate to evaluate the effect of anti-APRIL mAb treatment on reducing serum IgA levels in C57/BL6 mice. 11-week-old mice were injected subchronically (once a week by ip injection) with 20 mg/kg mAb 4540, mAb 3833, or an isotype control antibody for seven weeks. The basal serum level of total IgA was quantified by ELISA. As shown in FIG. 41, treatment with mAb 4540 or mAb 3833 reduced serum IgA levels in C57/BL6 mice.

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All publications, patents and registration numbers mentioned in the present description are hereby incorporated by reference in their entirety, as if each individual publication or patent were specifically and individually indicated for inclusion as a reference.

Equivalents

While specific embodiments of the present invention have been discussed, the above description is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon consideration of this specification and the claims below. The full scope of the invention is to be determined by reference to the claims, together with the full scope of their equivalents, and the specification, together with such variations.

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SEQUENCE LIST

<110> VISTERRA, INC.

<120> ANTIBODY MOLECULES AGAINST APRIL AND THEIR APPLICATIONS

<130> P2029-7004WO

<140>

<141>

<150> 62/422.848

<151> 2016-11-16

<150> 62/399.087

<151> 2016-09-23

<150> 62/313.684

<151> 2016-03-25

<150> 62/259.897

<151> 2015-11-25

<160> 346

<170>PatentIn version 3.5

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Gly Tyr Ser Ile Thr Ser Gly Tyr

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Ser Tyr Asp Gly Tyr

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Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val

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Arg Ala Ser Glu Ser Val Ser Ile Ile Gly Thr Asn Ser Ile His

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His Ala Ser Asn Leu Glu Thr

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Leu Gln Ser Arg Lys Ile Pro Tyr Thr

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Ser Gly Tyr Tyr Trp Asn

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Tyr Ile Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Leu Lys Asn

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Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp

35 40 45

Met Gly Tyr Ile Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe

65 70 75 80

Leu Lys Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Asn Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val Trp Gly Thr

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

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Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Met Ser Leu Gly

1 5 10 15

Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Ser Ile Ile

20 25 30

Gly Thr Asn Ser Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr His Ala Ser Asn Leu Glu Thr Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp

65 70 75 80

Pro Val Glu Glu Asp Asp Val Ala Ile Tyr Tyr Cys Leu Gln Ser Arg

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Lys Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

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Gly Tyr Thr Phe Thr Asp Tyr

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Tyr Pro Leu Arg Gly Ser

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<212> PROTEIN

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His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr

1 5 10

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Arg Ala Ser Glu Ser Val Asp Asn Asp Gly Ile Arg Phe Met His

1 5 10 15

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<212> PROTEIN

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<400> 15

Arg Ala Ser Asn Leu Glu Ser

15

<210> 16

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<212> PROTEIN

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<400> 16

Gln Gln Ser Asn Lys Asp Pro Tyr Thr

15

<210> 17

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<212> PROTEIN

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Asp Tyr Thr Ile His

15

<210> 18

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<212> PROTEIN

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<400> 18

Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Asn Glu Lys Phe Lys

1 5 10 15

asp

<210> 19

<211> 120

<212> PROTEIN

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Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Arg Leu Ser Cys Glu Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Ile His Trp Val Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Asn Glu Lys Phe

50 55 60

Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Val Tyr

65 70 75 80

Leu Glu Leu Gly Arg Leu Thr Ser Lys Asp Ser Ala Val Tyr Phe Cys

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Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Leu Thr Val Ser Ser

115 120

<210> 20

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Asn Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Asp

20 25 30

Gly Ile Arg Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn

65 70 75 80

Pro Val Glu Thr Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Lys Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys

100 105 110

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Gly Tyr Thr Phe Thr Ser Tyr

15

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Tyr Ile Gly Asn Gly Tyr

15

<210> 23

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Tyr Tyr Pro Trp Phe Thr Tyr

15

<210> 24

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<212> PROTEIN

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Arg Ala Ser Glu Asn Ile Tyr Ser Tyr Leu Ala

1 5 10

<210> 25

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<212> PROTEIN

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Asn Ala Lys Thr Leu Ala Glu

15

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<400> 26

Gln His His Tyr Asp Thr Pro Phe Thr

15

<210> 27

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<212> PROTEIN

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Ser Tyr Gly Ile Asn

15

<210> 28

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Tyr Ile Tyr Ile Gly Asn Gly Tyr Ala Glu Tyr Asn Glu Arg Phe Lys

1 5 10 15

gly

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Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser

1 5 10 15

Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Gly Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Tyr Ile Gly Asn Gly Tyr Ala Glu Tyr Asn Glu Arg Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ser Asp Thr Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Phe Cys

85 90 95

Ala Leu Tyr Tyr Pro Trp Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ala

115

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Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Ser Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val

35 40 45

Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Gly Asn Tyr Tyr Cys Gln His His Tyr Asp Thr Pro Phe

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 31

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000

<210> 32

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Tyr Pro Arg Asp Ser Ser

15

<210> 33

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Glu Gly Tyr Asp Tyr Asp Lys Arg Gly Phe Asp Tyr

1 5 10

<210> 34

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Lys Ala Ser Gln Ser Val Ser Phe Ala Gly Thr Asn Leu Met His

1 5 10 15

<210> 35

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<400> 35

Arg Ala Ser Asn Leu Glu Pro

15

<210> 36

<211> 9

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<400> 36

Gln Gln Ser Arg Glu Tyr Pro Trp Thr

15

<210> 37

<211> 5

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<400> 37

Ser Tyr Asp Val Phe

15

<210> 38

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Trp Ile Tyr Pro Arg Asp Ser Ser Thr Lys Tyr Asn Glu Lys Phe Lys

1 5 10 15

gly

<210> 39

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<400> 39

Gln Val Gln Leu His Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Asp Val Phe Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Tyr Pro Arg Asp Ser Ser Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Lys Glu Gly Tyr Asp Tyr Asp Lys Arg Gly Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Leu Thr Val Ser Ser

115 120

<210> 40

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<400> 40

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Ile Ile Ser Cys Lys Ala Ser Gln Ser Val Ser Phe Ala

20 25 30

Gly Thr Asn Leu Met His Trp Tyr Gln Gln Arg Pro Gly Gln Gln Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Pro Gly Val Pro Thr

50 55 60

Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Asn Ile His

65 70 75 80

Pro Val Glu Glu Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Arg

85 90 95

Glu Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 41

<400> 41

000

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Asp Pro Glu Thr Gly Gly

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Trp Asn Asp Gly Asp Tyr

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Lys Ser Ser Gln Ser Leu Leu Tyr Ser Asn Gly Lys Thr Tyr Leu Asn

1 5 10 15

<210> 45

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Gln Val Ser Lys Leu Asp Pro

15

<210> 46

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Leu Gln Gly Thr Tyr Tyr Pro Tyr Thr

15

<210> 47

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Asp Tyr Glu Met His

15

<210> 48

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Ala Ile Asp Pro Glu Thr Gly Gly Thr Ala Tyr Asn Gln Arg Phe Lys

1 5 10 15

gly

<210> 49

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Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Glu Met His Trp Val Lys Gln Thr Pro Val His Gly Leu Glu Trp Ile

35 40 45

Gly Ala Ile Asp Pro Glu Thr Gly Gly Thr Ala Tyr Asn Gln Arg Phe

50 55 60

Lys Gly Lys Ala Ile Leu Thr Thr Asp Lys Ser Ser Ile Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Trp Asn Asp Gly Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr

100 105 110

Val Ser Ser

115

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Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Ile Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser

20 25 30

Asn Gly Lys Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Lys Arg Leu Met Tyr Gln Val Ser Lys Leu Asp Pro Gly Ile Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Tyr Cys Leu Gln Gly

85 90 95

Thr Tyr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

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Gly Tyr Ser Phe Thr Gly Tyr

15

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Asn Pro Tyr Asn Gly Asp

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Glu Gly Asp Gly Tyr Tyr Trp Tyr Phe Asp Val

1 5 10

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Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Ile Ser Phe Met Asn

1 5 10 15

<210> 55

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<400> 55

Ala Ala Ser Asn Gln Gly Ser

15

<210> 56

<211> 9

<212> PROTEIN

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<400> 56

Gln Gln Ser Lys Glu Val Pro Arg Thr

15

<210> 57

<211> 5

<212> PROTEIN

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<400> 57

Gly Tyr Phe Met Asn

15

<210> 58

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<212> PROTEIN

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<400> 58

Arg Ile Asn Pro Tyr Asn Gly Asp Thr Phe Tyr Asn Gln Lys Phe Lys

1 5 10 15

gly

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<212> PROTEIN

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<220>

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<400> 59

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Phe Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asn Pro Tyr Asn Gly Asp Thr Phe Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala His

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Leu Tyr Tyr Cys

85 90 95

Ala Ser Glu Gly Asp Gly Tyr Tyr Trp Tyr Phe Asp Val Trp Gly Ala

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 60

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 60

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr

20 25 30

Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His

65 70 75 80

Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys

85 90 95

Glu Val Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 61

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 61

Gly Tyr Thr Phe Thr Asp His

15

<210> 62

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 62

Asp Pro Asp Thr Gly Asp

15

<210> 63

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 63

Trp Thr Gly Gly Asp Tyr

15

<210> 64

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 64

Asp His Glu Met His

15

<210> 65

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 65

Val Ile Asp Pro Asp Thr Gly Asp Thr Thr Tyr Asn Gln Lys Phe Lys

1 5 10 15

gly

<210> 66

<211> 115

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 66

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp His

20 25 30

Glu Met His Trp Val Arg Gln Thr Pro Val His Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Asp Pro Asp Thr Gly Asp Thr Thr Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Asp Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Phe Tyr Cys

85 90 95

Thr Arg Trp Thr Gly Gly Asp Tyr Trp Gly His Gly Thr Thr Leu Thr

100 105 110

Val Ser Ser

115

<210> 67

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 67

Lys Ser Ser Gln Ser Leu Leu Tyr Ser Asp Gly Lys Thr Tyr Leu Asn

1 5 10 15

<210> 68

<400> 68

000

<210> 69

<400> 69

000

<210> 70

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 70

Asp Ala Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Ile Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Lys Arg Leu Met Tyr Gln Val Ser Lys Leu Asp Pro Gly Ile Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Leu Gln Gly

85 90 95

Thr Tyr Tyr Pro Tyr Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 71

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 71

gatgtacagc ttcaggagtc aggacctggc ctcgtgaaac cttctcagtc tctgtctctc 60

acctgctctg tcactggcta ctccatcacc agtggttatt actggaactg gatccggcag 120

tttcggaa acaaactgga atggatgggc tacataagct acgatggtta caataactac 180

aacccatctc tcaaaaatcg aatctccatc actcgtgaca catctaagaa ccagtttttc 240

ctgaagttga attctgtgac tactgaggac acagccacat attactgtgc aaactactat 300

gattacgaag actggtactt cggtgtctgg ggcacaggga ccacggtcac cgtctcctca 360

<210> 72

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 72

gacattgtgc tgacccaatc tccagcttct ttggctatgt ctctagggaa gagggccacc 60

atctcctgca gagccagcga aagtgtcagt attattggta ctaattcaat acactggtac 120

caacagaaac caggacagcc acccaaactc ctcatctatc atgcatccaa cctagaaact 180

ggagtccctg ccaggttcag tggcagtggg tctagaacag acttcaccct caccattgat 240

cctgtggagg aagatgatgt tgcaatctat tactgtctgc aaagtaggaa gattccgtac 300

acgttcggag gggggaccaa gctggaaata aaa 333

<210> 73

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 73

caggtccagc tgcagcagtc tggagctgag ctggtgaaac ccggggcatc agtgaggctg 60

tcctgcgagg cttctggcta caccttcacg gactatacta tacactgggt aaagcagagg 120

tctggacagg gtcttgagtg gattggatgg atttaccctc taagaggtag tataaactac 180

aatgagaaat tcaaggacaa ggccacattg actgcggaca aatcctccag cacagtctat 240

ttggagcttg gtagattgac atctaaggac tctgcggtct atttctgtgc aagacacgga 300

gcctactata gtaacgcctt tgactactgg ggccaaggca ccactctcac agtctcctca 360

<210> 74

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 74

aacattgtaa tgacccaatc tccagcttca ttggctgtgt ctctaggtca gagggccacc 60

atctcctgca gagccagcga gagtgttgat aatgatggca ttagatttat gcactggtac 120

cagcagaaac caggacagcc acccaaactc ctcatctatc gtgcatccaa cctagaatct 180

gggatccctg ccaggttcag tggcagtggg tctaggacag acttcaccct cactattaat 240

cctgtggaga ctgatgatgt tgcaacctat tactgtcagc aaagtaataa ggatccgtac 300

acgttcggag gggggaccaa gctggagctg aaa 333

<210> 75

<211> 348

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 75

gaggtccagc ttcagcagtc tggagctgag ctggtgaggc ctgggtcctc agtgaagatg 60

tcctgcaaga cttctggata tactttcaca agctacggta taaactgggt gaagcagagg 120

cctggacagg gcctggaatg gattggatat attttattg gaaatggtta tgctgagtac 180

aatgagaggt tcaagggcaa ggccacactg acttcagaca catcctccag cacagcctac 240

atgcagctca gcagcctgac atctgaggac tctgcaatct atttctgtgc actatactat 300

ccctggttta cttactgggg ccaggggact ctggtcactg tctctgca 348

<210> 76

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 76

gacatccaga tgactcagtc tccagcctcc ctttctgcat ctgtgggaga ttctgtcacc 60

atcacatgtc gagcaagtga gaatatttac agttatttag catggtatca gcagaaacag 120

ggaaaatctc ctcagctcct ggtctataat gcaaaaacct tagctgaagg tgtgccatca 180

aggttcagtg gcagtggatc aggcacacag ttttctctga agatcaacag cctgcagcct 240

gaagattttg ggaattatta ctgtcaacat cattatgata ctccgttcac gttcggaggg 300

gggaccaagc tggaaataaa a 321

<210> 77

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 77

caggttcagc tgcaccagtc tggacctgag ctggtgaagc ctggggcttc agtgaagttg 60

tcctgcaaga cttctggcta caccttcaca agctacgatg tcttctgggt gaagcagagg 120

cctggacagg gacttgagtg gattggatgg atttatccta gagatagtag tactaaatac 180

aatgagaagt tcaagggcaa ggccacattg actgtagaca catcctccag cacagcatac 240

atggagctcc acagcctgac atctgaggac tctgcggtct atttctgtgc aaaagagggg 300

tatgattatg acaagagggg ctttgactac tggggccaag gcaccactct cacagtctcc 360

tca 363

<210> 78

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 78

gacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccatc 60

atctcctgca aggccagcca aagtgtcagt tttgctggta ctaatttaat gcactggtac 120

caacagagac cagggcagca acccaaactc ctcatctatc gtgcatccaa cctagaacct 180

ggggttccta ccaggtttag tggcagtggg tctaggacag acttcaccct caatatccat 240

cctgtggagg aagatgatgc tgcaacctat tactgtcagc aaagtaggga atatccgtgg 300

acgttcggtg gaggcaccaa gctggaaatc aaa 333

<210> 79

<211> 345

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 79

caggttcaac tgcagcagtc tggggctgag ctggtgaggc ctggggcttc agtgacgctg 60

tcctgcaagg cttcgggcta cacttttact gactatgaaa tgcactgggt gaagcagaca 120

cctgtgcatg gcctggaatg gattggagct attgatcctg aaactggtgg tactgcctac 180

aatcagaggt tcaagggcaa ggccatactg actacagaca aatcctccat cacagcctac 240

atggagctcc gcagcctgac atctgaggac tctgccgtct attactgtac aagatggaat 300

gatggcgact actggggcca aggcaccact ctcacagtct cctca 345

<210> 80

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 80

gatgttgtga tgacccagac tccactgtct ttgtcggtta ccattggaca accagcctcc 60

120

tttcaacaga ggcctggcca gtctccaaag cgcctaatgt atcaggtgtc caaactggac 180

cctggcatcc ctgacaggtt cagtggcagt ggatcagaaa cagattttac acttaaaatc 240

agcagagtgg aggctgaaga tttgggactt tattactgct tgcaaggtac atattatccg 300

tacacgttcg gaggggggac caagctggaa ataaaa 336

<210> 81

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 81

gaggtccagc tgcagcagtc tggacctgag ctggtgaagc ctggggcttc agtgaagatg 60

tcctgcaagg cttctggtta ctcctttact ggctacttta tgaactgggt gaagcagagc 120

catggaaaga gccttgagtg gattggacgt attaatcctt acaatggtga tactttctac 180

aaccagaagt tcaagggcaa ggccacattg actgtagaca aatcctctag cacagcccac 240

atggagctcc ggagcctgac atctgaggac tctgcactct attattgtgc aagcgaaggt 300

gatggttact actggtactt cgatgtctgg ggcgcaggga ccacggtcac cgtctcctca 360

<210> 82

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 82

gacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccacc 60

atctcctgca gagccagcga aagtgttgat aattatggca ttagttttat gaactggttc 120

caacagaaac caggacagcc acccaaactc ctcatctatg ctgcatccaa ccaaggatcc 180

ggggtccctg ccaggtttag tggcagtggg tctgggacag acttcagcct caacatccat 240

cctatggagg aggatgatac tgcaatgtat ttctgtcagc aaagtaagga ggttcctcgg 300

acgttcggtg gaggcaccaa gctggaaatc aaa 333

<210> 83

<211> 345

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 83

caggttcaac tgcagcagtc tggggctgag ctggtgaggc ctggggcttc agtgaagctg 60

tcctgcaagg cttcgggcta cacatttact gaccatgaaa tgcactgggt gagacagaca 120

cctgtgcatg gcctggaatg gattggagtt attgatcctg acactggtga tactacctac 180

aatcagaaat tcaagggcaa ggccacactg actgcagaca aatcctccag cacagcctac 240

atggacctcc gcagcctgac atctgaggac tctgccgtct tttactgtac acggtggact 300

gggggggact actggggcca tggcaccact ctcacagtct cctca 345

<210> 84

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 84

gatgctgtga tgacccagac tccactgtct ttgtcggtta ccattggaca accagcctct 60

atctcttgca agtcgagtca gagcctctta tatagtgatg gaaagacata tttgaattgg 120

ttccaacaga ggccaggcca gtctccaaag cgcctaatgt atcaggtgtc caaactggac 180

cctggcatcc ctgacaggtt cagtggcagt ggatcagaga cagattttac acttaaaatc 240

agcagagtgg aggctgagga tttgggagtt tattactgct tgcaaggtac atattatccg 300

tatacgttcg gatcggggac caagctggaa ataaaa 336

<210> 85

<211> 250

<212> PROTEIN

<213> Homo sapiens

<400> 85

Met Pro Ala Ser Ser Pro Phe Leu Leu Ala Pro Lys Gly Pro Pro Gly

1 5 10 15

Asn Met Gly Gly Pro Val Arg Glu Pro Ala Leu Ser Val Ala Leu Trp

20 25 30

Leu Ser Trp Gly Ala Ala Leu Gly Ala Val Ala Cys Ala Met Ala Leu

35 40 45

Leu Thr Gln Gln Thr Glu Leu Gln Ser Leu Arg Arg Glu Val Ser Arg

50 55 60

Leu Gln Gly Thr Gly Gly Pro Ser Gln Asn Gly Glu Gly Tyr Pro Trp

65 70 75 80

Gln Ser Leu Pro Glu Gln Ser Ser Asp Ala Leu Glu Ala Trp Glu Asn

85 90 95

Gly Glu Arg Ser Arg Lys Arg Arg Ala Val Leu Thr Gln Lys Gln Lys

100 105 110

Lys Gln His Ser Val Leu His Leu Val Pro Ile Asn Ala Thr Ser Lys

115 120 125

Asp Asp Ser Asp Val Thr Glu Val Met Trp Gln Pro Ala Leu Arg Arg

130 135 140

Gly Arg Gly Leu Gln Ala Gln Gly Tyr Gly Val Arg Ile Gln Asp Ala

145 150 155 160

Gly Val Tyr Leu Leu Tyr Ser Gln Val Leu Phe Gln Asp Val Thr Phe

165 170 175

Thr Met Gly Gln Val Val Ser Arg Glu Gly Gln Gly Arg Gln Glu Thr

180 185 190

Leu Phe Arg Cys Ile Arg Ser Met Pro Ser His Pro Asp Arg Ala Tyr

195 200 205

Asn Ser Cys Tyr Ser Ala Gly Val Phe His Leu His Gln Gly Asp Ile

210 215 220

Leu Ser Val Ile Ile Pro Arg Ala Arg Ala Lys Leu Asn Leu Ser Pro

225 230 235 240

His Gly Thr Phe Leu Gly Phe Val Lys Leu

245 250

<210> 86

<211> 234

<212> PROTEIN

<213> Homo sapiens

<400> 86

Met Pro Ala Ser Ser Pro Phe Leu Leu Ala Pro Lys Gly Pro Pro Gly

1 5 10 15

Asn Met Gly Gly Pro Val Arg Glu Pro Ala Leu Ser Val Ala Leu Trp

20 25 30

Leu Ser Trp Gly Ala Ala Leu Gly Ala Val Ala Cys Ala Met Ala Leu

35 40 45

Leu Thr Gln Gln Thr Glu Leu Gln Ser Leu Arg Arg Glu Val Ser Arg

50 55 60

Leu Gln Gly Thr Gly Gly Pro Ser Gln Asn Gly Glu Gly Tyr Pro Trp

65 70 75 80

Gln Ser Leu Pro Glu Gln Ser Ser Asp Ala Leu Glu Ala Trp Glu Asn

85 90 95

Gly Glu Arg Ser Arg Lys Arg Arg Ala Val Leu Thr Gln Lys Gln Lys

100 105 110

Asn Asp Ser Asp Val Thr Glu Val Met Trp Gln Pro Ala Leu Arg Arg

115 120 125

Gly Arg Gly Leu Gln Ala Gln Gly Tyr Gly Val Arg Ile Gln Asp Ala

130 135 140

Gly Val Tyr Leu Leu Tyr Ser Gln Val Leu Phe Gln Asp Val Thr Phe

145 150 155 160

Thr Met Gly Gln Val Val Ser Arg Glu Gly Gln Gly Arg Gln Glu Thr

165 170 175

Leu Phe Arg Cys Ile Arg Ser Met Pro Ser His Pro Asp Arg Ala Tyr

180 185 190

Asn Ser Cys Tyr Ser Ala Gly Val Phe His Leu His Gln Gly Asp Ile

195 200 205

Leu Ser Val Ile Ile Pro Arg Ala Arg Ala Lys Leu Asn Leu Ser Pro

210 215 220

His Gly Thr Phe Leu Gly Phe Val Lys Leu

225 230

<210> 87

<211> 247

<212> PROTEIN

<213> Homo sapiens

<400> 87

Met Pro Ala Ser Ser Pro Phe Leu Leu Ala Pro Lys Gly Pro Pro Gly

1 5 10 15

Asn Met Gly Gly Pro Val Arg Glu Pro Ala Leu Ser Val Ala Leu Trp

20 25 30

Leu Ser Trp Gly Ala Ala Leu Gly Ala Val Ala Cys Ala Met Ala Leu

35 40 45

Leu Thr Gln Gln Thr Glu Leu Gln Ser Leu Arg Arg Glu Val Ser Arg

50 55 60

Leu Gln Gly Thr Gly Gly Pro Ser Gln Asn Gly Glu Gly Tyr Pro Trp

65 70 75 80

Gln Ser Leu Pro Glu Gln Ser Ser Asp Ala Leu Glu Ala Trp Glu Asn

85 90 95

Gly Glu Arg Ser Arg Lys Arg Arg Ala Val Leu Thr Gln Lys Gln Lys

100 105 110

Lys Gln His Ser Val Leu His Leu Val Pro Ile Asn Ala Thr Ser Lys

115 120 125

Asp Asp Ser Asp Val Thr Glu Val Met Trp Gln Pro Ala Leu Arg Arg

130 135 140

Gly Arg Gly Leu Gln Ala Gln Gly Tyr Gly Val Arg Ile Gln Asp Ala

145 150 155 160

Gly Val Tyr Leu Leu Tyr Ser Gln Val Leu Phe Gln Asp Val Thr Phe

165 170 175

Thr Met Gly Gln Val Val Ser Arg Glu Gly Gln Gly Arg Gln Glu Thr

180 185 190

Leu Phe Arg Cys Ile Arg Ser Met Pro Ser His Pro Asp Arg Ala Tyr

195 200 205

Asn Ser Cys Tyr Ser Ala Gly Val Phe His Leu His Gln Gly Asp Ile

210 215 220

Leu Ser Val Ile Ile Pro Arg Ala Arg Ala Lys Leu Asn Leu Ser Pro

225 230 235 240

His Gly Thr Phe Leu Gly Leu

245

<210> 88

<211> 222

<212> PROTEIN

<213> Homo sapiens

<400> 88

Met Pro Ala Ser Ser Pro Phe Leu Leu Ala Pro Lys Gly Pro Pro Gly

1 5 10 15

Asn Met Gly Gly Pro Val Arg Glu Pro Ala Leu Ser Val Ala Leu Trp

20 25 30

Leu Ser Trp Gly Ala Ala Leu Gly Ala Val Ala Cys Ala Met Ala Leu

35 40 45

Leu Thr Gln Gln Thr Glu Leu Gln Ser Leu Arg Arg Glu Val Ser Arg

50 55 60

Leu Gln Gly Thr Gly Gly Pro Ser Gln Asn Gly Glu Gly Tyr Pro Trp

65 70 75 80

Gln Ser Leu Pro Glu Gln His Ser Val Leu His Leu Val Pro Ile Asn

85 90 95

Ala Thr Ser Lys Asp Asp Ser Asp Val Thr Glu Val Met Trp Gln Pro

100 105 110

Ala Leu Arg Arg Gly Arg Gly Leu Gln Ala Gln Gly Tyr Gly Val Arg

115 120 125

Ile Gln Asp Ala Gly Val Tyr Leu Leu Tyr Ser Gln Val Leu Phe Gln

130 135 140

Asp Val Thr Phe Thr Met Gly Gln Val Val Ser Arg Glu Gly Gln Gly

145 150 155 160

Arg Gln Glu Thr Leu Phe Arg Cys Ile Arg Ser Met Pro Ser His Pro

165 170 175

Asp Arg Ala Tyr Asn Ser Cys Tyr Ser Ala Gly Val Phe His Leu His

180 185 190

Gln Gly Asp Ile Leu Ser Val Ile Ile Pro Arg Ala Arg Ala Lys Leu

195 200 205

Asn Leu Ser Pro His Gly Thr Phe Leu Gly Phe Val Lys Leu

210 215 220

<210> 89

<211> 330

<212> PROTEIN

<213> Homo sapiens

<400> 89

Met Ala Ala Arg Arg Ser Gln Arg Arg Arg Gly Arg Arg Gly Glu Pro

1 5 10 15

Gly Thr Ala Leu Leu Val Pro Leu Ala Leu Gly Leu Gly Leu Ala Leu

20 25 30

Ala Cys Leu Gly Leu Leu Leu Ala Val Val Ser Leu Gly Ser Arg Ala

35 40 45

Ser Leu Ser Ala Gln Glu Pro Ala Gln Glu Glu Leu Val Ala Glu Glu

50 55 60

Asp Gln Asp Pro Ser Glu Leu Asn Pro Gln Thr Glu Glu Ser Gln Asp

65 70 75 80

Pro Ala Pro Phe Leu Asn Arg Leu Val Arg Pro Arg Arg Ser Ala Pro

85 90 95

Lys Gly Arg Lys Thr Arg Ala Arg Arg Ala Ile Ala Ala His Tyr Glu

100 105 110

Val His Pro Arg Pro Gly Gln Asp Gly Ala Gln Ala Gly Val Asp Gly

115 120 125

Thr Val Ser Gly Trp Glu Glu Ala Arg Ile Asn Ser Ser Ser Pro Leu

130 135 140

Arg Tyr Asn Arg Gln Ile Gly Glu Phe Ile Val Thr Arg Ala Gly Leu

145 150 155 160

Tyr Tyr Leu Tyr Cys Gln Ser Ser Asp Ala Leu Glu Ala Trp Glu Asn

165 170 175

Gly Glu Arg Ser Arg Lys Arg Arg Ala Val Leu Thr Gln Lys Gln Lys

180 185 190

Lys Gln His Ser Val Leu His Leu Val Pro Ile Asn Ala Thr Ser Lys

195 200 205

Asp Asp Ser Asp Val Thr Glu Val Met Trp Gln Pro Ala Leu Arg Arg

210 215 220

Gly Arg Gly Leu Gln Ala Gln Gly Tyr Gly Val Arg Ile Gln Asp Ala

225 230 235 240

Gly Val Tyr Leu Leu Tyr Ser Gln Val Leu Phe Gln Asp Val Thr Phe

245 250 255

Thr Met Gly Gln Val Val Ser Arg Glu Gly Gln Gly Arg Gln Glu Thr

260 265 270

Leu Phe Arg Cys Ile Arg Ser Met Pro Ser His Pro Asp Arg Ala Tyr

275 280 285

Asn Ser Cys Tyr Ser Ala Gly Val Phe His Leu His Gln Gly Asp Ile

290 295 300

Leu Ser Val Ile Ile Pro Arg Ala Arg Ala Lys Leu Asn Leu Ser Pro

305 310 315 320

His Gly Thr Phe Leu Gly Phe Val Lys Leu

325 330

<210> 90

<211> 205

<212> PROTEIN

<213> Homo sapiens

<400> 90

Met Gly Gly Pro Val Arg Glu Pro Ala Leu Ser Val Ala Leu Trp Leu

1 5 10 15

Ser Trp Gly Ala Ala Leu Gly Ala Val Ala Cys Ala Met Ala Leu Leu

20 25 30

Thr Gln Gln Thr Glu Leu Gln Ser Leu Arg Arg Glu Val Ser Arg Leu

35 40 45

Gln Gly Thr Gly Gly Pro Ser Gln Asn Gly Glu Gly Tyr Pro Trp Gln

50 55 60

Ser Leu Pro Glu Gln His Ser Val Leu His Leu Val Pro Ile Asn Ala

65 70 75 80

Thr Ser Lys Asp Asp Ser Asp Val Thr Glu Val Met Trp Gln Pro Ala

85 90 95

Leu Arg Arg Gly Arg Gly Leu Gln Ala Gln Gly Tyr Gly Val Arg Ile

100 105 110

Gln Asp Ala Gly Val Tyr Leu Leu Tyr Ser Gln Val Leu Phe Gln Asp

115 120 125

Val Thr Phe Thr Met Gly Gln Val Val Ser Arg Glu Gly Gln Gly Arg

130 135 140

Gln Glu Thr Leu Phe Arg Cys Ile Arg Ser Met Pro Ser His Pro Asp

145 150 155 160

Arg Ala Tyr Asn Ser Cys Tyr Ser Ala Gly Val Phe His Leu His Gln

165 170 175

Gly Asp Ile Leu Ser Val Ile Ile Pro Arg Ala Arg Ala Lys Leu Asn

180 185 190

Leu Ser Pro His Gly Thr Phe Leu Gly Phe Val Lys Leu

195 200 205

<210> 91

<211> 241

<212> PROTEIN

<213> Mus musculus

<400> 91

Met Pro Ala Ser Ser Pro Gly His Met Gly Gly Ser Val Arg Glu Pro

1 5 10 15

Ala Leu Ser Val Ala Leu Trp Leu Ser Trp Gly Ala Val Leu Gly Ala

20 25 30

Val Thr Cys Ala Val Ala Leu Leu Ile Gln Gln Thr Glu Leu Gln Ser

35 40 45

Leu Arg Arg Glu Val Ser Arg Leu Gln Arg Ser Gly Gly Pro Ser Gln

50 55 60

Lys Gln Gly Glu Arg Pro Trp Gln Ser Leu Trp Glu Gln Ser Pro Asp

65 70 75 80

Val Leu Glu Ala Trp Lys Asp Gly Ala Lys Ser Arg Arg Arg Arg Ala

85 90 95

Val Leu Thr Gln Lys His Lys Lys Lys His Ser Val Leu His Leu Val

100 105 110

Pro Val Asn Ile Thr Ser Lys Ala Asp Ser Asp Val Thr Glu Val Met

115 120 125

Trp Gln Pro Val Leu Arg Arg Gly Arg Gly Leu Glu Ala Gln Gly Asp

130 135 140

Ile Val Arg Val Trp Asp Thr Gly Ile Tyr Leu Leu Tyr Ser Gln Val

145 150 155 160

Leu Phe His Asp Val Thr Phe Thr Met Gly Gln Val Val Ser Arg Glu

165 170 175

Gly Gln Gly Arg Arg Glu Thr Leu Phe Arg Cys Ile Arg Ser Met Pro

180 185 190

Ser Asp Pro Asp Arg Ala Tyr Asn Ser Cys Tyr Ser Ala Gly Val Phe

195 200 205

His Leu His Gln Gly Asp Ile Ile Thr Val Lys Ile Pro Arg Ala Asn

210 215 220

Ala Lys Leu Ser Leu Ser Pro His Gly Thr Phe Leu Gly Phe Val Lys

225 230 235 240

Leu

<210> 92

<211> 240

<212> PROTEIN

<213> Mus musculus

<400> 92

Met Pro Ala Ser Ser Pro Gly His Met Gly Gly Ser Val Arg Glu Pro

1 5 10 15

Ala Leu Ser Val Ala Leu Trp Leu Ser Trp Gly Ala Val Leu Gly Ala

20 25 30

Val Thr Cys Ala Val Ala Leu Leu Ile Gln Gln Thr Glu Leu Gln Ser

35 40 45

Leu Arg Arg Glu Val Ser Arg Leu Gln Arg Ser Gly Gly Pro Ser Gln

50 55 60

Lys Gln Gly Glu Arg Pro Trp Gln Ser Leu Trp Glu Gln Ser Pro Asp

65 70 75 80

Val Leu Glu Ala Trp Lys Asp Gly Ala Lys Ser Arg Arg Arg Arg Ala

85 90 95

Val Leu Thr Gln Lys His Lys Lys Lys His Ser Val Leu His Leu Val

100 105 110

Pro Val Asn Ile Thr Ser Lys Asp Ser Asp Val Thr Glu Val Met Trp

115 120 125

Gln Pro Val Leu Arg Arg Gly Arg Gly Leu Glu Ala Gln Gly Asp Ile

130 135 140

Val Arg Val Trp Asp Thr Gly Ile Tyr Leu Leu Tyr Ser Gln Val Leu

145 150 155 160

Phe His Asp Val Thr Phe Thr Met Gly Gln Val Val Ser Arg Glu Gly

165 170 175

Gln Gly Arg Arg Glu Thr Leu Phe Arg Cys Ile Arg Ser Met Pro Ser

180 185 190

Asp Pro Asp Arg Ala Tyr Asn Ser Cys Tyr Ser Ala Gly Val Phe His

195 200 205

Leu His Gln Gly Asp Ile Ile Thr Val Lys Ile Pro Arg Ala Asn Ala

210 215 220

Lys Leu Ser Leu Ser Pro His Gly Thr Phe Leu Gly Phe Val Lys Leu

225 230 235 240

<210> 93

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 93

Gly Phe Ser Leu Thr Ile Tyr

15

<210> 94

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 94

Trp Ser Asp Gly Ser

15

<210> 95

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 95

Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr

1 5 10

<210> 96

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 96

Arg Ala Ser Lys Asn Ile Tyr Ser Tyr Leu Ala

1 5 10

<210> 97

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 97

Asn Ala Lys Thr Leu Pro Glu

15

<210> 98

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 98

Gln His His Tyr Gly Thr Pro Leu Thr

15

<210> 99

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 99

Ile Tyr Asp Val His

15

<210> 100

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 100

Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile Ser

1 5 10 15

<210> 101

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 101

Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ile Tyr

20 25 30

Asp Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile

50 55 60

Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Phe

65 70 75 80

Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ala

115

<210> 102

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 102

Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Glu Thr Ile Thr Ile Thr Cys Arg Ala Ser Lys Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val

35 40 45

Tyr Asn Ala Lys Thr Leu Pro Glu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 103

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 103

Gly Tyr Ile Phe Thr Asp Tyr

15

<210> 104

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 104

Tyr Pro Gly Ser Gly Asn

15

<210> 105

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 105

Glu Ser Asn Tyr Val Gly Tyr Tyr Ala Met Asp Tyr

1 5 10

<210> 106

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 106

Arg Ser Ser Gln Ser Val Val Asn Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 107

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 107

Lys Val Ser Asn Arg Phe Ser

15

<210> 108

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 108

Phe Gln Gly Ser His Val Pro Trp Thr

15

<210> 109

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 109

Asp Tyr Thr Ile Asn

15

<210> 110

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 110

Trp Ile Tyr Pro Gly Ser Gly Asn Arg Lys Tyr Asn Asp Lys Phe Lys

1 5 10 15

gly

<210> 111

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 111

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ala Gly Tyr Ile Phe Thr Asp Tyr

20 25 30

Thr Ile Asn Trp Val Lys Gln Ser Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Tyr Pro Gly Ser Gly Asn Arg Lys Tyr Asn Asp Lys Phe

50 55 60

Lys Gly Lys Ala Thr Met Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Glu Ser Asn Tyr Val Gly Tyr Tyr Ala Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 112

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 112

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Val Val Asn Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Asn Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 113

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 113

Gly Tyr Thr Phe Thr Asn Tyr

15

<210> 114

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 114

Tyr Pro Gly Gly Ile Gly Gly Gly Tyr

15

<210> 115

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 115

Ser Glu Thr Gly Arg Ala Met Asp Tyr

15

<210> 116

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 116

Lys Ala Ser Gln Asp Ile Asn Lys Tyr Ile Ala

1 5 10

<210> 117

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 117

Tyr Thr Ser Thr Leu Lys Pro

15

<210> 118

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 118

Leu Gln Tyr Asp Asn Leu Asn Thr

15

<210> 119

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 119

Asn Tyr Trp Ile Gly

15

<210> 120

<211> 20

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 120

Asp Ile Tyr Pro Gly Gly Ile Gly Gly Gly Tyr Thr Lys Tyr Asn Glu

1 5 10 15

Lys Phe Lys Gly

20

<210> 121

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 121

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ala Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Trp Ile Gly Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile

35 40 45

Gly Asp Ile Tyr Pro Gly Gly Ile Gly Gly Gly Tyr Thr Lys Tyr Asn

50 55 60

Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser

65 70 75 80

Thr Ala Tyr Met Gln Leu Gly Ser Leu Thr Ser Glu Asp Ser Ala Ile

85 90 95

Tyr Phe Cys Ser Arg Ser Glu Thr Gly Arg Ala Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 122

<211> 106

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 122

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly

1 5 10 15

Gly Lys Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Lys Tyr

20 25 30

Ile Ala Trp Tyr Gln His Lys Pro Gly Lys Gly Pro Arg Leu Leu Ile

35 40 45

His Tyr Thr Ser Thr Leu Lys Pro Gly Ile Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Arg Asp Tyr Ser Phe Ser Ile Ser Asp Leu Glu Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Asn Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 123

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 123

Gly Tyr Ser Phe Thr Asp Tyr

15

<210> 124

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 124

Asp Pro Ser Asn Gly Gly

15

<210> 125

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 125

Arg Asp Asn Tyr Gly Ser Gly Thr Met Asp Tyr

1 5 10

<210> 126

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 126

Lys Ala Ser Gln Asn Val Gly Thr Asp Val Ser

1 5 10

<210> 127

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 127

Trp Ala Ser Asn Arg Phe Thr

15

<210> 128

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 128

Glu Gln Tyr Ser Ile Tyr Pro Leu Thr

15

<210> 129

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 129

Asp Tyr Asn Ile Tyr

15

<210> 130

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 130

Tyr Ile Asp Pro Ser Asn Gly Gly Pro Gly Tyr Asn Gln Lys Phe Arg

1 5 10 15

gly

<210> 131

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 131

Glu Ile Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asp Tyr

20 25 30

Asn Ile Tyr Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asp Pro Ser Asn Gly Gly Pro Gly Tyr Asn Gln Lys Phe

50 55 60

Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Phe

65 70 75 80

Leu His Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Asp Asn Tyr Gly Ser Gly Thr Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 132

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 132

Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asp

20 25 30

Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Pro Leu Ile

35 40 45

Tyr Trp Ala Ser Asn Arg Phe Thr Gly Val Pro Asp Arg Phe Ile Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser

65 70 75 80

Glu Asp Leu Ala Asp Tyr Phe Cys Glu Gln Tyr Ser Ile Tyr Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 133

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 133

Gly Tyr Ser Phe Thr Asp Asp

15

<210> 134

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 134

Asp Pro Leu Asn Gly Gly

15

<210> 135

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 135

Arg Asp Asn Tyr Ala Thr Gly Thr Met Asp Tyr

1 5 10

<210> 136

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 136

Lys Ala Ser Lys Asn Val Gly Thr Asp Val Ser

1 5 10

<210> 137

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 137

Glu Gln Tyr Ser Ser Tyr Pro Leu Thr

15

<210> 138

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 138

Asp Asp Asn Met Tyr

15

<210> 139

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 139

Tyr Ile Asp Pro Leu Asn Gly Gly Thr Gly Tyr Asn Gln Lys Phe Lys

1 5 10 15

gly

<210> 140

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 140

Glu Ile Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asp Asp

20 25 30

Asn Met Tyr Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asp Pro Leu Asn Gly Gly Thr Gly Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Phe

65 70 75 80

Leu His Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Asp Asn Tyr Ala Thr Gly Thr Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 141

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 141

Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Lys Asn Val Gly Thr Asp

20 25 30

Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Pro Leu Ile

35 40 45

Tyr Trp Ala Ser Asn Arg Phe Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Val Gln Ser

65 70 75 80

Glu Asp Leu Ala Asp Tyr Phe Cys Glu Gln Tyr Ser Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 142

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 142

Tyr Pro Ile Asn Gly Tyr

15

<210> 143

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 143

Asp Ser Asn Tyr Val Gly Trp Tyr Phe Asp Val

1 5 10

<210> 144

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 144

Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His

1 5 10 15

<210> 145

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 145

Ser Gln Ser Thr His Val Pro Arg Thr

15

<210> 146

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 146

Arg Ala Ser Lys Ser Val Ser Thr Ser Gly Tyr Ser Tyr Met His

1 5 10 15

<210> 147

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 147

Phe Thr Ser Asp Leu Glu Pro

15

<210> 148

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 148

Gln His Ser Arg Glu Leu Pro Tyr Pro

15

<210> 149

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 149

Asp Tyr Asn Met Asp

15

<210> 150

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 150

Asn Ile Tyr Pro Ile Asn Gly Tyr Thr Gly Tyr Asn Gln Arg Phe Lys

1 5 10 15

Asn

<210> 151

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 151

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Asn Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Asn Ile Tyr Pro Ile Asn Gly Tyr Thr Gly Tyr Asn Gln Arg Phe

50 55 60

Lys Asn Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Ser Asn Tyr Val Gly Trp Tyr Phe Asp Val Trp Gly Ala

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 152

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 152

Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser

85 90 95

Thr His Val Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 153

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 153

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Thr Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Phe Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser

20 25 30

Gly Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Phe Thr Ser Asp Leu Glu Pro Gly Val Pro Ala

50 55 60

Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His

65 70 75 80

Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln His Ser Arg

85 90 95

Glu Leu Pro Tyr Pro Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 154

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 154

Gly Tyr Thr Phe Ala Asp Tyr

15

<210> 155

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 155

Phe Pro Gly Ser Gly Ser

15

<210> 156

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 156

Gly Asp Ser Gly Arg Ala Met Asp Tyr

15

<210> 157

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 157

Tyr Thr Ser Thr Leu Gln Ser

15

<210> 158

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 158

Leu Gln Tyr Asp Asn Leu Leu Thr

15

<210> 159

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 159

Asp Tyr Tyr Ile Asn

15

<210> 160

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 160

Trp Ile Phe Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Lys Phe Lys

1 5 10 15

gly

<210> 161

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 161

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ala Asp Tyr

20 25 30

Tyr Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Phe Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Leu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Gly Asp Ser Gly Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser

115

<210> 162

<211> 106

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 162

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly

1 5 10 15

Gly Lys Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Lys Tyr

20 25 30

Ile Ala Trp Tyr Gln His Lys Pro Gly Lys Gly Pro Arg Leu Leu Ile

35 40 45

His Tyr Thr Ser Thr Leu Gln Ser Gly Ile Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Arg Asp Tyr Ser Phe Ser Ile Ser Asn Leu Glu Pro

65 70 75 80

Glu Asp Asn Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Leu Thr

85 90 95

Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 163

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 163

Gly Phe Ser Leu Thr Asp Tyr

15

<210> 164

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 164

Trp Asn Asp Gly Ser

15

<210> 165

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 165

Asn Trp Tyr Gly Gly Tyr Trp Phe Ala Tyr

1 5 10

<210> 166

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 166

Arg Ser Ser Glu Asn Ile Tyr Ser Tyr Leu Ala

1 5 10

<210> 167

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 167

Asn Ala Asn Ala Leu Ala Glu

15

<210> 168

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 168

Gln His His Tyr Gly Thr Pro Phe Thr

15

<210> 169

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 169

Asp Tyr Asp Val His

15

<210> 170

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 170

Val Ile Trp Asn Asp Gly Ser Thr Asp Tyr Asn Thr Ala Phe Ile Ser

1 5 10 15

<210> 171

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 171

Gln Ala His Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr

20 25 30

Asp Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Asn Asp Gly Ser Thr Asp Tyr Asn Thr Ala Phe Ile

50 55 60

Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Phe

65 70 75 80

Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Tyr Gly Gly Tyr Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ala

115

<210> 172

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 172

Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Ala Gly

1 5 10 15

Glu Thr Val Thr Ile Thr Cys Arg Ser Ser Glu Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val

35 40 45

Tyr Asn Ala Asn Ala Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Val Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe

85 90 95

Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 173

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 173

caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagag cctgtccatc 60

acctgcacag tctctggttt ctcattaacc atctatgatg tacactgggt tcgccagtct 120

cggaaagg gtctggagtg gctgggagtg atatggagtg atggaagcac agactataat 180

gcagctttca tatctagact gagcatcagc aaggacaact ccaagagcca agttttcttt 240

aaaatgaaca gtctgcaagc tgatgacaca gccatatact actgtgccag aaattgggtc 300

gaccaggcct ggtttgctta ctggggccaa gggactctgg tcactgtctc tgca 354

<210> 174

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 174

gacatccaga tgactcagtc tccagcctcc ctatctgcat ctgtgggaga aactatcacc 60

atcacatgtc gagcaagtaa gaatatttac agttatttag catggtatca gcagaaacag 120

ggaaaatctc ctcagctcct ggtctataat gcaaaaacct taccagaagg tgtgccatca 180

aggttcagtg gcagtggatc aggcacacag ttttctctga agatcaacag cctgcagcct 240

gaagattttg ggagttatta ctgtcaacat cattatggta ctccgctcac gttcggtgct 300

gggaccaagc tggagctgaa a 321

<210> 175

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 175

caggtccaac tgcagcagtc tggacctgag ctggtgaagc ctggagcttc agtgaagctg 60

tcctgcaagg ctgctggcta catcttcact gactatacta taaactgggt gaagcagagt 120

cctggacagg gacttgagtg gattggatgg atttatcctg gaagtggtaa tcgtaaatac 180

aatgacaagt tcaagggcaa ggccacaatg actgcagaca aatcctccag cacagcctac 240

atgcagctca gcagcctgac ctctgaggat tctgcggtct atttctgtgc aagagagagt 300

aactacgtgg ggtactatgc tatggactat tggggtcaag gaacctcagt caccgtctcc 360

tca 363

<210> 176

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 176

gatgttttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60

atctcttgca gatctagtca gagcgttgta aatagtaatg gaaacaccta tttagaatgg 120

tacctgcaga aaccaggcca gtctccaaat ctcctgatct acaaagtttc caatcgattt 180

tctggggtcc cagacaggtt cagtggcagt ggatcggggga cagatttcac actcaagatc 240

agcagagtgg aggctgagga tctgggagtt tattactgtt ttcaaggttc acatgttccg 300

tggacgttcg gtggaggcac caagctggaa atcaaa 336

<210> 177

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 177

caggtccagc tgcagcagtc tggagctgag ctggtaaggc ctgggacttc agtgaagatg 60

tcctgcaagg ctgctggata caccttcaca aactactgga taggttggggt aaagcagagg 120

cctggacatg gccttgagtg gattggagat atttaccctg gaggtatagg aggtggttat 180

actaagtaca atgagaagtt caagggcaag gccacactga ctgcagacac atcctccagc 240

acagcctaca tgcagctcgg cagcctgaca tctgaggact ctgccatcta tttctgttca 300

agatcggaaa ctggacgggc tatggactac tggggtcaag gaacctcagt caccgtctcc 360

tca 363

<210> 178

<211> 318

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 178

gacatccaga tgacacagtc tccatcctca ctgtctgcat ctctgggagg caaagtcacc 60

atcacttgca aggcaagcca agacattaat aagtatatag cttggtacca acacaagcct 120

ggaaaaggtc cataggctgct catacattac acatctacat taaagccagg catcccatca 180

aggttcagtg gaagtgggtc tgggagagat tattccttca gcatcagtga cctggagcct 240

gaagatattg caacttatta ttgtctacag tatgataatc tgaacacgtt cggagggggg 300

accaagctgg aaataaaa 318

<210> 179

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 179

gagatccagc tgcagcagtc tggacctgag ctggtgaagc ctggggcttc agtgaaggtg 60

tcctgcaagg cttctggtta ttcattcact gactacaaca tctactgggt gaagcagagc 120

catggaaaga gccttgagtg gattggatat attgatcctt ccaatggtgg tcctggctac 180

aaccagaagt tcaggggcaa ggccacattg actgttgaca agtcctccag cacagccttc 240

ctgcatctca acagcctgac atctgaggac tctgcagtct attactgtgc aagaagggac 300

aactacggct cggggactat ggactactgg ggtcaaggaa cctcagtcac cgtctcctca 360

<210> 180

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 180

gacattgtga tgacccagtc tcaaaaattc atgtccacat cagtaggaga cagggtcagc 60

atcacctgta aggccagtca gaatgtgggt actgatgtat cctggtatca acagaaacca 120

gggaaatctc ctaaaccact gatttactgg gcatcaaacc ggttcactgg agtccctgat 180

cgcttcatag gtagtggatc tgggacagat ttcactctca ccatcagcaa tgtgcagtct 240

gaagacttgg cagattattt ctgtgagcaa tatagcatct atccgctcac gttcggtgct 300

gggaccaagc tggagctgaa a 321

<210> 181

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 181

gagatccagc tgcagcagtc tggacctgag ctggtgaagc ctggggcgtc agtgaaggta 60

tcctgcaagg cttctggtta ctcattcact gacgacaaca tgtactggggt gaagcagagc 120

catggaaaga gccttgagtg gattggatat attgatcctc tcaatggtgg tactggctac 180

aaccagaaat tcaagggcaa ggccacactg actgttgaca agtcctccag cacagccttc 240

ctgcatctca acagcctgac atctgaggac tctgcagtct attactgtgc aagaagggac 300

aactacgcca cggggactat ggactactgg ggtcaaggaa cctcagtcac cgtctcctca 360

<210> 182

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 182

gacattgtga tgacccagtc tcaaaaattc atgtccacat cagtaggaga cagggtcagc 60

atcacctgca aggccagtaa gaatgtgggt actgatgtat cctggtatca acagaaacca 120

gggaaatctc ctaaaccact gatttactgg gcatcaaacc ggttcactgg agtccctgat 180

cgcttcacag gcagtggatc tgggacagat ttcactctca ccatcaacaa tgtgcagtct 240

gaagacttgg cagattattt ctgtgagcaa tatagcagct atccgctcac gttcggtgct 300

gggaccaagc tggagctgaa a 321

<210> 183

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 183

gaggtccagc tgcagcagtc tggccctgag ctggtgaagc ctggggcttc agtgaagata 60

tcctgcaagg cttctggata cacattcact gactacaaca tggactgggt gaagcagagc 120

catggaaaga gccttgagtg gattggaaat atttatccta tcaatggtta tactggctac 180

aaccagaggt tcaagaacaa ggccacattg actgtagaca agtcctccag cacagcctac 240

atggaactcc acagcctgac atctgaggac tctgcggtct attactgcgc aagagatagt 300

aactacgttg gctggtactt cgatgtctgg ggcgcaggga ccacggtcac cgtctcctca 360

<210> 184

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 184

gatgttgtga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60

atctcttgca gatctagtca gagccttgta cacagtaatg gaaacaccta tttacattgg 120

tacctgcaga agccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 180

tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac attcaagatc 240

agcagagtgg aggctgagga tctgggagtt tatttctgct ctcaaagtac acatgttcct 300

cggacgttcg gtggaggcac caagctggaa atcaaa 336

<210> 185

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 185

gacattgtgc tgacacagtc tcctgcttcc ttaactgtat ctctggggca gagggccacc 60

ttctcatgca gggccagcaa aagtgtcagt acatctggct atagttatat gcactggtac 120

caacagaaac caggacagcc acccaaactc ctcatctatt ttacatccga cctagaacct 180

ggggtccctg ccaggttcac tggcagtggg tctgggacag acttcaccct caacatccat 240

cctgtggagg aggaggatgc tgcaacctat tactgtcagc acagtaggga gcttccgtac 300

cccttcggag gggggaccaa gttggaaata aaa 333

<210> 186

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 186

caggtccagc tacagcagtc tggacctgag ctggtgaagc ctggggcttc agtgaagata 60

tcctgcaagg cttctggcta caccttcgct gactactata taaactgggt gaagcagagg 120

cctggacagg gacttgagtg gattggatgg atttttcctg gaagtggtag tacttactac 180

aatgagaagt tcaagggcaa ggccacactt actgtagaca aatcctccag cacagcctac 240

atgttgctca gcagcctgac ctctgaggac tctgcggtct atttctgtgc aagaggggac 300

tccggtaggg ctatggacta ctggggtcaa ggaacctcag tcaccgtctc ctca 354

<210> 187

<211> 318

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 187

gacatccaga tgacacagtc tccatcctca ctgtctgcat ctctgggagg caaagtcacc 60

atcacttgca aggcaagcca agacattaac aaatatatag cttggtacca acacaagcct 120

ggaaaaggtc ctaggctgct catacattac acatctacat tacagtcagg catcccatca 180

aggttcagtg gaagtgggtc tgggagagat tattccttca gcatcagcaa cctggagcct 240

gaagataatg caacttatta ttgtctacag tatgataatc ttctcacgtt cggtgctggg 300

accaagctgg agctgaaa 318

<210> 188

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 188

caggcgcacc tgaaggagtc aggacctggc ctggtggcgc cctcacagag cctgtccatc 60

acctgcacag tctctggttt ctcattaacc gactatgatg tacactgggt tcgccagtct 120

cggaaagg gtctggagtg gctgggagtg atatggaatg atggaagcac agactataat 180

acagctttca tatctagact gaccatcagc aaggacaact ccaagagcca agttttcttt 240

aaaatgaaca gtctgcaagc tgatgacaca gccatatact actgtgccag aaattggtat 300

ggtggctact ggtttgctta ctggggccaa gggactctgg tcactgtctc tgca 354

<210> 189

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 189

gacatccaga tgactcagtc tccagcctcc ctatctgcat ctgcgggaga aactgtcacc 60

atcacatgtc gatcaagtga gaatatttac agttatttag catggtatca gcagaaacag 120

ggaaaatctc ctcagctcct agtctataat gcaaatgcct tagcagaagg tgtgccatcg 180

aggttcagtg gcagtggatc agtcacacag ttttctctga agatcaacag cctgcagcct 240

gaagattttg ggagttatta ctgtcaacat cattatggta ctccattcac gttcggctcg 300

gggacaaagt tggaaataaa a 321

<210> 190

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 190

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Asn Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val Trp Gly Gln

100 105 110

Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 191

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 191

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Asp Gly Tyr Thr Tyr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val Trp Gly Gln

100 105 110

Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 192

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 192

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val Trp Gly Gln

100 105 110

Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 193

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 193

Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Asn Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 194

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 194

Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Asn Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 195

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 195

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Asn Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 196

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 196

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Asn Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 197

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 197

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Met Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ser Val Ser Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Ser Trp Ile Arg Lys Pro Pro Gly Lys Gly Leu Glu Tyr

35 40 45

Ile Gly Tyr Val Ser Tyr Asp Gly Ser Thr Tyr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Arg Phe Ser

65 70 75 80

Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Tyr Trp Gly Gln

100 105 110

Gly Ile Leu Val Thr Val Ser Ser

115 120

<210> 198

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 198

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Met Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ser Val Ser Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Asn Trp Ile Arg Lys Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Arg Phe Ser

65 70 75 80

Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val Trp Gly Gln

100 105 110

Gly Ile Leu Val Thr Val Ser Ser

115 120

<210> 199

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 199

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Asn Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Val Ala Ser Ile Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Val

50 55 60

Lys Gly Arg Ile Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Phe Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 200

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 200

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Asn Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Val Ala Tyr Ile Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Val

50 55 60

Lys Gly Arg Ile Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Phe Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 201

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 201

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

35 40 45

Val Ala Tyr Ile Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val Trp Gly Gln

100 105 110

Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 202

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 202

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Ser Ile Ile

20 25 30

Gly Thr Asn Ser Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr His Ala Ser Asn Leu Glu Thr Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Pro Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Ser Arg

85 90 95

Lys Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 203

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 203

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly

1 5 10 15

Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ile Ile

20 25 30

Gly Thr Asn Ser Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr His Ala Ser Asn Leu Glu Thr Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn

65 70 75 80

Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Leu Gln Ser Arg

85 90 95

Lys Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 204

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 204

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Ser Ile Ile

20 25 30

Gly Thr Asn Ser Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr His Ala Ser Gln Ser Ile Ser Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Arg

85 90 95

Lys Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 205

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 205

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Ser Ile Ile

20 25 30

Gly Thr Asn Ser Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr His Ala Ser Asn Leu Glu Thr Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Arg Thr Glu Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Ser Arg

85 90 95

Lys Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 206

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 206

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ile Ile

20 25 30

Gly Thr Asn Ser Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

35 40 45

Lys Leu Leu Ile Tyr His Ala Ser Tyr Leu Glu Ser Gly Val Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Ser Arg

85 90 95

Lys Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 207

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 207

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ile Ile

20 25 30

Gly Thr Asn Ser Met His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

35 40 45

Lys Leu Leu Ile Tyr His Ala Ser Asn Leu Glu Ser Gly Val Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Ser Arg

85 90 95

Lys Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 208

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 208

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ile Ile

20 25 30

Gly Thr Asn Ser Met His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

35 40 45

Lys Leu Leu Ile Tyr His Ala Ser Asn Leu Glu Ser Gly Val Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser

65 70 75 80

Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Ser Arg

85 90 95

Lys Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 209

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 209

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Asn Glu Lys Phe

50 55 60

Lys Asp Arg Val Thr Ser Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Val Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 210

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 210

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Arg Ile Tyr Pro Leu Arg Gly Ser Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ser Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Val Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 211

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 211

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Asn Glu Lys Phe

50 55 60

Lys Asp Arg Val Thr Met Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Val Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 212

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 212

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Glu Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Asn Glu Lys Phe

50 55 60

Lys Asp Arg Val Thr Met Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Lys Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 213

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 213

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Met Tyr Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Tyr Pro Leu Arg Gly Ser Ile Asn Phe Asn Glu Lys Phe

50 55 60

Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 214

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 214

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Tyr Pro Leu Arg Gly Ser Ile Asn Phe Asn Glu Lys Phe

50 55 60

Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 215

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 215

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Asp

20 25 30

Gly Ile Arg Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Pro Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Lys Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 216

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 216

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Asp

20 25 30

Gly Ile Arg Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Pro Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Glu Pro Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Lys Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 217

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 217

Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Asn Asp

20 25 30

Gly Ile Arg Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Asp

50 55 60

Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Lys Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 218

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 218

Asp Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Asn Asp

20 25 30

Gly Ile Arg Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Asp

50 55 60

Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn

65 70 75 80

Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Lys Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Leu Lys

100 105 110

<210> 219

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 219

Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Asp

20 25 30

Gly Ile Arg Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Val Glu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Ser Trp

85 90 95

Glu Ile Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 220

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 220

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Thr Ile Tyr

20 25 30

Asp Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ala Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile

50 55 60

Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 221

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 221

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Thr Ile Tyr

20 25 30

Asp Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile

50 55 60

Ser Arg Phe Thr Ile Ser Lys Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 222

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 222

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Thr Ile Tyr

20 25 30

Asp Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ala Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Lys Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 223

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 223

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Thr Ile Tyr

20 25 30

Asp Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Lys Asp Asn Ser Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 224

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 224

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ile Tyr

20 25 30

Asp Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 225

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 225

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ile Tyr

20 25 30

Asp Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 226

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 226

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Met Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ser Val Ser Gly Asp Ser Ile Thr Ile Tyr

20 25 30

Asp Trp His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Val Trp Ser Asp Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Arg Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 227

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 227

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ile Tyr

20 25 30

Asp Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 228

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 228

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asn Ala Lys Thr Leu Pro Glu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 229

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 229

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Val

35 40 45

Tyr Asn Ala Lys Thr Leu Pro Glu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 230

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 230

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asn Ala Lys Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 231

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 231

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Val

35 40 45

Tyr Asn Ala Lys Thr Leu Pro Glu Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 232

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 232

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asn Ala Lys Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 233

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 233

Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asn Ala Lys Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 234

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 234

Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asn Ala Lys Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 235

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 235

Gln Leu Gln Leu Gln Glu Ser Gly Ser Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Phe Ser Leu Thr Asp Tyr

20 25 30

Asp Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Asn Asp Gly Ser Thr Asp Tyr Asn Pro Ser Leu Ile

50 55 60

Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Tyr Gly Gly Tyr Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 236

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 236

Gln Leu Gln Leu Gln Glu Ser Gly Ser Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Thr Asp Tyr

20 25 30

Asp Trp His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Asn Asp Gly Ser Thr Asp Tyr Asn Pro Ser Leu Ile

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Asn Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Tyr Gly Gly Tyr Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 237

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 237

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Thr Asp Tyr

20 25 30

Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Asn Asp Gly Ser Thr Asp Tyr Ala Thr Ser Val Ile

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Tyr Gly Gly Tyr Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 238

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 238

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Thr Asp Tyr

20 25 30

Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Val Ile Trp Asn Asp Gly Ser Thr Asp Tyr Ala Thr Ser Val Ile

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Tyr Gly Gly Tyr Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 239

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 239

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Met Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ser Val Ser Gly Gly Ser Ile Thr Asp Tyr

20 25 30

Asp Trp His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Val Trp Asn Asp Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Arg Phe Ser Leu

65 70 75 80

Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Tyr Gly Gly Tyr Trp Phe Ala Tyr Trp Gly Gln Gly Ile

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 240

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 240

Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Thr Asp Tyr

20 25 30

Asp Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu

35 40 45

Ala Val Ile Trp Asn Asp Gly Ser Thr Asp Tyr Ser Pro Ser Leu Lys

50 55 60

Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val Val Leu

65 70 75 80

Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Tyr Gly Gly Tyr Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 241

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 241

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Glu Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Val

35 40 45

Tyr Asn Ala Asn Ala Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Val Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 242

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 242

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Glu Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Val

35 40 45

Tyr Asn Ala Asn Ala Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Val Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 243

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 243

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asn Ala Asn Ala Ser Ala Glu Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln His Tyr Gly Thr Pro Phe

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 244

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 244

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Leu

35 40 45

Tyr Asn Ala Asn Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe

85 90 95

Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 245

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 245

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Leu

35 40 45

Tyr Asn Ala Asn Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe

85 90 95

Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 246

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 246

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asp Ile Tyr Pro Gly Gly Ile Gly Gly Gly Tyr Thr Lys Tyr Asn

50 55 60

Glu Lys Phe Lys Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Ser

65 70 75 80

Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val

85 90 95

Tyr Tyr Cys Ser Arg Ser Glu Thr Gly Arg Ala Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 247

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 247

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asp Ile Tyr Pro Gly Gly Ile Gly Gly Gly Tyr Thr Lys Tyr Ala

50 55 60

Gln Lys Leu Gln Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Ser

65 70 75 80

Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val

85 90 95

Tyr Tyr Cys Ser Arg Ser Glu Thr Gly Arg Ala Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 248

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 248

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asp Ile Tyr Pro Gly Gly Ile Gly Gly Gly Tyr Thr Lys Tyr Ala

50 55 60

Gln Lys Phe Gln Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Ser

65 70 75 80

Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val

85 90 95

Tyr Tyr Cys Ser Arg Ser Glu Thr Gly Arg Ala Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 249

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 249

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asp Ile Tyr Pro Gly Gly Ile Gly Gly Gly Tyr Thr Lys Tyr Asn

50 55 60

Glu Lys Phe Lys Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Ser

65 70 75 80

Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val

85 90 95

Tyr Phe Cys Ser Arg Ser Glu Thr Gly Arg Ala Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 250

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 250

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Leu Lys Arg Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Trp Met Gly Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asp Ile Tyr Pro Gly Gly Ile Gly Gly Gly Tyr Thr Asn Tyr Ala

50 55 60

Gln Lys Phe Lys Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Ser Ser

65 70 75 80

Thr Ala Tyr Met Gln Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val

85 90 95

Tyr Tyr Cys Ser Arg Ser Glu Thr Gly Arg Ala Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 251

<211> 106

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 251

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Asn Lys Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

His Tyr Thr Ser Thr Leu Lys Pro Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Asn Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 252

<211> 106

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 252

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Lys Tyr

20 25 30

Ile Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

His Tyr Thr Ser Thr Leu Lys Pro Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Arg Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Asn Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 253

<211> 106

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 253

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Asn Lys Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Thr Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Ser Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Asn Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 254

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 254

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ala Asp Tyr

20 25 30

Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Phe Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Arg Val Thr Met Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg Gly Asp Ser Gly Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 255

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 255

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ala Asp Tyr

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Phe Pro Gly Ser Gly Ser Thr Tyr Tyr Ala Glu Lys Phe

50 55 60

Lys Gly Arg Val Thr Ser Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Val Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Asp Ser Gly Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 256

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 256

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ala Asp Tyr

20 25 30

Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Phe Pro Gly Ser Gly Ser Thr Tyr Tyr Ala Gln Lys Leu

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Asp Ser Gly Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 257

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 257

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ala Asp Tyr

20 25 30

Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Phe Pro Gly Ser Gly Ser Thr Tyr Tyr Ala Gln Lys Leu

50 55 60

Gln Gly Arg Val Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Asp Ser Gly Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 258

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 258

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Leu Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ala Asp Tyr

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Phe Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Asp Ser Gly Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 259

<211> 106

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 259

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Lys Tyr

20 25 30

Ile Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

His Tyr Thr Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Leu Thr

85 90 95

Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 260

<211> 106

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 260

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Lys Tyr

20 25 30

Ile Ala Trp Tyr Gln His Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

His Tyr Thr Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Arg Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Leu Thr

85 90 95

Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 261

<211> 106

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 261

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Asn Lys Tyr

20 25 30

Leu Ala Trp Tyr Gln His Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

His Tyr Thr Ser Thr Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 262

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 262

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ile Tyr

20 25 30

Asp Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 263

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 263

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ile Tyr

20 25 30

Asp Trp His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 264

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 264

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ile Tyr

20 25 30

Asp Trp His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 265

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 265

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ile Tyr

20 25 30

Asp Trp His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 266

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 266

Asp Tyr Ser Phe Thr Gly Tyr

15

<210> 267

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 267

His Pro Tyr Tyr Gly Gly

15

<210> 268

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 268

Glu Arg Ser Asn Phe His Ala Leu Asp Tyr

1 5 10

<210> 269

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 269

Gly Tyr Asn Met Asn

15

<210> 270

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 270

Asn Ile His Pro Tyr Tyr Gly Gly Thr Ser Phe Asn Gln Lys Phe Met

1 5 10 15

gly

<210> 271

<211> 119

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 271

Glu Ile Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Asp Tyr Ser Phe Thr Gly Tyr

20 25 30

Asn Met Asn Trp Val Met Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Asn Ile His Pro Tyr Tyr Gly Gly Thr Ser Phe Asn Gln Lys Phe

50 55 60

Met Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Arg Ser Asn Phe His Ala Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Ser Val Thr Val Ser Ser

115

<210> 272

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 272

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Thr Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Phe Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser

20 25 30

Gly Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Phe Thr Ser Asp Leu Glu Pro Gly Val Pro Ala

50 55 60

Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His

65 70 75 80

Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln His Ser Arg

85 90 95

Glu Leu Pro Tyr Pro Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 273

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 273

Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys Ser

1 5 10 15

<210> 274

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 274

Gln Ala Ser Gln Asp Ile Asn Lys Tyr Leu Ala

1 5 10

<210> 275

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 275

Tyr Thr Ser Thr Leu Glu Thr

15

<210> 276

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 276

Asp Tyr Tyr Met Asn

15

<210> 277

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 277

Trp Ile Phe Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Gln Lys Phe Gln

1 5 10 15

gly

<210> 278

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 278

Trp Ile Phe Pro Gly Ser Gly Ser Thr Tyr Tyr Ala Gln Lys Leu Gln

1 5 10 15

gly

<210> 279

<400> 279

000

<210> 280

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 280

Arg Ala Ser Glu Ser Val Asp Asn Asp Gly Ile Arg Phe Leu His

1 5 10 15

<210> 281

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 281

Arg Ala Ser Asn Arg Glu Thr

15

<210> 282

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 282

Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

gly

<210> 283

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 283

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Ile His Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Ala Asn Lys Ser Ile Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 284

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 284

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Asp

20 25 30

Gly Ile Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr Arg Ala Ser Asn Arg Glu Thr Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Lys Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 285

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 285

Arg Ala Ser Thr Arg Ala Thr

15

<210> 286

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 286

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Asp

20 25 30

Gly Ile Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr Arg Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Arg Thr Glu Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Lys Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 287

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 287

Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Ser Pro Ser Phe Gln

1 5 10 15

gly

<210> 288

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 288

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Ile His Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Val Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Phe Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 289

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 289

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 290

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 290

Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Ala Glu Lys Phe Lys

1 5 10 15

gly

<210> 291

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 291

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Ala Glu Lys Phe

50 55 60

Lys Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 292

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 292

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Ala Asp Lys Ser Ile Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 293

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 293

Arg Ala Ser Thr Leu Glu Thr

15

<210> 294

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 294

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Ile His Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Ala Asn Lys Ser Ser Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 295

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 295

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Asp

20 25 30

Gly Ile Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr Arg Ala Ser Thr Leu Glu Thr Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Lys Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 296

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 296

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Ile His Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Ala Asp Lys Ser Ile Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 297

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 297

gagatccagc tgcagcagtc tggagctgaa ctggtgaagc ctggggcttc agtgaagata 60

tcctgcaagg cttctgatta ctcattcact ggctacaaca tgaactgggt gatgcagagc 120

catggaaaga gccttgagtg gattggaaat attcatcctt actatggtgg tactagcttc 180

aatcagaagt tcatgggcaa ggccacattg actgcagaca aatcttccag cacagcctac 240

atgcagctca acagcctgac atctgaagac tctgcagtct attactgtgc aagagagaga 300

agtaacttcc atgctctgga ctactggggt cagggaacct cagtcaccgt ctcctca 357

<210> 298

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 298

gacattgtgc tgacacagtc tcctgcttcc ttaactgtat ctctggggca gagggccacc 60

ttctcatgca gggccagcaa aagtgtcagt acatctggct atagttatat gcactggtac 120

caacagaaac caggacagcc acccaaactc ctcatctatt ttacatccga cctagaacct 180

ggggtccctg ccaggttcac tggcagtggg tctgggacag acttcaccct caacatccat 240

cctgtggagg aggaggatgc tgcaacctat tactgtcagc acagtaggga gcttccgtac 300

cccttcggag gggggaccaa gttggaaata aaa 333

<210> 299

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 299

caggtacaac tccaggaatc cgggcctggg ctcgtcaaac caagcgaaac actctctctc 60

acctgcaccg tttctggggtt ttctcttact atctatgacg tacattgggt aaggcaacca 120

cccgggaagg ggctggagtg gatcggtgta atctggtcag atggatctac agactacaac 180

ccatccctta aaagcagggt gaccattttct aaggacactt ccaagaacca agtatccctt 240

aaattgtcct ctgtaaccgc agcagacacc gcagtttact actgcgcacg aaattgggtt 300

gaccaagcat ggtttgcata ttggggacag ggaactcttg tcactgtgtc ttca 354

<210> 300

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 300

gatattcaaa tgacccaatc cccctcatca ctttcagcat ctgtcggtga tcgggtcacc 60

attacttgca gagccagtaa gaatatctac agctacctgg cttggtatca gcaaaaacct 120

ggtaaggccc ctaaacttct cgtttacaat gctaagaccc ttcccgaggg agttccttcc 180

aggttttccg gtagcgggag tggaacagat ttcaccttga ctatttctag cttgcagccc 240

gaggatttcg ctacatacta ctgccagcat cactatggaa cccccctgac cttcggtcag 300

ggaaccaagc tcgagatcaa a 321

<210> 301

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 301

caagtccagc tcgtacagag cggggcagag ctgaagaagc ctggggcctc cgtcaaggtc 60

tcctgtaagg cttctggtta cacatttgcc gactactaca tgaactgggt acggcaagcc 120

ccaggtcaag ggctggaatg gatgggatgg atttttccag ggagcggcag cacttactac 180

aaccagaaat ttcaaggtcg tgtgacaatg accgtggata aaagcagctc tacagcttac 240

atggagcttt cccgcttgag gtccgatgat actgccgtat attattgtgc ccgtggtgac 300

tcaggtaggg ccatggacta ttggggacag ggcaccctcg tgaccgtgtc cagc 354

<210> 302

<211> 318

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 302

gatatccaga tgacacaatc cccttcatcc ttgagcgcat cagttggcga cagggtcacc 60

ataacttgtc aggctagtca ggatattaac aagtacctgg cttggtatca acacaagcct 120

ggaaaggccc ccaaattgct gattcactac acctctacat tggaaactgg cgtacccagt 180

cgcttttctg ggagtggaag cggaactgat ttcactttca ctatatccag tcttcagcca 240

gaagatatcg caacttacta ttgtcttcag tatgataact tgcttacttt cggaggaggg 300

accaaagttg aaatcaag 318

<210> 303

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 303

caggtgcagt tggtccaatc cggggctgag gtgaagaagc ctggggcctc tgttaaagtt 60

agttgcaagg catcaggcta caccttcgct gactactaca tcaactgggt tagacaggcc 120

cccgggcagg ggttggagtg gatgggttgg atttttccag gatcaggttc aacatattac 180

gcacaaaaac tgcaaggtag agtaaccatg acaactgata ctagcacctc cacagcctat 240

atggaactcc gctctctcag gagtgacgat acagccgttt attactgcgc ccgtggggat 300

tcaggccgtg caatggatta ctggggtcaa gggaccctcg tgaccgtaag ttca 354

<210> 304

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 304

caagttcagt tggtgcaaag cggggcagaa gtgaagaaac ctggtgcttc tgtgaaagtt 60

tcctgcaagg ccagcggcta cacctttact gattacacaa tacactgggt acggcaggca 120

actgggcaag gattggaatg gatggggtgg atatacccat tgcgagggtc tataaactac 180

240

atggaactct catctctcag gagtgaggat accgccgtgt atttctgcgc acgacacggt 300

gcatattact caaacgcttt cgactattgg ggccagggca cccttgtgac tgttagtagc 360

<210> 305

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 305

gagatagtaa tgactcagtc tcccgctaca cttagtgtaa gcccagggga gcgagcaacc 60

ctcagttgca gagcatctga gagtgttgat aatgatggaa tacgttttct ccattggtat 120

caacaaaaac cagggcaggc ccccagattg ctgatctacc gtgcttccaa tcgcgagact 180

ggcattcctg cacgtttcag cggcagcggc tcgggaaccg agtttacact tactattagc 240

tcactccagt ctgaagactt cgctgtgtat tactgtcagc aatccaacaa ggacccatac 300

actttcggag gcggcactaa ggttgagatc aaa 333

<210> 306

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 306

gagatagtta tgactcagtc tcccgccaca ctttcagtaa gtcccggtga acgcgccacc 60

ctgtcctgcc gtgcttccga atcagtggat aatgacggca ttaggtttt gcactggtac 120

caacaaaagc ccggacaggc cccccgcctg ctgatatatc gtgcatcaac acgagcaaca 180

gggatccccg ctcgatttag tggatccggga agcaggaccg aatttacact taccattttcc 240

tcacttcagt cagaagattt cgccgtttac tactgtcagc agtcaaataa ggatccttac 300

acatttgggg gcggtacaaa agtcgagatc aaa 333

<210> 307

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 307

gaggtccagt tggtccagtc aggagccgaa gtcaagaagc ctggggaaag cctgaaaata 60

agttgcaaag ctagtggata tacatttaca gattatacca ttcattgggt ccggcaaatg 120

cggaaaag gcttggagtg gatggggtgg atttatcccc tccgaggctc aataaattat 180

240

ttgcagtgga gttcattgaa ggctagtgac accgctatgt atttctgcgc tagacatggt 300

gcatattatt caaatgcctt cgactattgg ggccagggca ccctcgtcac tgtgagttcc 360

<210> 308

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 308

caggtgcaac ttgttcagtc aggggctgaa gtaaagaagc caggctcatc agtcaaggta 60

tcatgcaaag catctggcta tacatttaca gattacacca ttcactggggt gaggcaagct 120

cccggtcaag gtctcgagtg gatggggtgg atataccctc tcagaggctc tataaattac 180

gctcagaaat ttcaagggag agttacaatt actgctgata aaagtaccag cactgcttat 240

atggagcttt cctcacttcg ttcagaggac accgccgttt acttttgtgc ccggcatggt 300

gcctattatt caaatgcctt cgattattgg gggcagggaa ctttggtcac agtttcatct 360

<210> 309

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 309

caagttcaac ttgtccaaag tggggctgaa gttaaaaaac ctggatcatc agtcaaggtt 60

tcatgcaaag ccagcggtta cacatttaca gactatacaa tacattgggt tcgacaggct 120

cccggggcaag ggctcgaatg gatgggatgg atttatcccc tcaggggctc aattaactat 180

gctgagaaat ttaagggtcg tgtaacactc accgccgata aatccacctc aaccgtatat 240

atggagcttt cttctcttcg ctctgaagat accgccgtct atttctgcgc acgacacggg 300

gcatactatt ctaatgcttt tgactactgg ggacaaggga cacttgtgac cgttagtagc 360

<210> 310

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 310

caagtgcagt tggtccagag tggagcagag gtgaagaagc ctggtgcttc cgtcaaggtg 60

agttgcaagg catctggtta tactttcact gactacacaa ttcattggggt caggcaggcc 120

cctggacagg gactggaatg gatgggatgg atctatccac ttagaggatc aatcaactat 180

gctcaaaagt tccagggtcg tgtaacaatg accgcagaca aaagtatctc aactgtatac 240

atggaattgt cccgattgag gagcgacgac acagccgtat attattgtgc caggcacgga 300

gcctactaca gtaatgcctt cgactactgg gggcagggca cccttgttac cgtgtccagc 360

<210> 311

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 311

caagtgcagc tcgttcagtc tggcgcagaa gtgaagaagc caggagcttc cgttaaagtg 60

tcctgtaaag cctctggata tacattcaca gattatacaa ttcactgggt gagacaagca 120

accggtcaag gtctcgaatg gatgggctgg atataccccc tccgaggttc catcaactac 180

gctcaaaaat tccaaggacg agtcactatg acagcaaaca agagttcctc cactgtatat 240

atggaactct ctagtttgcg ctctgaagac accgccgtgt acttctgtgc caggcacggc 300

gcatactatt ctaatgcatt tgactattgg gggcagggca cattggtaac agttagttcc 360

<210> 312

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 312

gaaattgtaa tgacccagag ccccgccacc cttagtgtgt ccccaggcga gagggccact 60

ctttcttgcc gcgcaagcga atccgtagac aacgatggta taagattttt gcattggtat 120

cagcaaaagc caggccaggc accccggctt ctcatctaca gagctagcac cctcgaaact 180

ggaatccccg ctcgtttttc aggatctggt agcggaacag aatttacttt gacaattagt 240

agtttgcagt cagaggactt tgctgtctat tattgccagc agtctaataa agatccatac 300

accttcggcg gagggaccaa agtagagatt aaa 333

<210> 313

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 313

caagttcagt tggtgcaaag cggggcagaa gtgaagaaac ctggtgcttc tgtgaaagtt 60

tcctgcaagg ccagcggcta cacctttact gattacacaa tacactgggt acggcaggca 120

actgggcaag gattggaatg gatggggtgg atatacccat tgcgagggtc tataaactac 180

240

atggaactct catctctcag gagtgaggat accgccgtgt atttctgcgc acgacacggt 300

gcatattact caaacgcttt cgactattgg ggccagggca cccttgtgac tgttagtagc 360

<210> 314

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 314

Lys Ser Ser Gln Ser Val Asp Asn Asp Gly Ile Arg Phe Leu His

1 5 10 15

<210> 315

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 315

Arg Ala Ser Thr Arg Glu Ser

15

<210> 316

<211> 111

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 316

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Asp Asn Asp

20 25 30

Gly Ile Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Thr Arg Glu Ser Gly Val Pro Asp

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Lys Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 317

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 317

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 318

<211> 333

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 318

gacattgtaa tgacccagtc tcccgatagc ctcgctgtct cactcggaga acgcgcaacc 60

atcaactgca agtcctccca aagcgttgac aatgacggca ttaggttttt gcactggtac 120

cagcagaaac ccggtcaacc tcctaagttg ctcatttacc gagcatctac ccgcgagtca 180

ggagtacctg atcgcttttc cggtagcggt agtggaacag attttactct gaccattagt 240

tcactccagg cagaagatgt ggctgtctac tactgccaac agtcaaataa agacccttat 300

accttcggtg ggggtaccaa agtagagatc aaa 333

<210> 319

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polynucleotide"

<400> 319

caggtgcagt tggtccagag cggggcagag gttaagaagc ctggggcctc agtaaaggta 60

tcctgcaagg cttctgggta caccttcaca gattacacta ttcattgggt gcgccaagca 120

cctggtcaag gccttgaatg gatgggatgg atttacccct tgcgagggag tattaattat 180

gcacagaagt tccagggaag ggttactctt accgccgaca agtccacatc aaccgtttac 240

atggagcttt cctctctcag gtccgaagac actgctgtat atttctgcgc tcggcatggg 300

gcttattaca gcaacgcctt cgattactgg ggtcagggta cattggtcac agtgtccagt 360

<210> 320

<211> 327

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 320

Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser

1 5 10 15

Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe

20 25 30

Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly

35 40 45

Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu

50 55 60

Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr

65 70 75 80

Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys

85 90 95

Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro

100 105 110

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys

115 120 125

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val

130 135 140

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

145 150 155 160

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu

165 170 175

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His

180 185 190

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys

195 200 205

Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln

210 215 220

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu

225 230 235 240

Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

245 250 255

Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn

260 265 270

Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu

275 280 285

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val

290 295 300

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln

305 310 315 320

Lys Ser Leu Ser Leu Ser Pro

325

<210> 321

<211> 328

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 321

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

225 230 235 240

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro

325

<210> 322

<211> 328

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 322

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Ile Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro

325

<210> 323

<211> 323

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 323

Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser

1 5 10 15

Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe

20 25 30

Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly

35 40 45

Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu

50 55 60

Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr

65 70 75 80

Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr

85 90 95

Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro

100 105 110

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

115 120 125

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

130 135 140

Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val

145 150 155 160

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser

165 170 175

Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu

180 185 190

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala

195 200 205

Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro

210 215 220

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

225 230 235 240

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

245 250 255

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

260 265 270

Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

275 280 285

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

290 295 300

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

305 310 315 320

Leu Ser Pro

<210> 324

<211> 323

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 324

Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser

1 5 10 15

Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe

20 25 30

Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly

35 40 45

Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu

50 55 60

Ser Ser Val Val Thr Val Thr Ser Ser Asn Phe Gly Thr Gln Thr Tyr

65 70 75 80

Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr

85 90 95

Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro

100 105 110

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

115 120 125

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

130 135 140

Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Met

145 150 155 160

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser

165 170 175

Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu

180 185 190

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala

195 200 205

Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro

210 215 220

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

225 230 235 240

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

245 250 255

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

260 265 270

Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

275 280 285

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

290 295 300

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

305 310 315 320

Leu Ser Pro

<210> 325

<211> 323

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 325

Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser

1 5 10 15

Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe

20 25 30

Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly

35 40 45

Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu

50 55 60

Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr

65 70 75 80

Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr

85 90 95

Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro

100 105 110

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

115 120 125

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

130 135 140

Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val

145 150 155 160

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser

165 170 175

Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu

180 185 190

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala

195 200 205

Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro

210 215 220

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

225 230 235 240

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

245 250 255

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

260 265 270

Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

275 280 285

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

290 295 300

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

305 310 315 320

Leu Ser Pro

<210> 326

<211> 323

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

polypeptide"

<400> 326

Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser

1 5 10 15

Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe

20 25 30

Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly

35 40 45

Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu

50 55 60

Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr

65 70 75 80

Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr

85 90 95

Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro

100 105 110

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

115 120 125

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

130 135 140

Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val

145 150 155 160

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser

165 170 175

Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu

180 185 190

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala

195 200 205

Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro

210 215 220

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

225 230 235 240

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ser

245 250 255

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

260 265 270

Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

275 280 285

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

290 295 300

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

305 310 315 320

Leu Ser Pro

<210> 327

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (1)..(1)

<223> /replace="Lys"

<220>

<221> OPTION

<222> (2)..(2)

<223> /replace="Ser"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Gln"

<220>

<221> OPTION

<222> (14)..(14)

<223> /replace="Leu"

<220>

<221> OTHER_FEATURES

<222> (1)..(15)

<223> /note="The remainder of the variant presented in the sequence is not

have preferences over those presented in the annotations

for variant provisions"

<400> 327

Arg Ala Ser Glu Ser Val Asp Asn Asp Gly Ile Arg Phe Met His

1 5 10 15

<210> 328

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Thr"

<220>

<221> OPTION

<222> (5)..(5)

<223> /replace="Arg"

<220>

<221> OPTION

<222>(6)..(6)

<223> /replace="Ala"

<220>

<221> OPTION

<222>(7)..(7)

<223> /replace="Thr"

<220>

<221> OTHER_FEATURES

<222> (1)..(7)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 328

Arg Ala Ser Asn Leu Glu Ser

15

<210> 329

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (12)..(12)

<223> /replace="Ser" or "Ala"

<220>

<221> OPTION

<222> (13)..(13)

<223> /replace="Pro" or "Gln"

<220>

<221> OPTION

<222> (14)..(14)

<223> /replace="Ser"

<220>

<221> OPTION

<222> (16)..(16)

<223> /replace="Gln"

<220>

<221> OPTION

<222> (17)..(17)

<223> /replace="Gly"

<220>

<221> OTHER_FEATURES

<222> (1)..(17)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 329

Trp Ile Tyr Pro Leu Arg Gly Ser Ile Asn Tyr Asn Glu Lys Phe Lys

1 5 10 15

asp

<210> 330

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (3)..(3)

<223> /replace="Thr"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Phe"

<220>

<221> OPTION

<222>(6)..(6)

<223> /replace=" "

<220>

<221> OPTION

<222>(7)..(7)

<223> /replace="Asp" or "Ser"

<220>

<221> OTHER_FEATURES

<222> (1)..(8)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 330

Gly Tyr Ser Ile Thr Ser Gly Tyr

15

<210> 331

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (1)..(1)

<223> /replace="Tyr" or " "

<220>

<221> OPTION

<222> (2)..(2)

<223> /replace="Pro"

<220>

<221> OPTION

<222> (3)..(3)

<223> /replace="Leu" or "Arg"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Asn" or "Arg"

<220>

<221> OPTION

<222> (5)..(5)

<223> /replace="Ser"

<220>

<221> OPTION

<222>(6)..(6)

<223> /replace="Asp" or "Ser"

<220>

<221> OTHER_FEATURES

<222> (1)..(6)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 331

Asn Ser Tyr Asp Gly Tyr

15

<210> 332

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (1)..(1)

<223> /replace="Glu" or "His"

<220>

<221> OPTION

<222> (2)..(2)

<223> /replace=" "

<220>

<221> OPTION

<222> (3)..(3)

<223> /replace="Asp" or "Ala"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Gly" or "Tyr"

<220>

<221> OPTION

<222>(6)..(6)

<223> /replace="Asp" or " "

<220>

<221> OPTION

<222>(7)..(7)

<223> /replace="Tyr" or "Ser" or "Lys"

<220>

<221> OPTION

<222>(8)..(8)

<223> /replace="Asn" or "Arg"

<220>

<221> OPTION

<222>(9)..(9)

<223> /replace="Ala" or "Gly"

<220>

<221> OPTION

<222> (11)..(11)

<223> /replace="Asp"

<220>

<221> OPTION

<222> (12)..(12)

<223> /replace="Tyr"

<220>

<221> OTHER_FEATURES

<222> (1)..(12)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 332

Tyr Gly Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val

1 5 10

<210> 333

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (1)..(1)

<223> /replace="Lys"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Gln"

<220>

<221> OPTION

<222>(7)..(7)

<223> /replace="Ser"

<220>

<221> OPTION

<222>(8)..(8)

<223> /replace="Phe" or "Ile"

<220>

<221> OPTION

<222>(9)..(9)

<223> /replace="Ala" or "Ile" or "Asp"

<220>

<221> OPTION

<222> (11)..(11)

<223> /replace="Thr"

<220>

<221> OPTION

<222> (12)..(12)

<223> /replace="Asn" or "Arg"

<220>

<221> OPTION

<222> (13)..(13)

<223> /replace="Leu" or "Ser"

<220>

<221> OPTION

<222> (14)..(14)

<223> /replace="Ile"

<220>

<221> OPTION

<222> (15)..(15)

<223> /replace="His"

<220>

<221> OTHER_FEATURES

<222> (1)..(15)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 333

Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Ile Ser Phe Met Asn

1 5 10 15

<210> 334

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (1)..(1)

<223> /replace="Arg" or "His"

<220>

<221> OPTION

<222> (5)..(5)

<223> /replace="Leu"

<220>

<221> OPTION

<222>(6)..(6)

<223> /replace="Glu"

<220>

<221> OPTION

<222>(7)..(7)

<223> /replace="Pro" or "Thr"

<220>

<221> OTHER_FEATURES

<222> (1)..(7)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 334

Ala Ala Ser Asn Gln Gly Ser

15

<210> 335

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (1)..(1)

<223> /replace="Leu"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Arg" or "Asn"

<220>

<221> OPTION

<222> (5)..(5)

<223> /replace="Lys"

<220>

<221> OPTION

<222>(6)..(6)

<223> /replace="Tyr" or "Ile" or "Asp"

<220>

<221> OPTION

<222>(8)..(8)

<223> /replace="Trp" or "Tyr"

<220>

<221> OTHER_FEATURES

<222> (1)..(9)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 335

Gln Gln Ser Lys Glu Val Pro Arg Thr

15

<210> 336

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (1)..(1)

<223> /replace=" "

<220>

<221> OPTION

<222> (2)..(2)

<223> /replace="Asp" or "Ser"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Phe" or "Thr" or "Asp"

<220>

<221> OPTION

<222> (5)..(5)

<223> /replace="Met" or "Ile" or "Val"

<220>

<221> OPTION

<222>(6)..(6)

<223> /replace="His" or "Phe"

<220>

<221> OTHER_FEATURES

<222> (1)..(6)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 336

Ser Gly Tyr Tyr Trp Asn

15

<210> 337

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (1)..(1)

<223> /replace="Arg or "Trp"

<220>

<221> OPTION

<222> (3)..(3)

<223> /replace="Tyr" or " "

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Pro"

<220>

<221> OPTION

<222> (5)..(5)

<223> /replace="Leu" or "Arg"

<220>

<221> OPTION

<222>(6)..(6)

<223> /replace="Asn" or "Arg"

<220>

<221> OPTION

<222>(7)..(7)

<223> /replace="Ser"

<220>

<221> OPTION

<222>(8)..(8)

<223> /replace="Asp" or "Ser"

<220>

<221> OPTION

<222>(9)..(9)

<223> /replace="Thr" or "Ile"

<220>

<221> OPTION

<222> (10)..(10)

<223> /replace="Phe" or "Lys"

<220>

<221> OPTION

<222> (13)..(13)

<223> /replace="Gln" or "Glu"

<220>

<221> OPTION

<222> (14)..(14)

<223>/replace="Lys"

<220>

<221> OPTION

<222> (15)..(15)

<223> /replace="Phe"

<220>

<221> OPTION

<222> (17)..(17)

<223> /replace="Gly" or "Asp"

<220>

<221> OTHER_FEATURES

<222> (1)..(17)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 337

Tyr Ile Asn Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Leu Lys

1 5 10 15

Asn

<210> 338

<211> 4

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 338

Asp Asp Ser Asp

1

<210> 339

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 339

Val Thr Phe Thr Met Gly Gln Val

15

<210> 340

<211> 4

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 340

Met Pro Ser His

1

<210> 341

<211> 4

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<400> 341

Pro Arg Ala Arg

1

<210> 342

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (12)..(12)

<223> /replace="Pro"

<220>

<221> OPTION

<222> (13)..(13)

<223> /replace="Ser"

<220>

<221> OPTION

<222> (14)..(14)

<223> /replace="Leu"

<220>

<221> OPTION

<222> (15)..(15)

<223> /replace="Lys"

<220>

<221> OTHER_FEATURES

<222> (1)..(16)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 342

Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile Ser

1 5 10 15

<210> 343

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Met"

<220>

<221> OTHER_FEATURES

<222> (1)..(5)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 343

Asp Tyr Tyr Ile Asn

15

<210> 344

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (12)..(12)

<223> /replace="Ala"

<220>

<221> OPTION

<222> (13)..(13)

<223> /replace="Gln"

<220>

<221> OPTION

<222> (15)..(15)

<223> /replace="Leu"

<220>

<221> OPTION

<222> (16)..(16)

<223> /replace="Gln"

<220>

<221> OTHER_FEATURES

<222> (1)..(17)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 344

Trp Ile Phe Pro Gly Ser Gly Ser Thr Tyr Tyr Asn Glu Lys Phe Lys

1 5 10 15

gly

<210> 345

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222> (1)..(1)

<223> /replace="Gln"

<220>

<221> OTHER_FEATURES

<222> (1)..(11)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 345

Lys Ala Ser Gln Asp Ile Asn Lys Tyr Ile Ala

1 5 10

<210> 346

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial Sequence Description: Synthetic

peptide"

<220>

<221> OPTION

<222>(6)..(6)

<223> /replace="Glu"

<220>

<221> OPTION

<222>(7)..(7)

<223> /replace="Thr"

<220>

<221> OTHER_FEATURES

<222> (1)..(7)

<223> /note="The remainder of the variant presented in the sequence

have no preference over those presented in

annotations for variant provisions"

<400> 346

Tyr Thr Ser Thr Leu Gln Ser

15

<---

Claims (61)

1. Anti-proliferation-inducing ligand A (APRIL) antibody molecule comprising a heavy chain variable region (VH) containing three complementarity-determining heavy chain regions (HCDR1, HCDR2 and HCDR3) and a light chain variable region (VH) containing three complementarity-determining regions. complementarity of the light chain region (LCDR1, LCDR2 and LCDR3). where VH contains HCDR1 containing the amino acid sequence of SEQ ID NO:11; HCDR2 containing the amino acid sequence of SEQ ID NO:12, and HCDR3 containing the amino acid sequence of SEQ ID NO:13; and VL contains LCDR1 containing the amino acid sequence of SEQ ID NO:280; LCDR2 containing the amino acid sequence of SEQ ID NO:285 and LCDR3 containing the amino acid sequence of SEQ ID NO:16 according to Chothia numbering; or where VH contains HCDR1 containing the amino acid sequence of SEQ ID NO:17; HCDR2 containing the amino acid sequence of SEQ ID NO:282, and HCDR3 containing the amino acid sequence of SEQ ID NO:13; and VL contains LCDR1 containing the amino acid sequence of SEQ ID NO:280; LCDR2 containing the amino acid sequence of SEQ ID NO:285, and LCDR3 containing the amino acid sequence of SEQ ID NO:16 according to Kabat numbering. 2. An antibody molecule according to claim 1, which contains one or both of the following: (i) a VH containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or that is homologous in at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of any amino acid sequence of SEQ ID NO:283, 288, 289, 291, 292, 294, 296, or 317; or (ii) a VL containing an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or that is homologous in at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% of the amino acid sequence of SEQ ID NO:286. 3. An antibody molecule according to claim 1 or 2, which contains: (i) a VH containing the amino acid sequence of SEQ ID NO:296, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues, or which is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous to the amino acid sequence of SEQ ID NO:296; or (ii) a VL containing the amino acid sequence of SEQ ID NO:286, or an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or which is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homologous to the amino acid sequence of SEQ ID NO:286. 4. An antibody molecule according to any one of claims 1 to 3, which is a synthetic or isolated antibody molecule and/or is a humanized antibody molecule, optionally wherein the antibody molecule comprises one or more framework regions derived from a human germline framework sequence. 5. An antibody molecule according to any one of claims 1 to 4, which contains an IgG1, IgG2, IgG3 or IgG4 heavy chain constant region, optionally, where the antibody molecule contains an IgG2 heavy chain constant region and/or contains a light chain kappa or lambda constant region, for example, the kappa light chain constant region. 6. An antibody molecule according to any one of claims 1 to 5, wherein the Fc region of the antibody molecule contains: (i) one or more mutations located at the interface between the CH2 and CH3 domains, optionally, where one or more mutations increase the binding affinity for the neonatal FcRn receptor, the half-life of the antibody molecule, or both; (ii) 1, 2, 3, 4, 6 or all mutations selected from T250Q, M252Y, S254T, T256E, M428L, H433K or N434F IgG1; (iii) one or more mutations at positions 233-236 or 322 of human IgG1 or IgG2, or one or more substitutions at positions 327, 330 or 331 of human IgG4, optionally, where one or more mutations reduce complement dependent cytotoxicity (CDC); and/or (iv) 1, 2, 3, 4, 6, 7 or all mutations selected from E233P, L234V, L235A, G236, K322A, A327G, A330S or P331S. 7. An antibody molecule according to any one of claims 1 to 6, which contains two heavy chain variable regions and two light chain variable regions, or is a Fab, F(ab')2, Fv, Fd, or a single chain Fv fragment (scFv). 8. An antibody molecule against proliferation-inducing ligand A (APRIL) comprising a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO:296 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO:286. 9. An antibody molecule against proliferation-inducing ligand A (APRIL) comprising a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO:296 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO:286; wherein the antibody molecule comprises an IgG2 heavy chain constant region and a light chain kappa constant region. 10. A pharmaceutical composition for the treatment of IgA nephropathy in a subject, comprising an effective amount of an antibody molecule according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier. 11. A nucleic acid molecule encoding a heavy chain variable region (VH) and a light chain variable region (VL) of an antibody molecule according to any one of claims 1-9. 12. A nucleic acid molecule encoding a heavy chain variable region (VH) of an antibody molecule according to any one of claims 1-9. 13. A nucleic acid molecule encoding a light chain variable region (VL) of an antibody molecule according to any one of claims 1-9. 14. An expression vector containing a nucleic acid molecule according to any one of claims 11-13. 15. An isolated cell for obtaining an anti-APRIL antibody molecule, where the cell contains: (i) a nucleic acid molecule according to claim 11 or (ii) an expression vector containing the nucleic acid molecule according to claim 11. 16. A kit for the treatment of IgA nephropathy, containing an antibody molecule according to any one of claims 1 to 9 and instructions for use of the antibody molecule. 17. A method for producing an anti-APRIL antibody molecule, comprising culturing a cell according to claim 15 under conditions that ensure the production of an antibody molecule. 18. The method of claim 17, further comprising isolating or purifying the antibody molecule. 19. A method of treating IgA nephropathy in an individual, comprising administering to the individual an antibody molecule according to any one of claims 1 to 9 or a composition according to claim 10. 20. The method of claim 19, wherein the antibody molecule is administered intravenously or subcutaneously to the individual. 21. The method according to claim 19 or 20, where the antibody molecule is administered to the individual at a dose of from 0.1 mg/kg to 50 mg/kg, up to 0.2 mg/kg to 25 mg/kg, from 0.5 mg/kg up to 10 mg/kg, from 0.5 mg/kg to 5 mg/kg, from 0.5 mg/kg to 3 mg/kg, from 0.5 mg/kg to 2.5 mg/kg, from 0, 5 mg/kg to 2 mg/kg, 0.5 mg/kg to 1.5 mg/kg, 0.5 mg/kg to 1 mg/kg, 1 mg/kg to 1.5 mg/kg , 1 mg/kg to 2 mg/kg, 1 mg/kg to 2.5 mg/kg, 1 mg/kg to 3 mg/kg, 1 mg/kg to 10 mg/kg, or 1 mg /kg to 5 mg/kg or 1 mg/kg, 2 mg/kg, 4 mg/kg or 8 mg/kg, or in a fixed dose from 10 mg to 1000 mg, from 10 mg to 500 mg, from 10 mg to 250 mg, from 10 mg to 150 mg, from 10 mg to 100 mg, from 10 mg to 50 mg, from 250 mg to 500 mg, 150 mg to 500 mg, 100 mg to 500 mg, 50 mg to 500 mg, 25 mg to 250 mg, 50 mg to 150 mg, 50 mg to 100 mg, 100 mg to 150 mg , from 100 mg to 200 mg or from 150 mg to 250 mg, optionally, where the antibody molecule is administered once a week, twice a week, once every two weeks, or once every four weeks, or once a month, once every two months, or once every three months. 22. The method of any one of claims 19-21, wherein administration of the antibody molecule reduces the level of IgA in the peripheral tissue, optionally wherein the peripheral tissue is serum, mucosal tissue, bone marrow, or any combination thereof. 23. The method of any one of claims 19-22, wherein administration of the antibody molecule reduces the level of the IgA variant, optionally wherein the IgA variant is IgA1, polymeric IgA1 (pIgA1), O-linked glycosylation IgA1, or any combination thereof. 24. The method according to any one of claims 19-23, further comprising determining the level of IgA in a sample of peripheral tissue from an individual, optionally, where the peripheral tissue is serum, mucosal tissue or bone marrow. 25. The method of any one of claims 19-24, further comprising administering a second IgA nephropathy therapy to the patient. 26. A method of treating diabetic nephropathy in an individual, comprising administering to the individual an antibody molecule according to any one of claims 1 to 9 or a composition according to claim 10. 27. An antibody molecule according to any one of claims 1 to 9 or a composition according to claim 10 for use in a method for treating IgA nephropathy in an individual. 28. An antibody molecule for use according to claim 27, wherein the antibody molecule is administered to an individual intravenously or subcutaneously. 29. An antibody molecule for use according to claim 27 or 28, wherein the antibody molecule is administered to an individual at a dose of 0.1 mg/kg to 50 mg/kg, 0.2 mg/kg to 25 mg/kg, 0.5 mg/kg to 10 mg/kg, 0.5 mg/kg to 5 mg/kg, 0.5 mg/kg to 3 mg/kg, 0.5 mg/kg to 2.5 mg/kg, 0.5 mg/kg to 2 mg/kg, 0.5 mg/kg to 1.5 mg/kg, 0.5 mg/kg to 1 mg/kg, 1 mg/kg to 1.5 mg/kg, 1 mg/kg to 2 mg/kg, 1 mg/kg to 2.5 mg/kg, 1 mg/kg to 3 mg/kg, 1 mg/kg to 10 mg/kg, or 1 mg/kg to 5 mg/kg or 1 mg/kg, 2 mg/kg, 4 mg/kg, or 8 mg/kg, or in a fixed dose from 10 mg to 1000 mg, from 10 mg to 500 mg, from 10 mg to 250 mg, from 10 mg to 150 mg, from 10 mg to 100 mg, from 10 mg to 50 mg, from 250 mg to 500 mg, 150 mg to 500 mg, 100 mg to 500 mg, 50 mg to 500 mg, 25 mg to 250 mg, 50 mg to 150 mg, 50 mg to 100 mg, 100 mg to 150 mg , from 100 mg to 200 mg or from 150 mg to 250 mg, optionally, where the antibody molecule is administered once a week, twice a week, once every two weeks, or once every four weeks, or once a month, once every two months, or once every three months. 30. An antibody molecule for use according to any one of claims 27-29, wherein the antibody molecule reduces IgA levels in peripheral tissue, optionally wherein the peripheral tissue is serum, mucosal tissue, bone marrow, or any combination thereof. 31. An antibody molecule for use according to any one of claims 27-30, wherein the antibody molecule reduces the level of the IgA variant, optionally, where the IgA variant is IgA1, IgA1 in polymeric form (pIgA1), IgA1 with O-linked glycosylation, or any combination thereof . 32. An antibody molecule for use according to any one of claims 27-31, wherein the use includes determining the level of IgA in a sample of peripheral tissue from an individual, optionally, where the peripheral tissue is serum, mucosal tissue, or bone marrow. 33. An antibody molecule for use according to any one of claims 27-32, wherein the use includes administering a second therapy to IgA nephropathy in a patient. 34. An antibody molecule according to any one of claims 1 to 9 or a composition according to claim 10 for use in a method for treating diabetic nephropathy in an individual. 35. The use of an antibody molecule according to any one of claims 1 to 9 or a composition according to claim 10 for the preparation of a medicament for the treatment of IgA nephropathy in an individual. 36. Use according to claim 35, wherein the antibody molecule is administered intravenously or subcutaneously to the individual. 37. Use according to claim 35 or 36, where the antibody molecule is administered to the patient at a dose of 0.1 mg/kg to 50 mg/kg, 0.2 mg/kg to 25 mg/kg, 0.5 mg/kg up to 10 mg/kg, from 0.5 mg/kg to 5 mg/kg, from 0.5 mg/kg to 3 mg/kg, from 0.5 mg/kg to 2.5 mg/kg, from 0, 5 mg/kg to 2 mg/kg, 0.5 mg/kg to 1.5 mg/kg, 0.5 mg/kg to 1 mg/kg, 1 mg/kg to 1.5 mg/kg , 1 mg/kg to 2 mg/kg, 1 mg/kg to 2.5 mg/kg, 1 mg/kg to 3 mg/kg, 1 mg/kg to 10 mg/kg, or 1 mg /kg to 5 mg/kg or 1 mg/kg, 2 mg/kg, 4 mg/kg or 8 mg/kg, or in a fixed dose from 10 mg to 1000 mg, from 10 mg to 500 mg, from 10 mg to 250 mg, from 10 mg to 150 mg, from 10 mg to 100 mg, from 10 mg to 50 mg, from 250 mg to 500 mg, 150 mg to 500 mg, 100 mg to 500 mg, 50 mg to 500 mg, 25 mg to 250 mg, 50 mg to 150 mg, 50 mg to 100 mg, 100 mg to 150 mg , from 100 mg to 200 mg or from 150 mg to 250 mg, optionally, where the antibody molecule is administered once a week, twice a week, once every two weeks, or once every four weeks, or once a month, once every two months, or once every three months. 38. Use according to any one of claims 35-37, wherein the antibody molecule lowers the level of IgA in peripheral tissue, optionally wherein the peripheral tissue is serum, mucosal tissue, bone marrow, or any combination thereof. 39. Use according to any one of claims 35-38, wherein the antibody molecule reduces the level of the IgA variant, optionally, where the IgA variant is IgA1, IgA1 in polymeric form (pIgA1), IgA1 with O-linked glycosylation, or any combination thereof. 40. Use according to any one of claims 35 to 39, wherein the use comprises determining the level of IgA in a peripheral tissue sample from an individual, optionally wherein the peripheral tissue is serum, mucosal tissue, or bone marrow. 41. Use according to any one of claims 35 to 40, wherein the use comprises administering a second therapy for IgA nephropathy in a patient. 42. The use of an antibody molecule according to any one of claims 1 to 9 or a composition according to claim 10 for the preparation of a medicament for the treatment of diabetic nephropathy in an individual.

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