CN116670168A

CN116670168A - Antibody molecules against APRIL and uses thereof

Info

Publication number: CN116670168A
Application number: CN202180052360.4A
Authority: CN
Inventors: J·R·梅迪; Z·施莱弗; K·维斯瓦纳森; A·M·沃拉科特; H·阿达力豪; B·兰马克里斯南; G·巴布科克; J·雅布罗; A·沙克特; M·马图尔
Original assignee: Visterra Inc
Current assignee: Visterra Inc
Priority date: 2020-06-24
Filing date: 2021-06-24
Publication date: 2023-08-29

Abstract

Antibody molecules that specifically bind to APRIL are disclosed. The antibody molecules are useful in the treatment, prevention and/or diagnosis of disorders such as IgA nephropathy.

Description

Antibody molecules against APRIL and uses thereof

Cross Reference to Related Applications

The application requires No. 63/043, 558 submitted on 24 th month 6 of 2020; no. 63/091, 002 submitted on day 13 of 10 of 2020; no. 63/136, 950 submitted on day 13, 1, 2021; and priority of U.S. provisional application No. 63/195, 527 filed on 1, 6, 2021. The contents of the above-mentioned application are incorporated by reference in their entirety.

Sequence listing

The present application comprises a sequence listing submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy created at month 17 of 2021 was named P2029-7037WO_SL.txt, size 259,172 bytes.

Background

IgA nephropathy is one of the most common chronic glomerular diseases worldwide. Conservative epidemiological estimates indicate global morbidity of about 5-50 cases/million (children) and 10-40 cases/million (adults). The disease incidence shows regional preference, the prevalence of asia and america is high, and the disease burden in japan and china is particularly high. In japan, the number of IgA nephropathy cases confirmed by biopsy is estimated to be about 35 ten thousand. In the united states, this prediction is about 10 tens of thousands, and therefore it is the most commonly diagnosed 1 ° glomerular disease in adults. Although IgA nephropathy is a relatively inert disease, it can lead to End Stage Renal Disease (ESRD), i.e., 20-50% of patients develop renal failure over a 20-30 year time span. Given the need to confirm disease by renal biopsy, which can be severely underestimated, renal biopsy is practiced differently in a variety of clinical settings. The disease has complex pathogenesis, including genetic, epidemiological and potential environmental factors, affecting the etiology, pathology and progression of the disease. It also has different clinical manifestations, ranging from asymptomatic to end-stage renal failure (ESRD). IgA nephropathy is caused by IgA deposition, usually in the form of a mesangial immune complex. There is currently no disease-specific treatment for primary disease or disease progression.

There is a need to develop new methods for the treatment, prevention and diagnosis of IgA nephropathy and other diseases with similar disease mechanisms.

Disclosure of Invention

Thus, in certain aspects, the present disclosure provides a method of treating a disease, the method comprising administering to a subject in need thereof an anti-APRIL antibody molecule described herein, wherein the antibody molecule is administered as an agent (dose) that reduces the level of aberrant glycosylated IgA (a-g IgA) (e.g., aberrant glycosylated IgA1 (a-g IgA 1)) by at least 40% in the subject, thereby treating the disease. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1.

In one embodiment, the level of a-g IgA is reduced by at least 40% about 4 weeks after administration of the antibody molecule. In one embodiment, the level of a-g IgA is reduced by at least 40% about 8 weeks after administration of the antibody molecule. In one embodiment, the level of a-g IgA is reduced by at least 40% about 12 weeks after administration of the antibody molecule. In one embodiment, the level of a-g IgA is reduced by at least 40% about 16 weeks after administration of the antibody molecule. In one embodiment, the level of a-g IgA is reduced by at least 40% for a predetermined period of time, e.g., at least one, two, three, or four weeks, or at least one, two, or three months. In one embodiment, the level of a-g IgA is reduced by at least 50%. In one embodiment, the level of a-g IgA is reduced by at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. In one embodiment, the antibody molecule is administered as a single dose. In one embodiment, the antibody molecule is administered as a repeat agent. In one embodiment, the antibody molecule is administered subcutaneously. In one embodiment, the antibody molecule is administered intravenously.

In one embodiment, the disorder is an APRIL-related disorder. In one embodiment, the disorder is associated with an abnormal level of total IgA. In one embodiment, the disorder is a disorder associated with a-g IgA (e.g., a-g IgA 1).

In one embodiment, the disorder is IgA nephropathy (IgAN). In one embodiment, the IgAN is a family IgAN. In one embodiment, the IgAN is an adult IgAN. In one embodiment, the IgAN is post-transplant IgAN, pediatric IgAN, or crescent IgAN.

In one embodiment, the disease is Chronic Kidney Disease (CKD) or a disease associated with CKD. In one embodiment, CKD is advanced CKD, e.g., it estimates glomerular filtration rate (evfr) equal to or greater than about 30 or about 45.

In one embodiment, the disease is allergic purpura (HSP). In one embodiment, the disease is cutaneous vasculitis or IgA vasculitis. In one embodiment, the condition is IgA dermatitis, e.g., igA bullous skin disease. In one embodiment, the disorder isMacroglobulinemia (WM). In one embodiment, the disorder is lupus nephritis.

In one embodiment, the subject is a human. In one embodiment, the subject has or is determined to have an a-g IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the a-g IgA level in a reference subject (e.g., a subject not suffering from the disease, e.g., a healthy or normal subject). In one embodiment, the subject has or is determined to have a total IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the total IgA level in a reference subject (e.g., a subject not suffering from the disease, e.g., a healthy or normal subject). In one embodiment, the subject has received or is receiving a different therapeutic agent or treatment modality for treating the disorder. In one embodiment, the subject has not received or is not receiving a different therapeutic agent or treatment modality for treating the disorder. In one embodiment, the subject has or is determined to have a genomic predisposition locus for the disease (e.g., igA nephropathy). In one embodiment, the method further comprises determining whether the subject has a genomic predisposition locus for the disease (e.g., igA nephropathy).

In one embodiment, the anti-APRIL antibody molecule is an anti-APRIL antibody molecule described herein. In one embodiment, the anti-APRIL antibody molecule comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of any of antibodies 2218, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439 or 4237. In one embodiment, the anti-APRIL antibody molecule comprises VH and VL of any of antibodies 2218, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439, or 4237.

In one embodiment, the level of a-g IgA in a sample from the subject is determined. In one embodiment, the methods described herein further comprise determining the level of a-g IgA in a sample from the subject. In one embodiment, the method further comprises determining the level of total IgA in the sample. In one embodiment, the method further comprises determining the level of IgM and/or IgG in the sample. In one embodiment, the method further comprises obtaining a sample from the subject. In one embodiment, the sample is a blood or serum sample.

In one embodiment, the method further comprises administering a second therapeutic agent or treatment modality to the subject. In one embodiment, the second therapeutic agent or mode of treatment is a small molecule. In one embodiment, the second therapeutic agent or mode of treatment is an antibody molecule.

In one embodiment, the subject has received, is receiving, or is about to receive a vaccine, e.g., within 1, 2, 3, 4, 5, or 6 days, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of administration of the anti-APRIL antibody molecule. In one embodiment, the subject is in need of or is determined to be in need of receiving a vaccine, e.g., within 1, 2, 3, 4, 5, or 6 days, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of administration of the anti-APRIL antibody molecule. In one embodiment, the subject receives the vaccine prior to, concurrently with, or after administration of the anti-APRIL antibody molecule.

In one embodiment, administration of the anti-APRIL antibody molecule reduces the ability of a subject to produce an effective antigen-specific serum IgG and/or IgA response to a vaccine by no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%. In one embodiment, administration of the anti-APRIL antibody molecule does not reduce or significantly reduce the ability of the subject to produce an effective antigen-specific serum IgG and/or IgA response to the vaccine. In one embodiment, the subject has or maintains an effective (e.g., protective) antigen-specific serum IgG and/or IgA response to the vaccine following administration of the anti-APRIL antibody molecule.

In one embodiment, the vaccine comprises tetanus toxoid, diphtheria toxoid, or both (e.g.,). In one embodiment, the subject is administered an anti-APRIL antibody molecule, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, after administration,11. 12, 13, 14, 15, 16 weeks or longer, has or maintains an effective (e.g., protective) level of tetanus and/or diphtheria anti-toxoid IgG (e.g., equal to or greater than 0.1IU/mL in blood).

In one aspect, the disclosure discloses a method of treating a disease, the method comprising administering to a subject in need thereof an anti-APRIL antibody molecule, wherein the administration reduces the level of a-g IgA (e.g., a-g IgA 1) in the subject by at least 40%, thereby treating the disease. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1.

In one embodiment, the subject is a human. In one embodiment, the subject has or is determined to have an a-g IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the a-g IgA level in a reference subject (e.g., a subject not suffering from the disease, e.g., a healthy or normal subject). In one embodiment, the subject has or is determined to have a total IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the total IgA level in a reference subject (e.g., a subject not suffering from the disease, e.g., a healthy or normal subject). In one embodiment, the subject has received or is receiving a different therapeutic agent or treatment modality for treating the disorder. In one embodiment, the subject has not received or is not receiving a different therapeutic agent or treatment modality for treating the disorder. In one embodiment, the subject has or is determined to have a genomic predisposition locus for the disease (e.g., igA nephropathy). In one embodiment, the methods described herein further comprise determining whether the subject has a genomic predisposition locus for the disease (e.g., igA nephropathy).

In some embodiments, the anti-APRIL antibody molecule is an anti-APRIL antibody molecule described herein. In one embodiment, the anti-APRIL antibody molecule comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of any of antibodies 2218, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439 or 4237. In one embodiment, the anti-APRIL antibody molecule comprises VH and VL of any of antibodies 2218, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439, or 4237.

In one embodiment, the level of a-g IgA in a sample from the subject is determined. In one embodiment, the method further comprises determining the level of a-g IgA in the sample from the subject. In one embodiment, the method further comprises determining the level of total IgA in the sample. In one embodiment, the method further comprises determining the level of IgM and/or IgG in the sample. In one embodiment, the method further comprises obtaining a sample from the subject. In one embodiment, the sample is a blood or serum sample.

In one embodiment, the vaccine comprises tetanus toxoid, diphtheria toxoid, or both (e.g.,). In one embodiment, the subject has or maintains an effective (e.g., protective) level of tetanus and/or diphtheria anti-toxoid IgG (e.g., equal to or greater than 0.1IU/mL in blood) after administration of the anti-APRIL antibody molecule, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks or longer after administration.

In another aspect, the present disclosure provides a method of treating a disease, the method comprising administering to a subject in need thereof an anti-APRIL antibody molecule, wherein the antibody molecule is administered at a dose (dosage) (e.g., agent (dose) and frequency) that reduces or possibly reduces the level of a-g IgA (e.g., a-g IgA 1) in the subject (e.g., by at least 40%), thereby treating the disease. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1.

In one embodiment, the vaccine comprises tetanus toxoid, diphtheria toxoid, or both (e.g.,). In one embodimentThe subject has or maintains an effective (e.g., protective) level of tetanus and/or diphtheria anti-toxoid IgG (e.g., equal to or greater than 0.1IU/mL in blood) for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks or longer following administration of the anti-APRIL antibody molecule.

In another aspect, the disclosure provides a method of treating a disease, the method comprising selecting an agent or dose (e.g., agent and frequency) of an anti-APRIL antibody molecule, wherein administration of the antibody molecule at the agent or dose reduces the level of a-g IgA (e.g., a-g IgA 1) in a subject in need thereof by at least 40%; and administering the antibody molecule to the subject at the selected agent or dose, thereby treating the disease. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1.

In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 40% about 4 weeks after administration of the antibody molecule. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 40% about 8 weeks after administration of the antibody molecule. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 40% about 12 weeks after administration of the antibody molecule. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 40% about 16 weeks after administration of the antibody molecule. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 40% for a predetermined period of time, e.g., at least one, two, three, or four weeks, or at least one, two, or three months. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 50%. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. In one embodiment, the antibody molecule is administered as a single dose. In one embodiment, the antibody molecule is administered as a repeat agent. In one embodiment, the antibody molecule is administered subcutaneously. In one embodiment, the antibody molecule is administered intravenously.

In one aspect, the disclosure discloses a method of treating a disease, the method comprising administering an anti-APRIL antibody molecule to a subject in need thereof in response to determining that administration of the anti-APRIL antibody molecule reduces or potentially reduces the level of a-g IgA (e.g., a-g IgA 1) by at least 40%. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1.

In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 40% about 4 weeks after administration of the antibody molecule. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 40% about 8 weeks after administration of the antibody molecule. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 40% about 12 weeks after administration of the antibody molecule. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 40% about 16 weeks after administration of the antibody molecule. In one embodiment, the anti-APRIL antibody molecule reduces the level of a-g IgA by at least 40% for a predetermined period of time, e.g., at least one, two, three, or four weeks, or at least one, two, or three months. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 50%. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. In one embodiment, the antibody molecule is administered as a single dose. In one embodiment, the antibody molecule is administered as a repeat agent. In one embodiment, the antibody molecule is administered subcutaneously. In one embodiment, the antibody molecule is administered intravenously.

In another aspect, the disclosure discloses a method of treating a disease, the method comprising determining whether administration of an anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA (e.g., a-gIgA 1) by at least 40% in a subject in need thereof, and if the antibody molecule reduces or may reduce the level of a-g IgA by at least 40%, initiating, continuing or maintaining administration of the antibody molecule. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1.

In one embodiment, administration of the antibody molecule is stopped, discontinued, or altered if the antibody molecule does not or is not so low (that to) that the level of a-g IgA is reduced by at least 40%. In one embodiment, a different therapeutic agent or mode of treatment is administered if the antibody molecule does not or is unlikely to reduce the level of a-g IgA by at least 40%.

In one embodiment, the disease is allergic purpura (HSP). In one embodiment, the disease is cutaneous vasculitis or IgA vasculitis. In one embodiment, the condition is IgA dermatitis, e.g., igA bullous skin disease. In one embodiment, the disorder isMacroglobulinemia (WM). In one embodiment, theThe disorder is lupus nephritis.

In one embodiment, the vaccine comprises tetanus toxoid, diphtheria toxoid, or both (examplesAs an example of the presence of a metal such as,). In one embodiment, the subject has or maintains an effective (e.g., protective) level of tetanus and/or diphtheria anti-toxoid IgG (e.g., equal to or greater than 0.1IU/mL in blood) after administration of the anti-APRIL antibody molecule, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks or longer after administration.

In another aspect, the disclosure discloses a method of treating a disease, the method comprising determining whether administration of an anti-APRIL antibody molecule in an agent or dose reduces or may reduce the level of a-g IgA (e.g., a-g IgA 1) by at least 40% in a subject in need thereof, and if the antibody molecule reduces or may reduce the level of a-g IgA by at least 40% at the agent or dose, initiating, continuing or maintaining administration of the antibody molecule at the agent or dose. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1.

In one embodiment, administration of the antibody molecule at the agent or dose is stopped, discontinued, or altered if the antibody molecule at the agent or dose does not or is less likely to reduce the level of a-g IgA by at least 40%.

In one aspect, the disclosure discloses a method of treating a disease comprising determining whether a therapeutic agent or mode of treatment other than an anti-APRIL antibody molecule described herein reduces or would reduce the level of a-g IgA by at least 40% in a subject in need thereof, and if the therapeutic agent or mode of treatment does not reduce or would not reduce the level of a-g IgA by at least 40% in the subject, administering an anti-APRIL antibody molecule described herein. In one embodiment, the antibody molecule is administered in an agent or dose that reduces or may reduce the level of a-g IgA in a subject by at least 40%. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1.

In one embodiment, the therapeutic agent or mode of treatment reduces or may reduce the level of a-g IgA by at least 40% about 4 weeks after administration of the antibody molecule. In one embodiment, the therapeutic agent or mode of treatment reduces or may reduce the level of a-g IgA by at least 40% about 8 weeks after administration of the antibody molecule. In one embodiment, the therapeutic agent or mode of treatment reduces or may reduce the level of a-g IgA by at least 40% about 12 weeks after administration of the antibody molecule. In one embodiment, the therapeutic agent or mode of treatment reduces or may reduce the level of a-g IgA by at least 40% about 16 weeks after administration of the antibody molecule. In one embodiment, the therapeutic agent or mode of treatment reduces the level of a-g IgA by at least 40% for a predetermined period of time, e.g., at least one, two, three, or four weeks, or at least one, two, or three months. In one embodiment, the therapeutic agent or mode of treatment reduces or may reduce the level of a-g IgA by at least 50%. In one embodiment, the therapeutic agent or mode of treatment reduces or may reduce the level of a-g IgA by at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. In one embodiment, the therapeutic agent or mode of treatment is administered as a single dose. In one embodiment, the therapeutic agent or mode of treatment is administered as a repeat agent. In one embodiment, the antibody molecule is administered subcutaneously. In one embodiment, the antibody molecule is administered intravenously.

In one embodiment, the disorder is associated with an abnormal level of total IgA. In one embodiment, the disorder is a disorder associated with a-g IgA (e.g., a-g IgA 1).

In one embodiment, the anti-APRIL antibody molecule comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of any of antibodies 2218, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2922, 3327, 3530, 3525, 3125, 262, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439 or 4237. In one embodiment, the anti-APRIL antibody molecule comprises VH and VL of any of antibodies 2218, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439, or 4237.

In another aspect, the disclosure discloses a method of reducing the level of a-g IgA (e.g., a-g IgA 1) in a subject, the method comprising administering an anti-APRIL antibody molecule to a subject in need thereof, e.g., such that the level of a-g IgA in the subject is reduced by at least 40% of the agent or dose, thereby reducing the level of a-g IgA. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1.

In one embodiment, the subject has or is determined to have an APRIL-related disorder. In one embodiment, the subject has or is determined to have a condition associated with an abnormal level of total IgA. In one embodiment, the subject has or is determined to have a disorder associated with a-g IgA (e.g., a-g IgA 1).

In one embodiment, the subject has or is determined to have IgA nephropathy (IgAN). In one embodiment, the IgAN is a family IgAN. In one embodiment, the IgAN is an adult IgAN. In one embodiment, the IgAN is post-transplant IgAN, pediatric IgAN, or crescent IgAN.

In one embodiment, the subject has or is determined to have Chronic Kidney Disease (CKD) or a disease associated with CKD. In one embodiment, CKD is advanced CKD, e.g., it estimates glomerular filtration rate (evfr) equal to or greater than about 30 or about 45.

In one embodiment, the subject has or is determined to have allergic purpura (HSP). In one embodiment, the subject has or is determined to have cutaneous vasculitis or IgA vasculitis. In one embodiment, the subject has or is determined to have IgA dermatitis, e.g., igA bullous skin disease. In one embodiment, the object has or is determined to haveMacroglobulinemia (WM). In one embodiment, the subject has or is determined to have lupus nephritis.

In one embodiment, the vaccine comprisesTetanus toxoid, diphtheria toxoid, or both (e.g.,). In one embodiment, the subject has or maintains an effective (e.g., protective) level of tetanus and/or diphtheria anti-toxoid IgG (e.g., equal to or greater than 0.1IU/mL in blood) after administration of the anti-APRIL antibody molecule, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks or longer after administration.

In another aspect, the disclosure discloses a method of selecting an anti-APRIL antibody molecule for use in treating a disorder, the method comprising determining whether administration of the anti-APRIL antibody molecule reduces or potentially reduces the level of a-g IgA (e.g., a-g IgA 1) by at least 40% in a subject in need thereof, thereby selecting an anti-APRIL antibody molecule. In one embodiment, the level of a-g IgA comprises, or is, the level of a-gIgA 1.

In one embodiment, the subject has or is determined to have an APRIL-associated disorder. In one embodiment, the subject has or is determined to have a disease associated with an abnormal level of total IgA. In one embodiment, the subject has or is determined to have a disorder associated with a-g IgA (e.g., a-g IgA 1).

In another aspect, the disclosure provides a method of selecting an agent or dose (e.g., an agent and a frequency) of an anti-APRIL antibody molecule to treat a disease, the method comprising determining whether administration of the anti-APRIL antibody molecule at the agent or dose reduces or would reduce the level of a-g IgA (e.g., a-g IgA 1) by at least 40% in a subject in need thereof, thereby selecting the agent or dose. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1.

In another aspect, the disclosure discloses a method of selecting a subject for treating a disorder, the method comprising determining whether administration of an anti-APRIL antibody molecule reduces or potentially reduces the level of a-gIgA (e.g., a-g IgA 1) by at least 40% in a subject in need thereof, thereby selecting the subject. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1.

In one embodiment, the vaccine comprises tetanus toxoid, diphtheria toxoid, or both (e.g.,). In one embodiment, the subject has or remains effective after administration of the anti-APRIL antibody molecule, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks or more after administration (e.g.,protective) tetanus and/or diphtheria anti-toxoid IgG (e.g., equal to or greater than 0.1IU/mL in blood).

In another aspect, the disclosure discloses a method of treating IgA nephropathy, the method comprising administering to a subject in need thereof an effective amount of an anti-APRIL antibody molecule (e.g., an anti-APRIL antibody molecule described herein), wherein the subject has received, or is about to receive, a vaccine (e.g., a vaccine described herein) within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 weeks of administration of the anti-APRIL antibody molecule, thereby treating IgA nephropathy.

In one embodiment, the method further comprises administering a vaccine to the subject prior to, concurrently with, or after administration of the anti-APRIL antibody molecule.

In another aspect, the disclosure discloses a method of vaccinating a subject, the method comprising administering to the subject an effective amount of a vaccine (e.g., a vaccine described herein), wherein the subject has received, or is about to receive, an anti-APRIL antibody molecule (e.g., an APRIL antibody molecule described herein) within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 weeks of administration of the vaccine, thereby vaccinating the subject.

In one embodiment, the method further comprises administering to the subject an anti-APRIL antibody molecule prior to, concurrently with, or after administration of the vaccine.

In another aspect, the disclosure discloses a method of treating a disorder, the method comprising administering to a subject in need thereof an anti-APRIL antibody molecule, e.g., such that the level of IgM in the subject is, or is likely to be, reduced by at least a predetermined percentage, thereby treating the disorder.

In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of IgM by at least 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. In one embodiment, the antibody molecule is administered as a single dose. In one embodiment, the antibody molecule is administered as a repeat agent. In one embodiment, the antibody molecule is administered subcutaneously. In one embodiment, the antibody molecule is administered intravenously.

In one embodiment, the subject is a human. In one embodiment, the subject has or is determined to have an IgM level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the IgM level in a reference subject (e.g., a subject not suffering from the disease, e.g., a healthy or normal subject). In one embodiment, the subject has received or is receiving a different therapeutic agent or treatment modality for treating the disorder. In one embodiment, the subject has not received or is not receiving a different therapeutic agent or treatment modality for treating the disorder.

In one embodiment, the disorder is associated with an abnormal level of IgM. In one embodiment, the disorder is Chronic Kidney Disease (CKD) or kidney injury. In one embodiment, the disorder is fibrosis. In one embodiment, the disorder is IgM mediated kidney disease, e.g., anti-MAG kidney disease or anti-GM 1 related kidney disease. In one embodiment, the disorder is Systemic Lupus Erythematosus (SLE). In one embodiment, the administration does not reduce, or does not substantially reduce, the level of IgG in the subject. In one embodiment, administration reduces the level of IgG in the subject by no more than a predetermined percentage. In one embodiment, administration reduces the level of IgG in the subject by at least a predetermined percentage.

In one embodiment, the level of IgM in a sample from a subject is determined. In one embodiment, the method further comprises determining the level of IgM in the sample from the subject. In one embodiment, the method further comprises determining the level of total IgM in the sample. In one embodiment, the method further comprises determining the level of IgA (e.g., total IgA and/or a-g IgA) and/or IgG in the sample. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1. In one embodiment, the method further comprises obtaining a sample from the subject. In one embodiment, the sample is a blood or serum sample.

In one embodiment, the subject has received, is receiving, or is about to receive a vaccine, e.g., within 1, 2, 3, 4, 5, or 6 days, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of administration of the antibody molecule. In one embodiment, the subject is in need of or is determined to be in need of receiving a vaccine, e.g., within 1, 2, 3, 4, 5, or 6 days, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of administration of the antibody molecule. In one embodiment, the subject receives the vaccine prior to, concurrently with, or after administration of the antibody molecule.

In one embodiment, administration of the antibody molecule reduces the ability of a subject to produce an effective antigen-specific serum IgG and/or IgA response to the vaccine by no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%. In one embodiment, administration of the antibody molecule does not reduce or significantly reduce the ability of the subject to produce an effective antigen-specific serum IgG and/or IgA response to the vaccine. In one embodiment, the subject has or maintains an effective (e.g., protective) antigen-specific serum IgG and/or IgA response to the vaccine following administration of the antibody molecule.

In one embodiment, the vaccine comprises tetanus toxoid, diphtheria toxoid, or both (e.g.,). In one embodiment, the subject has or remains effective (e.g., protective) levels of tetanus and/or diphtheria anti-toxoid IgG (e.g., equal to or greater than 0.1IU/mL in blood) after administration of the antibody molecule, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks or longer after administration.

In another aspect, the disclosure discloses a method of reducing the level of IgM in a subject, the method comprising administering to a subject in need thereof an anti-APRIL antibody molecule, e.g., such that the level of IgM in the subject is reduced by an agent or dose that is likely to be at the level of IgM.

In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of IgM by less than 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%, for example, over a predetermined period of time. In one embodiment, the antibody molecule is administered as a single dose. In one embodiment, the antibody molecule is administered as a repeat agent. In one embodiment, the antibody molecule is administered subcutaneously. In one embodiment, the antibody molecule is administered intravenously.

In another aspect, the disclosure discloses a method of treating a disorder, the method comprising administering to a subject in need thereof an anti-APRIL antibody molecule, e.g., such that the level of IgA and IgM in the subject is, or is likely to be, reduced by at least a predetermined percentage, thereby treating the disorder.

In one embodiment, the level of IgA comprises, or is, the level of total IgA and/or a-g IgA. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1.

In one embodiment, the administration does not reduce, or does not substantially reduce, the level of IgG in the subject. In one embodiment, administration reduces the level of IgG in the subject by no more than a predetermined percentage. In one embodiment, administration reduces the level of IgG in a subject by at least a predetermined percentage.

In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%, for example, over a predetermined period of time. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of total IgA by at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%, for example, over a predetermined period of time. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of IgM by at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%, for example, over a predetermined period of time. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of IgA (e.g., sum and/or a-g IgA) by at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, and reduces or may reduce the level of IgM by at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, e.g., over a predetermined period of time. In one embodiment, the antibody molecule is administered as a single dose. In one embodiment, the antibody molecule is administered as a repeat agent. In one embodiment, the antibody molecule is administered subcutaneously. In one embodiment, the antibody molecule is administered intravenously.

In one embodiment, the subject is a human. In one embodiment, the subject has or is determined to have an a-g IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the a-g IgA level in a reference subject (e.g., a subject not suffering from the disease, e.g., a healthy or normal subject). In one embodiment, the subject has or is determined to have a total IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the total IgA level in a reference subject (e.g., a subject not suffering from the disease, e.g., a healthy or normal subject). In one embodiment, the subject has or is determined to have an IgM level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the a-g IgM level in a reference subject (e.g., a subject not suffering from the disease, e.g., a healthy or normal subject). In one embodiment, the subject has received or is receiving a different therapeutic agent or treatment modality for treating the disorder. In one embodiment, the subject has not received or is not receiving a different therapeutic agent or treatment modality for treating the disorder.

In one embodiment, the disorder is an APRIL-related disorder. In one embodiment, the disorder is associated with abnormal levels of IgA (e.g., total IgA and/or a-g IgA) and/or IgM, e.g., a disorder described herein. In one embodiment, the disorder is Systemic Lupus Erythematosus (SLE). In one embodiment, the administration does not reduce, or does not substantially reduce, the level of IgG in the subject. In one embodiment, administration reduces the level of IgG in the subject by no more than a predetermined percentage. In one embodiment, administration reduces the level of IgG in the subject by at least a predetermined percentage. In one embodiment, the level of IgA and/or IgM (and optionally IgG) in the sample from the subject is determined. In one embodiment, the method further comprises determining the level of a-g IgA in the sample from the subject. In one embodiment, the method further comprises determining the level of total IgA in the sample. In one embodiment, the method further comprises determining the level of IgM in the sample. In one embodiment, the method further comprises determining the level of IgG in the sample. In one embodiment, the method further comprises obtaining a sample from the subject. In one embodiment, the sample is a blood or serum sample.

In another aspect, the disclosure discloses a method of reducing the level of IgA and IgM in a subject, the method comprising administering to a subject in need thereof an anti-APRIL antibody molecule, e.g., such that a predetermined percentage of the level of IgA and IgM in the subject is or is likely to be administered, thereby reducing the level of IgA and IgM.

In one embodiment, the administration does not reduce, or does not substantially reduce, the level of IgG in the subject. In one embodiment, administration reduces the level of IgG in the subject by no more than a predetermined percentage. In one embodiment, administration reduces the level of IgG in the subject by at least a predetermined percentage.

In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA by at least 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%, for example, over a predetermined period of time. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of total IgA by at least 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%, for example, over a predetermined period of time. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of IgM by at least 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%, for example, over a predetermined period of time. In one embodiment, the anti-APRIL antibody molecule reduces or may reduce the level of IgA (e.g., sum and/or a-g IgA) by at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, and reduces or may reduce the level of IgM by at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, e.g., over a predetermined period of time. In one embodiment, the antibody molecule is administered as a single dose. In one embodiment, the antibody molecule is administered as a repeat agent. In one embodiment, the antibody molecule is administered subcutaneously. In one embodiment, the antibody molecule is administered intravenously.

In one embodiment, the disorder is an APRIL-related disorder. In one embodiment, the disorder is associated with abnormal levels of IgA (e.g., total IgA and/or a-g IgA) and/or IgM, e.g., a disorder described herein. In one embodiment, the disorder is Systemic Lupus Erythematosus (SLE). In one embodiment, the administration does not reduce, or does not substantially reduce, the level of IgG in the subject. In one embodiment, administration reduces the level of IgG in the subject by no more than a predetermined percentage. In one embodiment, administration reduces the level of IgG in a subject by at least a predetermined percentage. In one embodiment, the level of IgA and/or IgM (and optionally IgG) in the sample from the subject is determined. In one embodiment, the method further comprises determining the level of a-g IgA in the sample from the subject. In one embodiment, the method further comprises determining the level of total IgA in the sample. In one embodiment, the method further comprises determining the level of IgM in the sample. In one embodiment, the method further comprises determining the level of IgG in the sample. In one embodiment, the method further comprises obtaining a sample from the subject. In one embodiment, the sample is a blood or serum sample.

In one embodiment, the vaccine comprises tetanus toxoid, diphtheria toxoid, or both (e.g.,). In one embodiment, the subject is administered the antibody molecule, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 after administrationTetanus and/or diphtheria anti-toxoid IgG (e.g., equal to or greater than 0.1IU/mL in blood) levels that are or remain effective (e.g., protective) for 11, 12, 13, 14, 15, 16 weeks or longer.

In another embodiment, the present disclosure discloses a method of treating a disorder comprising administering to a subject in need thereof an effective amount of an anti-APRIL antibody molecule, wherein the disorder comprises:

(a) Advanced Chronic Kidney Disease (CKD) (e.g., an eGFR equal to or greater than about 30 or about 45);

(b) IgAN after implantation;

(c) Pediatric IgAN;

(d) Allergic purpura (HSP) or cutaneous vasculitis;

(e) IgAN associated with crescent Glomerulonephritis (GN);

(f) IgA vasculitis;

(g) IgA dermatitis;

(h) IgM-mediated neuropathy (anti-MAG or anti-GM 1);

(i)macroglobulinemia (WM); or (b)

(j) Lupus nephritis.

In one embodiment, administration causes or may cause IgA in the subject. In one embodiment, the administration is such that IgM in the subject is likely to be administered. In one embodiment, the level of IgA comprises, or is, the level of total IgA and/or a-g IgA. In one embodiment, the level of a-g IgA comprises, or is, the level of a-g IgA 1.

In one embodiment, the disorder is end stage Chronic Kidney Disease (CKD) (e.g., an eGFR of about 30 or greater or about 45). In one embodiment, the disorder is post-transplant IgAN. In one embodiment, the disorder is pediatric IgAN. In one embodiment, the disease is allergic purpura (HSP) or cutaneous vasculitis. In one embodiment, the disorder is IgAN with crescentic Glomerulonephritis (GN). In one embodiment, the disorder is IgA vasculitis. In one embodiment, the disorder is IgA dermatitis. In one embodiment, the disorder is IgM mediated kidney disease (anti-MAG or anti-GM 1). In one embodiment, the disorder is Macroglobulinemia (WM). In one implementationIn a mode, the condition is lupus nephritis.

In another aspect, the present disclosure discloses a method of treating a condition associated with an autoantigen, the method comprising administering to a subject in need thereof an effective amount of a therapeutic agent or mode of treatment, wherein the administration reduces or potentially reduces the level of the autoantigen in the subject by at least a predetermined percentage.

In one embodiment, the subject is a human. In one embodiment, the subject has or is determined to have an APRIL-associated disorder.

In one embodiment, the level of autoantigens in the sample from the subject is determined. In one embodiment, the method further comprises obtaining a sample from the subject. In one embodiment, the sample is a blood or serum sample.

Detailed description of the illustrated embodiments

1. A method of treating a condition, comprising:

administering to a subject in need thereof an anti-APRIL antibody molecule as described herein,

wherein the antibody molecule is administered as an agent that reduces or likely reduces the level of aberrant glycosylated IgA (a-g IgA) in the subject by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%),

thereby treating the condition.

2. A method of treating a condition, comprising:

wherein the administration reduces the level of a-g IgA in the subject by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%),

thereby treating the condition.

3. A method of treating a condition, comprising:

wherein the antibody molecule is administered at a dose (e.g., dose and frequency) that reduces or is likely to reduce a-g IgA levels in a subject by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%),

Thereby treating the condition.

4. A method of treating a condition, comprising:

selecting an agent or dose (e.g., an agent and a frequency) of an anti-APRIL antibody molecule described herein, wherein administration of the antibody molecule at the agent or dose reduces the level of a-g IgA in a subject in need thereof by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%); and

administering the antibody molecule to the subject at a selected agent or dose,

thereby treating the condition.

5. A method of treating a condition, comprising:

in response to determining that administration of an anti-APRIL antibody molecule described herein reduces a-g IgA levels in a subject in need thereof, or likely to reduce a-g IgA levels by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%), administering an anti-APRIL antibody molecule to the subject,

thereby treating the condition.

6. A method of treating a condition, comprising:

determining whether administration of an anti-APRIL antibody molecule described herein reduces or potentially reduces the level of a-g IgA in a subject in need thereof by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%),

If the antibody molecule reduces or potentially reduces the level of a-g IgA by at least 40%, administration of the antibody molecule is initiated, continued or maintained,

optionally, wherein if the antibody molecule does not or is not likely to reduce the level of a-g IgA by at least 40%, the administration of the antibody molecule is stopped, discontinued or altered, and/or a different therapeutic agent or mode of treatment is administered.

7. A method of treating a condition, comprising:

determining whether administration of an anti-APRIL antibody molecule described herein at an agent or dose reduces or potentially reduces the level of a-g IgA in a subject in need thereof by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%),

if the antibody molecule is brought to, or may bring about, at least 40% of the good a-g IgA level at the agent or dose, administration of the antibody molecule is initiated, continued or maintained at the agent or dose,

optionally, wherein administration of the antibody molecule at the agent or dose is stopped, discontinued or altered if the antibody molecule at the agent or dose does not or is not likely to reduce the level of a-g IgA by at least 40%.

8. A method of treating a condition, comprising:

determining whether administration of a therapeutic agent or mode of treatment other than an anti-APRIL antibody molecule described herein reduces or potentially reduces the level of a-g IgA in a subject in need thereof by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%),

the anti-APRIL antibody molecules described herein are administered to the subject if the therapeutic agent or mode of treatment does not or is not likely to reduce the level of a-g IgA by at least 40%.

9. A method of reducing the level of a-g IgA in a subject comprising:

the anti-APRIL antibody molecules described herein are administered to a subject in need thereof at an agent or dose that reduces the level of a-g IgA in the subject by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%),

thereby reducing the level of a-g IgA.

10. A method of selecting an anti-APRIL antibody molecule for use in treating a disorder, comprising:

Thereby selecting an anti-APRIL antibody molecule.

11. A method of selecting an agent or dose (e.g., agent and frequency) of an anti-APRIL antibody molecule to treat a disorder, comprising:

thereby selecting the agent or dose.

12. A method of selecting a subject to treat a disorder, the method comprising:

so that the object is selected and,

optionally, wherein if the antibody molecule does not reduce or is unlikely to reduce the level of a-g IgA by at least 40%, then stopping, interrupting or altering the administration of the antibody molecule, or administering a different therapeutic agent or mode of treatment.

13. The method of any one of embodiments 1-12, wherein a-g IgA comprises or is a-gIgA1.

14. The method of any one of embodiments 1-13, wherein the level of a-g IgA is reduced by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%) for a predetermined period of time, e.g., at least 1, 2, 3 or 4 weeks, or at least 1, 2 or 3 months.

15. The method of any one of embodiments 1-14, wherein the level of a-g IgA is reduced by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) about 4 weeks after administration of the antibody molecule.

16. The method of any one of embodiments 1-15, wherein the level of a-g IgA is reduced by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) about 8 weeks after administration of the antibody molecule.

17. The method of any one of embodiments 1-16, wherein the level of a-g IgA is reduced by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) about 12 weeks after administration of the antibody molecule.

18. The method of any one of embodiments 1-17, wherein the level of a-g IgA is reduced by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) about 16 weeks after administration of the antibody molecule.

19. The method of any one of embodiments 1-18, wherein the level of a-g IgA is reduced by at least 50%.

20. The method of any one of embodiments 1-19, wherein the level of a-g IgA is reduced by at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.

21. The method of any one of embodiments 1-20, wherein the antibody molecule is administered in a single dose.

22. The method of any one of embodiments 1-20, wherein the antibody molecule is administered as a repeat agent.

23. The method of any one of embodiments 1-22, wherein the antibody molecule is administered subcutaneously.

24. The method of any one of embodiments 1-22, wherein the antibody molecule is administered intravenously.

25. The method of any one of embodiments 1-24, wherein the disorder is an APRIL-related disorder.

26. The method of any one of embodiments 1-24, wherein the disorder is associated with an abnormal level of total IgA.

27. The method of any one of embodiments 1-26, wherein the disorder is a disorder associated with a-g IgA.

28. The method of any one of embodiments 1-27, wherein the disorder is IgA nephropathy (IgAN).

29. The method of embodiment 28, wherein the IgAN is a family IgAN.

30. The method of embodiment 28, wherein the IgAN is adult IgAN.

31. The method of embodiment 28, wherein the IgAN is post-transplant IgAN, pediatric IgAN, or crescent IgAN.

32. The method of any one of embodiments 1-27, wherein the disorder is Chronic Kidney Disease (CKD) or a disorder associated with CKD.

33. The method of embodiment 32, wherein CKD is advanced CKD, e.g., estimated glomerular filtration rate (eGFR) equal to or greater than about 30 or about 45.

34. The method of any one of embodiments 1-27, wherein the disorder is allergic purpura (HSP).

35. The method of any one of embodiments 1-27, wherein the disorder is cutaneous vasculitis or IgA vasculitis.

36. The method of any one of embodiments 1-27, wherein the disorder is IgA dermatitis, e.g., igA bullous skin disease.

37. The method of any one of embodiments 1-27, wherein the disorder is Giant ballProteinemia (WM).

38. The method of any one of embodiments 1-27, wherein the disorder is lupus nephritis.

39. The method of any one of embodiments 1-38, wherein the subject is a human.

40. The method of any one of embodiments 1-39, wherein the subject has or is determined to have an a-g IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the a-g IgA level in a reference subject (e.g., a subject not suffering from the disease, e.g., a healthy or normal subject).

41. The method of any one of embodiments 1-40, wherein the subject has or is determined to have a total IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the total IgA level in a reference subject (e.g., a subject not suffering from the disease, e.g., a healthy or normal subject).

42. The method of any one of embodiments 1-41, wherein the subject has received or is receiving a different therapeutic agent or treatment modality for treating the disorder.

43. The method of any one of embodiments 1-41, wherein the subject has not received or is not receiving a different therapeutic agent or treatment modality for treating the disorder.

44. The method of any of embodiments 1-43, wherein the subject has received, is receiving, or is about to receive a vaccine, e.g., within 1, 2, 3, 4, 5, or 6 days, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of administration of the antibody molecule.

45. The method of any one of embodiments 1-43, wherein the subject is in need of or determined to be in need of receiving a vaccine, e.g., within 1, 2, 3, 4, 5, or 6 days, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of administration of the antibody molecule.

46. The method of embodiment 44 or 45, wherein the subject receives the vaccine prior to, concurrently with, or after administration of the antibody molecule.

47. The method of any one of embodiments 44-46, wherein administration of the antibody molecule reduces the ability of the subject to produce an effective antigen-specific serum IgG and/or IgA response to the vaccine by no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%.

48. The method of any one of embodiments 44-47, wherein administration of the antibody molecule does not reduce or not significantly reduce the ability of the subject to produce an effective antigen-specific serum IgG and/or IgA response to the vaccine.

49. The method of any one of embodiments 44-48, wherein the subject has or maintains an effective (e.g., protective) antigen-specific serum IgG and/or IgA response to the vaccine following administration of the antibody molecule.

50. The method of any of embodiments 44-49, wherein the vaccine comprises tetanus toxoid, diphtheria toxoid, or both (e.g., )。

51. The method of embodiment 50, wherein the subject has or remains effective (e.g., protective) levels of tetanus and/or diphtheria anti-toxoid IgG (e.g., equal to or greater than 0.1IU/mL in blood) after administration of the antibody molecule, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks or longer after administration.

52. The method of any one of embodiments 1-51, wherein the subject has or is determined to have a genomic predisposition locus for the disease (e.g., igA nephropathy).

53. The method of any one of embodiments 1-52, further comprising determining whether the subject has a genomic predisposition locus for the disease (e.g., igA nephropathy).

54. The method of any one of embodiments 1-53, wherein the antibody molecule comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of any one of antibodies 2218, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439 or 4237.

55. The method of any one of embodiments 1-54, wherein the antibody molecule comprises VH and VL of any one of antibodies 2218, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439, or 4237.

56. The method of any one of embodiments 1-55, wherein the level of a-g IgA in the sample from the subject is determined.

57. The method of any one of embodiments 1-56, further comprising determining the level of a-g IgA in a sample from the subject.

58. The method of any one of embodiments 1-57, further comprising determining the level of total IgA in the sample.

59. The method of any one of embodiments 1-58, further comprising determining the level of IgM and/or IgG in the sample.

60. The method of any one of embodiments 1-59, further comprising obtaining a sample from the subject.

61. The method of embodiment 60, wherein the sample is a blood or serum sample.

62. The method of any one of embodiments 1-61, further comprising administering to the subject a second therapeutic agent or modality.

63. The method of embodiment 62, wherein the second therapeutic agent or therapeutic modality is a small molecule.

64. The method of embodiment 62, wherein the second therapeutic agent or modality is an antibody molecule.

65. A method of treating IgA nephropathy, comprising:

administering to a subject in need thereof an effective amount of an anti-APRIL antibody molecule (e.g., an anti-APRIL antibody molecule described herein),

wherein the subject has received or is about to receive a vaccine (e.g., a vaccine as described herein) within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 weeks of administration of the antibody molecule,

thereby treating IgA nephropathy.

66. The method of embodiment 65, further comprising administering to the subject a vaccine prior to, concurrently with, or after administration of the antibody molecule.

67. A method of vaccinating a subject comprising:

administering to the subject an effective amount of a vaccine (e.g., a vaccine as described herein),

wherein the subject has received or is about to receive an anti-APRIL antibody molecule (e.g., an anti-APRIL antibody molecule described herein) within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 weeks of administration of the vaccine,

Thereby vaccinating the subject.

68. The method of embodiment 67, further comprising administering an antibody molecule to the subject prior to, concurrently with, or after administration of the vaccine.

69. The method of any one of embodiments 44-68, wherein said vaccine is administered intramuscularly.

70. A composition for treating IgA nephropathy in a subject, wherein the composition comprises an anti-APRIL antibody molecule (e.g., an anti-APRIL antibody molecule described herein) of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg, or 800mg of a fixative,

wherein the subject has received or is about to receive a vaccine (e.g., a vaccine as described herein) within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 weeks of administration of the antibody molecule.

71. The composition for use of embodiment 70, wherein the subject has been administered a vaccine prior to, concurrently with, or after administration of the antibody molecule.

72. A composition for vaccinating a subject, the composition comprising an effective amount of a vaccine (e.g., a vaccine as described herein),

wherein the subject has received or is about to receive an anti-APRIL antibody molecule (e.g., an anti-APRIL antibody molecule described herein) at a dose of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg or 800mg of a fixative within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 weeks of administration of the vaccine.

73. The composition for use of embodiment 72, wherein the antibody molecule is administered to the subject prior to, concurrently with, or after administration of the vaccine.

74. A composition for treating a condition in a subject, the composition comprising:

a dose of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg, or 800mg of an anti-APRIL antibody molecule described herein as an immobilizing agent; and

wherein the dose reduces or potentially reduces the level of aberrant glycosylated IgA (a-g IgA) in the subject by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%).

75. A composition for treating a disorder in a subject, the composition comprising a dose of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg, or 800mg of an anti-APRIL antibody molecule described herein as a fixative,

wherein the dose reduces the level of a-g IgA in the subject by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%).

76. A composition for treating a condition in a subject, the composition comprising an anti-APRIL antibody molecule described herein in a dose (e.g., dose and frequency) that is such that it is likely to reduce the level of a-g IgA in the subject by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%),

Wherein the dose is about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg or 800mg of fixative.

77. A composition for treating a disorder in a subject, the composition comprising an anti-APRIL antibody molecule described herein administered to the subject at a dose of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg, or 800mg of a fixative;

wherein the formulated composition is administered if administration of a therapeutic agent or mode of treatment other than an anti-APRIL antibody molecule described herein reduces or potentially reduces the level of a-g IgA in a subject by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%).

78. A composition for reducing the level of a-g IgA in a subject, the composition comprising an anti-APRIL antibody molecule described herein in an agent or dose that reduces or would reduce the level of a-g IgA in the subject by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%),

wherein the agent or dose is about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg or 800mg of the fixative.

79. A method of treating IgA nephropathy, comprising:

about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg or 800mg of an anti-APRIL antibody molecule of a fixing agent (e.g., an anti-APRIL antibody molecule described herein) is administered to a subject in need thereof,

thereby treating IgA nephropathy.

80. The method of embodiment 79, further comprising administering to the subject a vaccine prior to, concurrently with, or after administration of the antibody molecule.

81. A method of vaccinating a subject comprising:

wherein the subject has received or is about to receive an anti-APRIL antibody molecule (e.g., an anti-APRIL antibody molecule described herein) at a dose of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg or 800mg of a fixative within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 weeks of administration of the vaccine;

Thereby vaccinating the subject.

82. The method of embodiment 81, further comprising administering an antibody molecule to the subject prior to, concurrently with, or after administration of the vaccine.

83. A method of treating a condition, comprising:

wherein the antibody molecule is administered at a dose of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg, or 800mg of the fixing agent; and

wherein the dose administered to the subject reduces or potentially reduces the level of aberrant glycosylated IgA (a-g IgA) in the subject by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%),

thereby treating the condition.

84. A method of treating a condition, comprising:

administering to a subject in need thereof a dose of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg or 800mg of an anti-APRIL antibody molecule described herein of a fixing agent,

Thereby treating the condition.

85. A method of treating a condition, comprising:

wherein the antibody molecule is administered at a dose (e.g., dose and frequency) that reduces a-g IgA levels in the subject by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) and

wherein the dose is about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg, or 800mg of fixative;

thereby treating the condition.

86. A method of treating a condition, comprising:

the selection of agents or dosages (e.g., agents and frequencies) of anti-APRIL antibody molecules described herein,

wherein the agent or dose is about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg, or 800mg of the fixing agent; and is also provided with

Administration of the antibody molecule at the agent or dose reduces the level of a-g IgA in a subject in need thereof by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%); and is also provided with

Administering the antibody molecule to the subject at a selected agent or dose,

thereby treating the condition.

87. A method of treating a condition, comprising:

in response to determining that administration of an anti-APRIL antibody molecule described herein reduces the level of a-g IgA in a subject in need thereof by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%), a dose of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg, or 800mg of an anti-APRIL antibody molecule of a fixative is administered to the subject,

thereby treating the condition.

88. A method of treating a condition, comprising:

if the antibody molecule reduces or would reduce the level of a-g IgA by at least 40%, then administration of the antibody molecule of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg or 800mg of fixative is initiated, continued or maintained,

89. A method of treating a condition, comprising:

if the antibody molecule is at least 40% lower in the level of a-g IgA at the agent or dose, administration of the antibody molecule is initiated, continued or maintained at the agent or dose,

wherein the agent or dose is about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg, or 800mg of the fixing agent;

optionally, wherein administration of the antibody molecule at the dose or dose is stopped, discontinued, or altered if the antibody molecule at the dose or dose does not or is unlikely to reduce the level of a-gIgA by at least 40%.

90. A method of treating a condition, comprising:

if the therapeutic agent or mode of treatment does not or is unlikely to reduce the level of a-g IgA by at least 40%, then the anti-APRIL antibody molecules described herein are administered to the subject at a dose of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg or 800mg of the fixing agent.

91. A method of reducing the level of a-g IgA in a subject comprising:

Thereby reducing the level of a-g IgA.

92. A method of selecting an anti-APRIL antibody molecule for use in treating a disorder, comprising:

determining whether administration of an anti-APRIL antibody molecule described herein at a dose of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg, or 800mg of a fixative results in or may reduce the level of a-g IgA in a subject in need thereof by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%),

thereby selecting an anti-APRIL antibody molecule.

93. A method of selecting an agent or dose (e.g., agent and frequency) of an anti-APRIL antibody molecule to treat a disorder, comprising:

Thereby selecting the agent or dose.

94. A method of selecting a subject to treat a disorder, the method comprising:

so that the object is selected and,

optionally, wherein if the antibody molecule does not or is not likely to reduce the level of a-g IgA by at least 40%, the administration of the antibody molecule is stopped, discontinued or altered, or a different therapeutic agent or mode of treatment is administered.

95. The method of any one of embodiments 79-94, wherein a-g IgA comprises or is a-gIgA1.

96. The method of any one of embodiments 79-95, wherein the level of a-g IgA is reduced by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%) for a predetermined period of time, e.g., at least 1, 2, 3 or 4 weeks, or at least 1, 2 or 3 months.

97. The method of any one of embodiments 79-96, wherein the level of a-g IgA is reduced by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) about 4 weeks after administration of the antibody molecule.

98. The method of any one of embodiments 79-97, wherein the level of a-g IgA is reduced by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) about 8 weeks after administration of the antibody molecule.

99. The method of any one of embodiments 79-98, wherein the level of a-g IgA is reduced by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) about 12 weeks after administration of the antibody molecule.

100. The method of any one of embodiments 79-99, wherein the level of a-g IgA is reduced by at least 40% (e.g., at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) about 16 weeks after administration of the antibody molecule.

101. The method of any one of embodiments 79-100, wherein the level of a-g IgA is reduced by at least 50%.

102. The method of any one of embodiments 79-101, wherein the level of a-g IgA is reduced by at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.

103. The method of any one of embodiments 79-102, wherein the antibody molecule is administered in a single dose, e.g., over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 months.

104. The method of any one of embodiments 79-102, wherein the antibody molecule is administered as a repeat.

105. The method of any one of embodiments 79-104, wherein the antibody molecule is administered subcutaneously.

106. The method of any one of embodiments 79-104, wherein the antibody molecule is administered intravenously.

107. The method of any one of embodiments 79-106, wherein the disorder is an APRIL-related disorder.

108. The method of any one of embodiments 79-107, wherein the disorder is associated with an abnormal level of total IgA.

109. The method of any one of embodiments 79-108, wherein the disorder is a disorder associated with a-gIgA.

110. The method of any one of embodiments 79-109, wherein the disorder is IgA nephropathy (IgAN).

111. The method of embodiment 110, wherein the IgAN is a family IgAN.

112. The method of embodiment 110, wherein the IgAN is adult IgAN.

113. The method of embodiment 110, wherein the IgAN is post-transplant IgAN, pediatric IgAN, or crescent IgAN.

114. The method of any one of embodiments 79-108, wherein the disorder is Chronic Kidney Disease (CKD) or a disorder associated with CKD.

115. The method of embodiment 114, CKD is advanced CKD, e.g., which estimates glomerular filtration rate (eGFR) equal to or greater than about 30 or about 45.

116. The method of any one of embodiments 79-108, wherein the disorder is allergic purpura (HSP).

117. The method of any one of embodiments 79-108 wherein the disorder is cutaneous vasculitis or IgA vasculitis.

118. The method of any one of embodiments 79-108, wherein the disorder is IgA dermatitis, e.g., igA bullous skin disease.

119. The method of any one of embodiments 79-108, wherein the disorderMacroglobulinemia (WM).

120. The method of any one of embodiments 79-108, wherein the disorder is lupus nephritis.

121. The method of any one of embodiments 79-120, wherein the subject is a human.

122. The method of any one of embodiments 79-121, wherein the subject has or is determined to have an a-g IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the a-g IgA level in a reference subject (e.g., a subject not suffering from the disease, e.g., a healthy or normal subject).

123. The method of any one of embodiments 79-122, wherein the subject has or is determined to have a total IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the total IgA level in a reference subject (e.g., a subject not suffering from the disease, e.g., a healthy or normal subject).

124. The method of any of embodiments 79-123, wherein the subject has received or is receiving a different therapeutic agent or treatment modality for treating the disorder.

125. The method of any of embodiments 79-123, wherein the subject has not received or is not receiving a different therapeutic agent or treatment modality for treating the disorder.

126. The method of any one of embodiments 79-125, wherein the subject has received, is receiving, or is about to receive a vaccine, e.g., within 1, 2, 3, 4, 5, or 6 days, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of administration of the antibody molecule.

127. The method of any one of embodiments 79-125, wherein the subject is in need of, or is determined to be in need of, receiving a vaccine, e.g., within 1, 2, 3, 4, 5, or 6 days, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of administration of the antibody molecule.

128. The method of embodiment 126 or 127, wherein the subject is receiving a vaccine prior to, concurrently with, or after administration of the antibody molecule.

129. The method of any one of embodiments 126-128, wherein administration of an antibody molecule reduces the ability of a subject to produce an effective antigen-specific serum IgG and/or IgA response to a vaccine by no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%.

130. The method of any one of embodiments 126-129, wherein administration of the antibody molecule does not reduce or not significantly reduce the ability of the subject to produce an effective antigen-specific serum IgG and/or IgA response to the vaccine.

131. The method of any one of embodiments 126-130, wherein the subject has or maintains an effective (e.g., protective) antigen-specific serum IgG and/or IgA response to the vaccine following administration of the antibody molecule.

132. The method of any of embodiments 126-131, wherein the vaccine comprises tetanus toxoid, diphtheria toxoid, or both (e.g., )。

133. The method of embodiment 132, wherein the subject has or remains effective (e.g., protective) levels of tetanus and/or diphtheria anti-toxoid IgG (e.g., equal to or greater than 0.1IU/mL in blood) after administration of the antibody molecule, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks or longer after administration.

134. The method of any one of embodiments 79-133, wherein the subject has or is determined to have a genomic predisposition locus for the disease (e.g., igA nephropathy).

135. The method of any one of embodiments 79-134, further comprising determining whether the subject has a genomic predisposition locus for the disease (e.g., igA nephropathy).

136. The method of any one of embodiments 79-135, wherein the antibody molecule comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of any one of antibodies 2218, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439 or 4237.

137. The method of any one of embodiments 79-136, wherein the antibody molecule comprises VH and VL of any one of antibodies 2218, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439, or 4237.

138. The method of any one of embodiments 79-137, wherein the level of a-g IgA in the sample from the subject is determined.

139. The method of any one of embodiments 79-138, further comprising determining the level of a-g IgA in a sample from the subject.

140. The method of any one of embodiments 79-139, further comprising determining the level of total IgA in the sample.

141. The method of any one of embodiments 79 to 140, further comprising determining the level of IgM and/or IgG in the sample.

142. The method of any one of embodiments 79-141, further comprising obtaining a sample from the subject.

143. The method of embodiment 142, wherein the sample is a blood or serum sample.

144. The method of any one of embodiments 79-143, further comprising administering to the subject a second therapeutic agent or modality.

145. The method of embodiment 144, wherein the second therapeutic agent or therapeutic modality is a small molecule.

146. The method of embodiment 144, wherein the second therapeutic agent or modality is an antibody molecule.

147. The composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered to the subject at a concentration of about 100, 150, 175, 180, 190, 200, 210, 220, 225, 230, 240, 250, or 300 mg/mL.

148. The composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered to the subject at a concentration of about 200 mg/mL.

149. The composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered to the subject at a fixed dose of about 200, 250, 300, 450, 400, 450, 500, 550, 600, 650, 700, 750, or 800 mg.

150. The composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered to the subject in a fixed dose of about 200mg (e.g., a volume of about 1 mL).

151. The composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered to the subject in a fixed dose of about 400mg (e.g., a total volume of about 2mL, e.g., 2 administrations in a 1mL volume or 1 administration in a 2mL volume).

152. The composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered to the subject at a fixed dose of at least 200 mg.

153. The composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered to the subject at a fixed dose of 800mg or less.

154. The composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered to the subject in a fixed dose of about 600mg (e.g., a total volume of about 3mL, e.g., 1 administration in a volume of 2mL and 1 administration in a volume of 1 mL).

155. The composition for use or method of any one of the preceding embodiments, wherein a single dose of an anti-APRIL antibody molecule is administered to the subject.

156. The composition for use or method of any one of the preceding embodiments, wherein one or more additional doses of an anti-APRIL antibody molecule are administered to the subject (e.g., 24 hours, 48 hours, 72 hours, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after the first administration).

157. The composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered subcutaneously to the subject.

158. The composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered intravenously to the subject.

159. The composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered in liquid form.

160. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of treating a condition in a human subject,

wherein the antibody molecule is administered at about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg of agent, or about 200mg, 400mg, 600mg or 800mg of fixative;

wherein the administration reduces the level of aberrant glycosylated IgA (a-g IgA) in the subject by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%; and is also provided with

Optionally, wherein the antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3) and VL comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3),

Wherein VH comprises: HCDR1 comprising SEQ ID NO:11, an amino acid sequence of seq id no; HCDR2 comprising SEQ ID NO:12, an amino acid sequence of seq id no; and HCDR3 comprising SEQ ID NO:13, an amino acid sequence of seq id no; and VL comprises: LCDR1 comprising SEQ ID NO:280, an amino acid sequence of 280; LCDR2 comprising SEQ ID NO:285 amino acid sequence; and LCDR3 comprising SEQ ID NO:16, an amino acid sequence of seq id no; or (b)

Wherein VH comprises: HCDR1 comprising SEQ ID NO:17, an amino acid sequence of seq id no; HCDR2 comprising SEQ ID NO: 282; and HCDR3 comprising SEQ ID NO:13, an amino acid sequence of seq id no; and VL comprises: LCDR1 comprising SEQ ID NO:280, an amino acid sequence of 280; LCDR2 comprising SEQ ID NO:285 amino acid sequence; and LCDR3 comprising SEQ ID NO:16, the amino acid sequence of the amino,

optionally, wherein the condition is IgA nephropathy.

161. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of reducing the level of a-g IgA in a human subject,

wherein the administration reduces the level of a-g IgA in the subject by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%; and is also provided with

Optionally, wherein the antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises three heavy chain complementarity determining regions (HCD R1, HCDR2 and HCDR 3) and VL comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3),

optionally, wherein the subject suffers from, or is at risk of suffering from, a disorder, such as IgA nephropathy.

162. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of treating a condition in a human subject,

Wherein the method comprises selecting an agent or dose of the antibody molecule;

administration of the antibody molecule at the agent or dose reduces the level of a-g IgA in the subject by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%; and is also provided with

Optionally wherein the antibody molecule is administered as about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg of agent, or about 200mg, 400mg, 600mg or 800mg of fixative,

optionally, wherein the condition is IgA nephropathy.

163. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of treating a condition in a human subject,

wherein the method comprises administering to the subject about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg of an agent, or about 200mg, 400mg, 600mg or 800mg of a fixing agent of the antibody molecule that reduces or would reduce the level of a-g IgA in the subject by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% in response to determining that administration of the antibody molecule described herein; and is also provided with

optionally, wherein the condition is IgA nephropathy.

164. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of treating a condition in a human subject,

wherein the method comprises determining whether administration of an anti-APRIL antibody molecule described herein reduces or potentially reduces the level of a-g IgA in a subject by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%,

if the antibody molecule reduces the level of a-g IgA by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, then administration of the antibody molecule of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg or 800mg of the fixative is initiated, continued or maintained; and is also provided with

Optionally wherein the condition is IgA nephropathy,

optionally, wherein if the antibody molecule does not or is not likely to reduce the level of a-g IgA by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, the administration of the antibody molecule is stopped, discontinued or altered, and/or a different therapeutic agent or mode of treatment is administered.

165. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of treating a condition in a human subject,

wherein the method comprises determining whether administration of a therapeutic agent or mode of treatment other than the antibody molecule reduces or would reduce the level of a-g IgA in a subject in need thereof by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%,

administering an antibody molecule to the subject at about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg, or 800mg of an immobilizing agent if the therapeutic agent or mode of treatment does not reduce or is less likely to reduce the level of a-g IgA by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%; and is also provided with

optionally, wherein the condition is IgA nephropathy.

166. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of treating a condition in a human subject,

Wherein the antibody molecule is administered at about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg of agent, or about 200mg, 400mg, 600mg or 800mg of fixative; and is also provided with

Wherein the subject has received or is about to receive a vaccine within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 weeks of administration of the antibody molecule, optionally wherein the vaccine comprises tetanus toxoid, diphtheria toxoidOr both (e.g.,)，

Optionally wherein the condition is IgA nephropathy,

optionally, wherein administration of the antibody molecule at the selected agent or dose reduces or may reduce the level of a-g IgA in the subject by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%.

167. A method of treating a condition, comprising:

administering to a human subject in need thereof about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg of an agent, or about 200mg, 400mg, 600mg or 800mg of an anti-APRIL antibody molecule of a fixative;

Wherein the antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3) and VL comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3),

optionally, wherein VH comprises: HCDR1 comprising SEQ ID NO:11, an amino acid sequence of seq id no; HCDR2 comprising SEQ ID NO:12, an amino acid sequence of seq id no; and HCDR3 comprising SEQ ID NO:13, an amino acid sequence of seq id no; and VL comprises: LCDR1 comprising SEQ ID NO:280, an amino acid sequence of 280; LCDR2 comprising SEQ ID NO:285 amino acid sequence; and LCDR3 comprising SEQ ID NO:16, an amino acid sequence of seq id no; or (b)

optionally wherein the condition is IgA nephropathy,

thereby treating the condition.

168. A method of reducing the level of a-g IgA comprising:

administering to a human subject in need thereof an anti-APRIL antibody molecule,

Optionally, wherein the antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises three heavy chain complementarity determining regions (HCDRl, HCDR2 and HCDR 3) and VL comprises three light chain complementarity determining regions (LCDRl, LCDR2 and LCDR 3),

optionally wherein the subject suffers from, or is at risk of suffering from, a disorder, such as IgA nephropathy,

thereby reducing the level of a-g IgA.

169. A method of treating a condition, comprising:

selecting an agent or dose of an anti-APRIL antibody molecule;

Optionally, wherein the subject has or is at risk of developing IgA nephropathy, thereby treating the disorder.

170. A method of treating a condition, comprising:

an anti-APRIL antibody molecule that reduces the level of a-g IgA in a subject by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% in response to determining that administration of the antibody molecule, administered to a human subject in need thereof an agent of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg or 800mg of a fixative; and is also provided with

optionally wherein the condition is IgA nephropathy,

thereby treating the condition.

171. A method of treating a condition, comprising:

determining whether administration of the anti-APRIL antibody molecule reduces or may reduce the level of a-g IgA in a subject by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%,

Optionally wherein if the antibody molecule does not or is not likely to reduce the level of a-g IgA by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, the administration of the antibody molecule is stopped, discontinued or altered, and/or a different therapeutic agent or mode of treatment is administered,

optionally wherein the condition is IgA nephropathy,

thereby treating the condition.

172. A method of treating a condition, comprising:

determining whether administration of a therapeutic agent or mode of treatment other than an anti-APRIL antibody molecule reduces or potentially reduces the level of a-g IgA in a subject in need thereof by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%,

if the therapeutic agent or mode of treatment does not or is not too low to reduce the level of a-g IgA by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, then administering the antibody molecule to the human subject with about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg or 800mg of the fixing agent; and is also provided with

optionally wherein the condition is IgA nephropathy,

thereby treating the condition.

173. A method of treating a condition, comprising:

administering to a human subject in need thereof about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg of an agent, or about 200mg, 400mg, 600mg or 800mg of an anti-APRIL antibody molecule of a fixative; and is also provided with

Wherein the subject has received or is about to receive a vaccine within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 weeks of administration of the antibody molecule, optionally wherein the vaccine comprises tetanus toxoid, diphtheria toxoid, or both (e.g.,)，

Optionally wherein the condition is IgA nephropathy,

optionally wherein administration of said antibody molecule at a selected agent or dose reduces or potentially reduces the level of a-g IgA in a subject by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%,

thereby treating the condition.

174. A method of selecting an anti-APRIL antibody molecule for use in treating a disorder, comprising:

determining whether administration of said antibody molecule at said agent or dose reduces or would reduce the level of a-g IgA in a human subject in need thereof by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%,

wherein the agent is about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg or 800mg of a fixative,

optionally wherein the condition is IgA nephropathy,

thereby selecting the antibody molecule.

175. A method of selecting an agent or dose of an anti-APRIL antibody molecule to treat a disorder, comprising:

optionally, wherein the agent is about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg or 800mg of a fixative,

optionally wherein the condition is IgA nephropathy,

thereby selecting the agent or dose.

176. A method of selecting a human subject to treat a disorder, comprising:

determining whether administration of an anti-APRIL antibody molecule at a dose of about 0.5mg/kg, 2.0mg/kg, 6mg/kg, 9mg/kg, 9.1mg/kg, 12mg/kg, or about 200mg, 400mg, 600mg, or 800mg of a fixing agent reduces or may reduce the level of a-g IgA in a subject by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%,

optionally wherein the condition is IgA nephropathy,

thereby selecting an object.

177. The antibody molecule, pharmaceutical composition, method for use according to any one of embodiments 160-176, wherein a-g IgA comprises or is a-g IgA1.

178. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-177, wherein the level of a-g IgA is reduced by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% for a predetermined period of time, e.g., at least 1, 2, 3 or 4 weeks, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months.

179. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-178, wherein the level of a-g IgA is reduced by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% about 4 weeks after administration of the antibody molecule.

180. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-179, wherein the level of a-g IgA is reduced by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% about 8 weeks after administration of the antibody molecule.

181. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-180, wherein the level of a-g IgA is reduced by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% about 12 weeks after administration of the antibody molecule.

182. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-181, wherein the level of a-g IgA is reduced by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% about 16 weeks after administration of the antibody molecule.

183. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-182, wherein the level of a-g IgA is reduced by at least 50%.

184. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-183, wherein the level of a-g IgA is reduced by at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.

185. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-184, e.g., over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 months.

186. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-185, wherein the antibody molecule is administered as a repeat, e.g., over a period of at least 3, 6, 9, 12, 15, 18, 24, 30, or 36 months, optionally wherein one or more additional doses of the anti-APRIL antibody molecule are administered to the subject (e.g., 24 hours, 48 hours, 72 hours, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after the first administration).

187. The antibody molecule, pharmaceutical composition, method for use according to any one of embodiments 160-186, wherein the antibody molecule is administered subcutaneously.

188. The antibody molecule, pharmaceutical composition, method for use according to any one of embodiments 160-186, wherein the antibody molecule is administered intravenously.

189. The antibody molecule, pharmaceutical composition, method for use according to any one of embodiments 160-188, wherein the disorder is an APRIL-related disorder.

190. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-189, wherein the disorder is associated with an abnormal level of total IgA.

191. The antibody molecule, pharmaceutical composition, method for use according to any one of embodiments 160-190, wherein the disorder is a disorder associated with a-g IgA.

192. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-191, wherein the disorder is IgA nephropathy (IgAN).

193. The antibody molecule, pharmaceutical composition, method for use of embodiment 192, wherein the IgAN is a familial IgAN.

194. The antibody molecule, pharmaceutical composition, method for use of embodiment 192, wherein the IgAN is an adult IgAN.

195. The antibody molecule, pharmaceutical composition, method for use of embodiment 192, wherein IgAN is post-transplant IgAN, pediatric IgAN, or crescent IgAN.

196. The antibody molecule, pharmaceutical composition, method for use according to any one of embodiments 160-191, wherein the disorder is Chronic Kidney Disease (CKD) or a disorder associated with CKD.

197. The antibody molecule, pharmaceutical composition, method for use of embodiment 196, wherein CKD is advanced CKD, e.g., which estimates glomerular filtration rate (eGFR) equal to or greater than about 30 or about 45.

198. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-191, wherein the disorder is allergic purpura (HSP).

199. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-191, wherein the disorder is cutaneous vasculitis or IgA vasculitis.

200. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-191, wherein the disorder is IgA dermatitis, e.g., igA bullous skin disease.

201. The antibody molecule, pharmaceutical composition, method for use according to any one of embodiments 160-191, wherein the disorder is Macroglobulinemia (WM).

202. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-191, wherein the disorder is lupus nephritis.

203. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-202, wherein the subject is a human patient.

204. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-203, wherein the subject has or is determined to have a-g IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the a-g IgA level in a reference subject (e.g., a subject not suffering from the disorder, e.g., a healthy or normal subject).

205. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-204, wherein the subject has or is determined to have a total IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the total IgA level in a reference subject (e.g., a subject not suffering from the disorder, e.g., a healthy or normal subject).

206. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-205, wherein the subject has received or is receiving a different therapeutic agent or treatment modality for treating the disorder.

207. The antibody molecule, pharmaceutical composition, method for use according to any one of embodiments 160-206, wherein the subject has not received or is not receiving a different therapeutic agent or treatment regimen for treating the disorder.

208. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-207, wherein the subject has received, is receiving, or is about to receive a vaccine, e.g., within 1, 2, 3, 4, 5, or 6 days, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of administration of the antibody molecule.

209. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-208, wherein a subject is in need of or is determined to be in need of receiving a vaccine, e.g., within 1, 2, 3, 4, 5, or 6 days, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of administration of the antibody molecule.

210. The antibody molecule, pharmaceutical composition, method for use of embodiment 208 or 209, wherein the subject is receiving a vaccine prior to, concurrently with, or after administration of the antibody molecule.

211. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-210, wherein administration of the antibody molecule reduces the ability of a subject to produce an effective antigen-specific serum IgG and/or IgA response to a vaccine by no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%.

212. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-211, wherein administration of the antibody molecule does not reduce or not significantly reduce the ability of a subject to produce an effective antigen-specific serum IgG and/or IgA response to a vaccine.

213. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-212, wherein the subject has or retains an effective (e.g., protective) antigen-specific serum IgG and/or IgA response to a vaccine following administration of the antibody molecule.

214. The antibody molecule, pharmaceutical composition, method for use of any of embodiments 160-213, wherein the vaccine comprises tetanus toxoid, diphtheria toxoid, or both (e.g.,)。

215. the antibody molecule, pharmaceutical composition, method for use of embodiment 214, wherein the subject has or remains effective (e.g., protective) levels of tetanus and/or diphtheria anti-toxoid IgG (e.g., equal to or greater than 0.1IU/mL in blood) after administration of the antibody molecule, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks or longer after administration.

216. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-215, wherein a subject has or is determined to have a genomic predisposition locus for the disease (e.g., igA nephropathy).

217. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-216, further comprising determining whether the subject has a genomic predisposition locus for the disease (e.g., igA nephropathy).

218. The antibody molecule, pharmaceutical composition, method for use according to any one of embodiments 160-217, wherein the antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3) and VL comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3),

Wherein VH comprises: HCDR1 comprising SEQ ID NO:17, an amino acid sequence of seq id no; HCDR2 comprising SEQ ID NO: 282; and HCDR3 comprising SEQ ID NO:13, an amino acid sequence of seq id no; and VL comprises: LCDR1 comprising SEQ ID NO:280, an amino acid sequence of 280; LCDR2 comprising SEQ ID NO:285 amino acid sequence; and LCDR3 comprising SEQ ID NO:16, and a sequence of amino acids.

219. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-218, wherein the antibody molecule comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO:296, and the VL comprises the amino acid sequence SEQ ID NO:286,

optionally, wherein the antibody molecule is IgG2.

220. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-219, wherein the level of a-g IgA in a sample from a subject is determined.

221. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-220, further comprising determining the level of a-g IgA in a sample from a subject.

222. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-221, further comprising determining the level of total IgA in the sample.

223. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-222, further comprising determining the level of total IgM and/or IgG in a sample.

224. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-223, further comprising obtaining a sample from a subject.

225. The antibody molecule, pharmaceutical composition, method for use of embodiment 224, wherein the sample is a blood or serum sample.

226. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-225, further comprising administering to the subject a second therapeutic agent or mode of treatment.

227. The antibody molecule, pharmaceutical composition, method for use of embodiment 226, wherein the second therapeutic agent or therapeutic modality is a small molecule.

228. The antibody molecule, pharmaceutical composition, method for use of embodiment 227, wherein the second therapeutic agent or mode of treatment is an antibody molecule.

229. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-228, wherein the anti-APRIL antibody molecule is administered to the subject at a concentration of about 100, 150, 175, 180, 190, 200, 210, 220, 225, 230, 240, 250, or 300 mg/mL.

230. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-229, wherein the anti-APRIL antibody molecule is administered to the subject at a concentration of about 200 mg/mL.

231. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-230, wherein the anti-APRIL antibody molecule is administered to the subject at about 200, 250, 300, 450, 400, 450, 500, 550, 600, 650, 700, 750, or 800mg of the fixative.

232. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-231, wherein the anti-APRIL antibody molecule is administered to the subject at about 200mg of the fixing agent (e.g., a volume of about 1 mL).

233. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-232, wherein the anti-APRIL antibody molecule is administered to the subject in a total volume of about 400mg of the fixing agent (e.g., about 2mL, e.g., 2 times 1mL volume administration or 1 time 2mL volume administration).

234. The antibody molecule, pharmaceutical composition, method for use of any one of embodiments 160-233, wherein the anti-APRIL antibody molecule is administered to the subject in a total volume of about 600mg of the fixing agent (e.g., about 3mL, e.g., 1 administration in a volume of 2mL and 1 administration in a volume of 1 mL).

235. The antibody molecule, pharmaceutical composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered to the subject in a fixed dose of at least 200 mg.

236. The antibody molecule, pharmaceutical composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered to the subject at a fixed dose of 800mg or less.

237. The antibody molecule, pharmaceutical composition for use or method of any one of the preceding embodiments, wherein the anti-APRIL antibody molecule is administered in the form of a liquid composition.

The present disclosure encompasses all combinations of any one or more of the foregoing aspects and/or embodiments, as well as combinations with any one or more of the embodiments provided in the detailed description and examples.

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

Brief description of the drawings

FIG. 1 depicts the mean percent change (. + -. Standard deviation) over time of aberrant glycosylated immunoglobulin concentrations relative to baseline for all patients of any ethnicity (drug-active population) for indicated treatments (pooled placebo, antibodies 2419-14060.5mg/kg, antibodies 2419-14062.0mg/kg, antibodies 2419-14066.0mg/kg, antibodies 2419-140612.0mg/kg, placebo+vaccine, and antibodies 2419-14066.0 mg/kg+vaccine).

FIG. 2 is a series of graphs showing the mean percent change from baseline of abnormally glycosylated immunoglobulin A (a-g-IgA 1; left panel) and immunoglobulin A (IgA; right panel) by treatment.

Figure 3 is a graph showing tetanus immunoglobulin G (IgG) titer levels in a safe population.

Fig. 4 is a graph showing diphtheria toxin immunoglobulin G (IgG) titer levels in a safe population.

FIG. 5 is a series of graphs showing IgA inhibition by mAb 2419-1406 in healthy volunteers. The results are shown as Subcutaneous (SC) administration (left panel) and Intravenous (IV) administration (right panel), as shown.

Detailed Description

Disclosed herein are binding with high affinity and specificity to APRIL, e.g., human APRIL, mouse APRIL, or bothAn antibody molecule. Advantageously, several of the antibody molecules described herein have a better ability to reduce (e.g., inhibit, block, or neutralize) one or more biological activities of APRIL. Nucleic acid molecules encoding the antibody molecules, expression vectors, host cells, compositions (e.g., pharmaceutical compositions), kits, and methods for making the antibody molecules are also provided. The antibody molecules and pharmaceutical compositions disclosed herein can be used (alone or in combination with other drugs or therapies) to treat, prevent and/or diagnose diseases and disorders, such as, for example, diseases and disorders associated with APRIL, such as IgA nephropathy (IgAN) or disorders associated with IgAN (e.g., end stage Chronic Kidney Disease (CKD), igAN after transplantation, pediatric IgAN, allergic purpura (HSP) or cutaneous vasculitis, igAN with moonphase Glomerulonephritis (GN), igA vasculitis, igA dermatitis (e.g., igA herpetiformis, igA bullous dermatoses), igM-mediated neuropathy (e.g., anti-MAG peripheral neuropathy or IgM-mediated neuropathy associated with anti-GM 1 antibodies), waldenstrom macroglobulinemia (WM, also known as Macroglobulinemia) or lupus nephritis).

IgA nephropathy is one of the most common chronic glomerular diseases, with global morbidity of about 5-50 cases/million (children) and 10-40 cases/million (adults). Although generally a relatively inert disease, igAN can progress to end stage renal disease (e.g., 20% -50% of patients develop renal failure within 20 to 30 years). IgA nephropathy patients with mild urine abnormalities, normotensive blood pressure and normal Glomerular Filtration Rate (GFR) typically require periodic monitoring. For patients with more advanced conditions, treatment regimens may include non-specific treatments to reduce blood pressure and proteinuria by RAS blockade, as well as other general measures such as lipid lowering, dietary sodium restriction, smoking cessation, and avoidance of NSAIDs and other nephrotoxins.

Without wishing to be bound by theory, it is believed that in some embodiments, the etiology of IgA nephropathy represents a double-click (two-hit) phenomenon in which the first click occurs in response to mucosal infection, as the resulting polymeric IgA1 (containing the hinge region of aberrant galactosylation (aberrant glycosylated IgA1 or a-g IgA 1)) appears to be a self antigen; while the second hit is the subsequent induction of autoantibodies that lead to immune complex formation. These circulating immune complexes then deposit in the kidneys where complement activation occurs, leading to promotion of inflammatory pathways, mesangial hyperplasia, glomerular injury, proteinuria, and renal progression leading to end stage renal disease. Without being bound by theory, it is believed that in certain embodiments, reduction of autoantigens and/or autoantibodies, and removal of immune complexes resulting therefrom and/or alleviation of complement activation, can have a beneficial effect on the progression of IgA nephropathy and other related diseases and disorders (e.g., post-transplant IgAN, pediatric IgAN, allergic purpura (HSP) or cutaneous vasculitis, igAN with crescentic Glomerulonephritis (GN), igA vasculitis, igA dermatitis (e.g., igA dermatitis herpetiformis, igA bullous dermatoses), igM-mediated neuropathy (e.g., anti-MAG peripheral neuropathy or IgM-mediated neuropathy associated with anti-GM 1 antibodies), waldenstrom Macroglobulinemia (WM), or lupus nephritis).

Without wishing to be bound by theory, it is believed that in some embodiments, aberrant biosynthesis of polymeric IgA and antigenic a-g IgA1 is associated with the pathogenesis and progression of the disease. In one embodiment, serum levels of a-g IgA1 are associated as a genetic trait with substantial genetic transmission in a substantial number of adult and pediatric familial IgA nephropathy cases. In one embodiment, a-g IgA1 plays a role in disease pathogenesis, e.g., as determined by ex vivo analysis of Peripheral Blood Mononuclear Cells (PBMC) from a patient. For example, a-g IgA1 may be secreted in immortalized B cells of IgA nephropathy patients, and IgA1 produced in lymphocytes of the patients may be correlated with serum levels of a-g IgA 1. As another example, immune complexes derived in part from IgA 1-producing cells (which are then reconstituted in vitro with serum from IgA nephropathy patients) can be pathogenic to mice following passive transfer. Without wishing to be bound by theory, it is believed that in some embodiments, serum levels of a-g IgA1 may predict disease outcome and provide diagnostic utility as biomarkers for clinical assessment of disease progression, treatment, and patient population stratification. For example, targeted reduction of IgA is therapeutically beneficial and may be effective in reducing immune deposition and kidney damage. In one embodiment, treatment with an antibody molecule described herein results in a reduction in the level of a clinically relevant autoantigen, e.g., a-g IgA.

Without wishing to be bound by theory, it is believed that in some embodiments, the anti-APRIL antibody molecules described herein (e.g., up to a single dose of 12.0 mg/kg) are safe and well tolerated in healthy adults. In one embodiment, a single dose of an anti-APRIL antibody molecule may inhibit free serum APRIL to a lower quantitative level. In one embodiment, serum a-g IgA1 is reduced in parallel with total serum IgA and recovered in a dose-dependent manner after detection of free APRIL in serum.

Without wishing to be bound by theory, it is believed that in some embodiments, the anti-APRIL antibody molecules described herein do not interfere with the ability of a subject to produce antigen-specific serum IgG or IgA-enhanced responses to vaccination (e.g., tetanus and diphtheria toxoid vaccination), suggesting that a qualitative T cell-dependent antibody response is preserved during the inhibition of APRIL.

Definition of the definition

The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

The term "or/and" as used herein means "and/or" and is used interchangeably herein unless the context clearly indicates otherwise.

"about" and "approximately" shall generally mean an acceptable degree of error of a measured quantity taking into account the nature or accuracy of the measurement. Exemplary degrees of error are within 20% of a given value range or value, typically within 10%, and more typically within 5%.

The compositions and methods described herein include polypeptides and nucleic acids having a specified sequence, or having a sequence that is substantially identical or similar to (e.g., at least 85%, 90%, 95% or more identical to) a specified sequence.

In describing amino acid sequences, the term "substantially identical" as used herein means that the first amino acid contains a sufficient or minimum number of amino acid residues: i) Identical to an aligned amino acid residue in the second amino acid sequence, or ii) conservative substitutions of aligned amino acid residues in the second amino acid sequence, whereby the first and second amino acid sequences may have a common domain and/or a common functional activity. For example, an amino acid sequence comprising a consensus domain having at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence (e.g., a sequence provided herein).

In describing nucleotide sequences, the term "substantially identical" as used herein means that a first nucleic acid sequence comprises 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 the same functional activity, or encode the same structural polypeptide domain or the same functional polypeptide activity. For example, a nucleotide sequence comprising at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence (e.g., a sequence provided herein).

The term "functional variant" refers to a polypeptide having or encoded by substantially the same amino acid sequence as the native sequence and capable of having one or more activities of the native sequence.

The calculation of homology or sequence identity between sequences (these 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 may be aligned for optimal comparison purposes (e.g., gaps may be introduced in one or both of the first and second amino acid or nucleic acid sequences to achieve optimal alignment, and non-homologous sequences may not be considered for comparison purposes). In a typical embodiment, the length of the reference sequence used for comparison purposes is at least 30%, such as at least 40%, 50%, 60%, such as at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at the corresponding amino acid positions or nucleotide positions are then compared. When an amino acid residue or nucleotide occupied at a position in a first sequence is identical to a corresponding position in a second sequence, then the molecules are identical at that position.

The percent identity between two sequences is related to the number of identical positions shared by the sequences, taking into account the number of gaps that need to be introduced for optimal alignment of the two sequences and the length of each gap.

Comparison of sequences and determination of percent identity between two sequences can be accomplished using mathematical algorithms. In some embodiments, the percent identity between two amino acid sequences may be determined using the Needleman and Wunsch (j.mol. Biol. (48): 444-453 (1970)) algorithm that has been incorporated into the GAP program in the GCG software package (available from gcg.com), using the Blossum62 matrix or PAM250 matrix, notch weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6. In certain embodiments, the percent identity between two nucleotide sequences is calculated using the GAP program (available from gcg.com) in the GCG software package, using the nws gapdna.cmp matrix and a GAP weight of 40, 50, 60, 70, or 80, a length weight of 1, 2, 3, 4, 5, or 6. One suitable set of parameters (and set of parameters to be employed unless otherwise indicated) is the Blossum62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a decoding gap penalty of 5.

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

The nucleic acid and protein sequences disclosed herein may also be used as "query sequences" to search public databases, for example, to identify other family components or related sequences. Such searches may be performed using Altschul et al, 1990, J.mol.biol.,215:403-10 (version 2.0). BLAST nucleotide searches can be performed using the NBLAST program, scoring = 100, word length = 12, to obtain nucleotide sequences homologous to the nucleic acids described herein. BLAST protein searches can be performed using the XBLAST program with a score=50 and a word length=3 to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gap alignment results for comparison purposes, one can, for example, altschul et al, 1997,Nucleic Acids Res, 25:3389-3402 uses notch BLAST. Default parameters for each program (e.g., XBLAST and NBLAST) can be used when using BLAST and notch BLAST programs. See ncbi.

As used herein, the term "hybridizes under low, medium, high, or very high stringency conditions" refers to conditions of hybridization and washing. Guidance for performing hybridization reactions can be found in CurrentProtocols in Molecular Biology (New Programming molecular biology laboratory guidelines, john Wiley father-son publishing company (John Wiley & Sons), new York (1989), 6.3.1-6.3.6), incorporated herein by reference. Both aqueous and non-aqueous processes are described in this reference, either of which may be employed. Specific hybridization conditions referred to herein are as follows: 1) Low stringency hybridization conditions, in 6X sodium chloride/sodium citrate (SSC) at about 45 ℃ followed by two washes in 0.2X SSC, 0.1% sds at least 50 ℃ (wash temperature can be increased to 55 ℃ for low stringency conditions); 2) Moderately stringent hybridization conditions, in about 45 ℃ in 6X-SSC followed by one or more washes in 0.2X SSC, 0.1% sds (60 ℃); 3) High stringency hybridization conditions are in 6 XSSC at about 45℃followed by one or more washes in 0.2XSSC, 0.1% SDS (65 ℃), and preferably 4) very high stringency hybridization conditions are 0.5M sodium phosphate, 7% SDS,65℃followed by one or more washes in 0.2XSSC, 1% SDS (65 ℃). Very high stringency conditions 4) are suitable conditions and are conditions that should be employed (unless otherwise indicated).

It will be appreciated that the molecules described herein may have other conservative or non-essential amino acid substitutions that do not materially affect the function of the molecule.

The term "amino acid" encompasses all molecules comprising an amino function and an acid function and which can be comprised in a naturally occurring amino acid-forming polymer, whether it be a natural or a synthetic molecule. Exemplary amino acids include naturally occurring amino acids; analogs, derivatives and analogs thereof; amino acid analogs having variant side chains; and all stereoisomers of any of the foregoing. As used herein, the term "amino acid" includes D-and L-mirror isomers and mimetic peptides.

A "conservative amino acid substitution" is one in which one amino acid residue is replaced with another amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been 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 (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

The terms "polypeptide", "peptide" and "protein" (if single-chain) are used interchangeably herein to refer to a polymer of amino acids of any length. The polymer may be a linear or branched polymer, may comprise modified amino acids, and may be intercalated with non-amino acids. The term also includes modified amino acid polymers; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as coupling to a labeling component. The polypeptides may be isolated from natural sources, may be produced by recombinant techniques from prokaryotic or eukaryotic hosts, or may be the product of synthetic methods.

The terms "nucleic acid", "nucleic acid sequence", "nucleotide sequence" or "polynucleotide sequence" and "polynucleotide" are used interchangeably herein. They refer to polymeric forms of nucleotides of any length, whether deoxyribonucleotides or ribonucleotides or analogs thereof. The polynucleotide may be single-stranded or double-stranded, and if single-stranded, may be the coding strand or the non-coding (antisense) strand. Polynucleotides may include modified nucleotides, such as methylated nucleotides and nucleotide analogs. The nucleotide sequence may be interspersed with non-nucleotide components. The polynucleotide may be further modified after polymerization, such as by coupling to a labeling component. The nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin, i.e., non-naturally occurring or associated with another polynucleotide in a non-natural arrangement.

The term "isolated" as used herein means that a substance is free from its native or natural environment (e.g., from a natural environment if it is naturally occurring). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, but the polynucleotide or polypeptide is isolated from some or all of the coexisting materials in the natural system. Such polynucleotides may be part of a vector and/or such polynucleotides or polypeptides may be part of a composition, but still be isolated, as the vector or composition is not part of the environment in which the polynucleotide or polypeptide naturally occurs.

As used herein, the term "treating" a disorder (e.g., igA nephropathy) refers to, in one embodiment, a subject (e.g., a human) having a disorder (e.g., igA nephropathy) and/or experiencing symptoms of a disorder (e.g., igA nephropathy) experiencing less severe symptoms and/or recovering more quickly when receiving an antibody molecule than when not receiving the antibody molecule. In one embodiment, when treating IgA nephropathy, after effective treatment of IgA nephropathy, a kidney biopsy will show little or no IgA deposition, e.g., in the form of immune complexes in the kidney membrane. For example, after administration of an antibody molecule described herein to effectively treat myeloma, less or no IgA deposition will be detected in a biological sample of the subject using immunofluorescence or diagnostic assays with electron microscopy. Other assays, such as urine tests, blood tests, iodinated peptide clearance tests, or renal imaging (e.g., ultrasound, X-ray, or cystoscopy), may also be used to monitor the patient's treatment or to detect the presence of symptoms of IgA nephropathy, such as a reduction (or absence) of symptoms of IgA nephropathy, after the subject has been treated for IgA nephropathy. Treatment may be, for example, a partial or complete reduction, amelioration, alleviation, inhibition, or reduction of the severity and/or reduction of the incidence of a condition, and optionally delay the appearance or onset of one or more consequences or symptoms, characteristics, and/or etiology of a condition (e.g., igA nephropathy). In one embodiment, the treatment is performed on a subject that does not show some signs of a disorder (e.g., igA nephropathy) and/or a subject that shows only early signs of a disorder (e.g., nephropathy). In one embodiment, the treatment is performed on a subject with one or more established signs of a disorder (e.g., igA nephropathy). In one embodiment, the treatment is of a subject diagnosed with a disease (e.g., igA nephropathy).

As used herein, the term "preventing" a disorder (e.g., igA nephropathy) refers to a subject (e.g., a human) being less likely to develop the disorder (e.g., igA nephropathy) if the subject (e.g., human) receives an antibody molecule.

Various aspects of the compositions and methods described herein are described in further detail below. Other definitions are provided throughout the specification.

APRIL

APRIL (a proliferation-inducing ligand), also known as CD256, TNF-and APOL-associated leukocyte expression ligand 2 (tal-2), or TNF-associated death ligand 1 (TRDL-1), is a TNF family cytokine encoded by the tumor necrosis factor ligand superfamily member 13 (TNFSF 13) gene (also known as APRIL, tal 2 or ztf 2). APRIL plays a role in many biological processes, such as signal transduction, regulation of cell proliferation and IgA class switching (Hahne et al, 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 activator F13B), also known as BLyS (B lymphocyte stimulator). Both cytokines are involved in regulating key aspects of innate and adaptive immune functions. APRIL and BAFF bind to lymphocyte receptors TACI (transmembrane activator and CAML interactors) and BCMA (B cell maturation antigen). APRIL and BAFF exhibit heterogeneous interactions through protein-protein interactions. Although both APRIL and BAFF have biochemistry (receptor binding), immunity, and even some structural overlap (e.g., because it involves a three-dimensional topology of the respective receptor binding domains), both cytokines are structurally and functionally distinct. APRIL binds to biologically relevant heparan sulfate (present in the extracellular matrix of cells as heparan sulfate proteoglycans); BAFF does not. This interaction plays a key biological role in promoting the oligomeric state of APRIL and its local interaction with TACI, which also requires adequate activity of HSPGS. Unlike BAFF as a potent activator of B cell proliferation and differentiation, APRIL appears to play a more specific role in regulating B cell phenotype, for example, because it is associated with IgA production and differentiation/survival of IgA positive plasma cells. Thus, targeted blockade of APRIL-receptor signaling pathways is expected to have less perturbation in B cell homeostasis and overall immune function than other anti-CD 20 therapies that primarily target early and early B cells (e.g., rituximab) or BAFF-targeted immune-related therapies (e.g., belimumab). APRIL has also been demonstrated to be highly expressed in other myeloid-related cells and lymphoid tissues, as well as in cancers of the blood system (e.g., myeloma, chronic Lymphocytic Leukemia (CLL)) and solid tumors (e.g., colon, thyroid, and breast).

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 (isoform α, also known as the "classical" sequence (SEQ ID NO: 85)) is provided below.

>huAPRIL

Several isoforms of human APRIL were produced by alternative splicing.

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

human isoform of sp|o 75888-2|tnf13_tumor necrosis factor ligand superfamily member 13 βos=homo sapiens gn=tnfsf 13

The sequence of isoform beta differs from the classical sequence as follows: SEQ ID NO:85 amino acids 113-129: KQHSVLHLVPINATSKD- & gtN

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

human isoform of sp|o 75888-3|tnf13_tumor necrosis factor ligand superfamily member 13 γos=homo sapiens gn=tnfsf 13

The sequence of isoform gamma differs from the classical sequence as follows: amino acids 247 to 249: deletion.

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

human isoform 4 OS of sp|o 75888-4|tnf13_tumor necrosis factor ligand superfamily member 13 = homo sapiens GN = TNFSF13

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

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

14.sp|O 43508-2|TNF12_tumor necrosis factor ligand superfamily member 12 human isoform TWE-PRILOS=Chiren GN=TNFSF12

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

human isoform 5 OS of sp|O 75888-5|TNF13_tumor necrosis factor ligand superfamily member 13 = homo sapiens GN = TNFSF13

The sequence of isoform 5 differs from the classical sequence as follows: amino acids 1-17: a deletion; amino acids 87-114: deletion.

Other variants and alternative sequences of human APRIL are described, for example, in MGC project group, 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 isoforms of human APRIL, e.g., one or more isoforms of human APRIL described herein. In one embodiment, the antibody molecule binds or substantially binds to a polypeptide having the amino acid sequence of SEQ ID NO:85, and a human APRIL of amino acid sequence.

Exemplary amino acid and nucleotide sequences of mouse APRIL are described, for example, in Yu et al, nat. Immunol.1:252-256 (2000); carninci et al, science 309:1559-1563 (2005); MGC project group, 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 provided below.

>muAPRIL

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

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 isoforms of mouse APRIL, e.g., one or more isoforms of mouse APRIL described herein. In one embodiment, the antibody molecule binds or substantially binds to a polypeptide 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 bind or substantially does not bind to mouse APRIL, it does not bind or substantially does not bind to one or more isoforms of mouse APRIL, e.g., one or more isoforms of mouse APRIL described herein. In one embodiment, the antibody molecule does not bind or substantially does not bind to a polypeptide having the sequence of SEQ ID NO:91 or 92. In one embodiment, the antibody molecule does not bind or substantially does not bind to a polypeptide having the sequence of SEQ ID NO:91 and a mouse APRIL having the amino acid sequence of SEQ ID NO:92 amino acid sequence of APRIL.

Exemplary human and mouse APRIL proteins (SEQ ID NOS: 85 and 91, respectively) are aligned with respect to FIG. 13 of International application publication No. WO2017/091683, the contents of which are incorporated herein by reference in their entirety.

Epitope(s)

The antibody molecules described herein are capable of binding to an epitope on APRIL (e.g., human APRIL, mouse APRIL, or both). For example, an epitope to which an antibody molecule described herein binds may include one or more epitope contact points described herein.

In one embodiment, the antibody molecule contacts (e.g., binds to or substantially binds to) one or more residues, or one or more regions, as described in any of figures 14, 22, 23A-23B, 24A-24B, 25A-25B, or 38A-38B, or any of tables 3-4 or 6, or table 8 of international application publication No. WO 2017/091683.

In one embodiment, the antibody molecule contacts (e.g., binds to 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, or all) of the amino acid residues shown in table 3. In one embodiment, the antibody molecule contacts (e.g., binds to or substantially binds to) all of the amino acid residues shown in table 3. For example, an antibody molecule described herein can include contacting the amino acid residues shown in table 3 in a manner that extends through the binding of 2 APRIL monomers (e.g., as indicated by the position of a versus B in table 3). While not being bound by theory, it is believed that in one embodiment, at least some of the amino acid residues shown in table 3 result in a high affinity interaction between the CDR2 domains of APRIL and TACI. In one embodiment, one or more of the amino acid residues in table 3 is contacted with an antibody molecule described herein to inhibit, or substantially inhibit, 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 structure of this epitope (e.g., defined both spatially and conformationally) is shown in FIG. 14 of International application publication No. W02017/091683.

TABLE 3 exemplary human APRIL amino acid residues (based on the amino acid numbering of SEQ ID NO: 85) that bind to an anti-APRIL antibody

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

The structure (space) representation of this epitope (sometimes referred to herein as the "core region") is shown in figure 15 of international application publication No. WO2017/091683, which shows that each APRIL protein molecule contains 2 stacked antiparallel 8-chain β -sheets (a-G), one internal and one external, in the βswiss coil topology. These β -sheets are linked by loops, which also define the desired epitope (defined based on secondary structure). Without wishing to be bound by theory, it is believed that these positions/structures define the following subgroups: the critical interactions with the CRD2 domains of APRIL and TACI will effect optional inhibition of APRIL binding to TACI by this antibody.

TABLE 4 exemplary human APRIL amino acid residues (based on the amino acid numbering of SEQ ID NO: 85) that bind to an anti-APRIL antibody

Amino acid position	Amino acids
		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 (e.g., SEQ ID NO: 85). For example, one or more mutations at these positions, e.g., asp129Ala, arg233Asn, his203Asp, or a combination thereof, do not reduce or substantially 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., neutralize the binding of APRIL to TACI).

In one embodiment, the antibody molecule binds to or substantially binds to one or more (e.g., 2, 4, 5, 6, 7, 8, 9, 10, or all) residues from human APRIL (e.g., SEQ ID NO: 85) at positions 105-114 and/or one or more (e.g., 2, 4, 5, 6, 7, 8, 9, 10, or all) residues from mouse APRIL (e.g., SEQ ID NO: 91) at positions 96-105.

In one embodiment, the antibody molecule contacts (e.g., binds to 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 to or substantially binds to) all of the amino acid residues shown in table 7.

TABLE 7 exemplary human APRIL amino acid residues (based on the amino acid numbering of SEQ ID NO: 85) that bind to an anti-APRIL antibody

Amino acid position	Amino acids
		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 having 1, 2, 3, 4, 5, or 6 CDRs of any one of 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, or 2419-1406, e.g., an anti-APRIL antibody molecule, binds to one or more amino acids as set forth in table 7. In one embodiment, for example, an antibody molecule having 1, 2, 3, 4, 5, or 6 CDRs of any of 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, e.g., a human-specific anti-APRIL antibody molecule, binds to mouse APRIL, wherein one or more (e.g., 2, 3, 4, or all) of the following positions in mouse APRIL are mutated (using mouse APRIL numbering), e.g., mutated to: a120D, N224R, H163Q, K219I or R181Q. In yet another embodiment, for example, an antibody molecule having 1, 2, 3, 4, 5, or 6 CDRs of any of 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, e.g., a human specific anti-APRIL antibody molecule, binds to mouse APRIL, when lysine at position 219 (using mouse APRIL numbering) is mutated, e.g., mutated to isoleucine (i.e., K219I).

In one embodiment, the antibody molecule contacts (e.g., binds to 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) of the amino acid residues of human APRIL shown in table 6 of international application publication No. WO 2017/091683. In one embodiment, the antibody molecule is an antibody molecule 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) of the amino acid residues of human APRIL selected from D132, V174, F176, V181, Q190, R195, R206, Y208, I228, or N237. In one embodiment, the antibody molecule contacts (e.g., binds to or substantially binds to) one or more (e.g., 2, 3, 4, 5, or all) of the amino acid residues of human APRIL selected from V174, F176, Q190, R195, R206, or Y208. In one embodiment, the antibody molecule contacts (e.g., binds to or substantially binds to) one or more (e.g., 2, 3, or all) of the amino acid residues of human APRIL selected from F176, V181, Q190, or I228. In one embodiment, the antibody molecule contacts (e.g., binds to or substantially binds to) one or more (e.g., 2 or all) of the amino acid residues of human APRIL selected from V174, R206, or Y208.

In one embodiment, the antibody molecule does not contact (e.g., does not bind or does not substantially 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 amino acid residues of human APRIL shown in table 6 of international application publication No. WO 2017/091683. In one embodiment, the antibody molecule is an antibody molecule 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 does not substantially bind) one or more (e.g., 2, 3, 4, 5, 6, or all) of the amino acid residues of human APRIL 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 does not substantially bind) one or more (e.g., 2, 3, or all) of the amino acid residues of human APRIL selected from V181, S226, I228, or N237. In one embodiment, the antibody molecule does not contact (e.g., does not bind or does not substantially bind) one or both of the amino acid residues of human APRIL selected from Y208 or N237. In one embodiment, the antibody molecule does not contact (e.g., does not bind or does not substantially bind) one or more (e.g., 2, 3, or all) of the amino acid residues of human APRIL selected from F176, V181, Q190, or N237.

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

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

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

In one embodiment, the epitope overlaps with the CRD2 receptor binding site. In one embodiment, the epitope is a nonlinear epitope, e.g., an epitope that spans the monomer interface. In one embodiment, the epitope is in a region associated with TACI and BCMA receptor blocking.

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) of the amino acid residues of human APRIL 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 to) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) of the amino acid residues of human APRIL 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) to a polypeptide selected from the group consisting of V133, V181, E185, Q187, G188, R189, Q190, E191, T192, R195, H218, L219, H220, S226, I228, P230 (located in monomer a); 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 of human APRIL of 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 to or substantially binds to) one or more (e.g., 2, 3, or all) of the amino acid residues of human APRIL selected from V181, Q190, T192, or I228. In one embodiment, the antibody molecule contacts (e.g., binds to or substantially binds to) one or both of the amino acid residues of human APRIL selected from a141 or H241 (located in monomer B). In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds) a polypeptide selected from the group consisting of V181, Q190, T192, and I228 (located in monomer a); one or more (e.g., 2, 3, 4, 5, or all) of the amino acid residues of a141 or H241 (located in monomer B) human APRIL.

In one embodiment, the antibody molecule comprises 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 monoclonal antibody 2419. In one embodiment, the antibody molecule comprises the heavy chain region, the light chain region, or both of monoclonal antibody 2419. In one embodiment, monoclonal antibody 2419 is a humanized antibody molecule.

In one embodiment, the epitope comprises a polypeptide selected from V133, V181, E185, Q187, G188, R189, Q190, E191, T192, R195, H218, L219, H220, S226, I228, P230 (located in monomer a); 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 of human APRIL of V121, I123, Q139, P140, a141, L142, N237, S239, P240, or H241 (located in monomer B). In one embodiment, the epitope comprises a polypeptide selected from V181, Q190, T192 and I228 (located in monomer a); one or more (e.g., 2, 3, 4, 5, or all) of the amino acid residues of a141 or H241 (located in monomer B) human APRIL.

In one embodiment, the structure of this epitope is shown in FIG. 38B of International application publication No. WO 2017/091683. In one embodiment, the epitope comprises 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 of international application publication No. WO 2017/091683.

In one embodiment, the antibody molecule contacts (e.g., binds to or substantially binds to) all of the amino acid residues shown in any one of tables 3-4 or 7 or 8 of international application publication No. WO 2017/091683. In one embodiment, the epitope comprises or consists of all of the amino acid residues shown in any one of tables 3-4 or 7 or 8 of International application publication No. WO 2017/091683.

In one embodiment, the antibody molecule has one or more of the following properties described herein, e.g., one or more (e.g., 2, 3, or all) of: (i) binds or substantially binds to human APRIL; (ii) binds or substantially binds to mouse APRIL; (iii) Inhibit or substantially inhibit the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both); or (iv) inhibit or substantially inhibit the binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both). In one embodiment, the antibody molecule binds or substantially binds to mouse 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 (e.g., APRIL molecules disclosed herein).

The term "antibody molecule" as used herein refers to a protein, such as an immunoglobulin chain or fragment thereof, comprising at least one immunoglobulin variable domain sequence. The term "antibody molecule" includes, for example, full length, mature antibodies and antigen binding fragments of antibodies. For example, an antibody molecule may comprise a heavy (H) chain variable region sequence (abbreviated herein as VH) and a light (L) chain variable region sequence (abbreviated herein as VL). In another example, an antibody molecule comprises two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequences, thereby forming two antigen binding sites, such as Fab, fab ', F (ab ') 2, fc, fd ', fv, single chain antibodies (e.g., scFv), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific), and chimeric (e.g., humanized) antibodies, and can be produced by modification of whole antibodies or those synthesized de novo using recombinant DNA techniques. These functional antibody fragments retain the ability to selectively bind to their corresponding antigens or receptors. Antibodies and antibody fragments may be from any antibody type (including but not limited to IgG, igA, igM, igD and IgE) and from any antibody subtype (e.g., igG1, igG2, igG3, and IgG 4). The antibody molecules may be monoclonal or polyclonal. The antibody molecule may also be a human, humanized, CDR-grafted or in vitro generated antibody. The antibody molecule may have a heavy chain constant region selected from the group consisting of IgG1, igG2, igG3, or IgG 4. The antibody molecule may also have a light chain selected from kappa or lambda. The term "immunoglobulin (Ig)" is used interchangeably with the term "antibody" herein.

Examples of antigen binding fragments include: (i) A Fab fragment, a monovalent fragment consisting of VL, VH, CL and CH1 domains; (ii) A F (ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked at a hinge region by a disulfide bridge; (iii) Fd fragment consisting of VH and CH1 domains; (iv) Fv fragment consisting of VL and VH domains of the antibody single arm; (v) A diabody (dAb) fragment consisting of a VH domain; (vi) a camelid or camelized variable domain; (vii) Single chain Fv (scFv), see, e.g., bird et al, (1988) Science 242:423-426; huston et al, (1988) Proc. Natl. Acad. Sci. USA 85: 5879-5883); (viii) single domain antibodies. These antibody fragments may be obtained by any suitable method, including a variety of conventional techniques known to those of ordinary skill in the art, and fragments are screened for the same use as the intact antibody.

The term "antibody" includes intact molecules as well as functional fragments thereof. The antibody constant regions can be altered (e.g., mutated) to modify the properties of the antibody, e.g., to increase or decrease one or more of: fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function, or complement function.

The antibody molecule may be a single chain antibody. Single chain antibodies (scFV) can be engineered (see, e.g., colcher, D.et al, (1999) Ann N Y Acad Sci 880:263-80; and Reiter, Y. (1996) Clin Cancer Res 2:245-52). Single chain antibodies can dimerize or multimerize to produce multivalent antibodies specific for different epitopes on the same target protein.

The antibody molecules described 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 antibodies, antibodies naturally deleted light chains, single domain antibodies derived from conventional 4 chain antibodies, engineered antibodies, and single domain backbones not derived from antibodies. The single domain antibody may be any single domain antibody in the art or any future single domain antibody. The single domain antibody may be derived from any species, including but not limited to: mice, humans, camels, llamas, fish, sharks, sheep, rabbits and cattle. According to some aspects, the single domain antibody is a naturally occurring single domain antibody known as a heavy chain antibody lacking a light chain. Such single domain antibodies are disclosed in, for example, WO94/04678. For clarity, this variable domain derived from a heavy chain antibody that naturally lacks a light chain is referred to herein as a VHH or nanobody to distinguish from a conventional VH of a four chain immunoglobulin. The VHH molecules may be derived from antibodies grown in Camelidae (Camelidae) species, for example from camels, llamas, dromedaries, alpacas and pack horses. In addition to camelidae, other species may also produce heavy chain antibodies naturally lacking the light chain; these VHHs are also included herein.

VH and VL regions can be further subdivided into regions of hypervariability, termed "Complementarity Determining Regions (CDRs)", with regions more conserved interposed therebetween, termed "framework regions (FR or FW)". The terms "complementarity determining region" and "CDR" as used herein refer to amino acid sequences within the variable regions of an antibody that confer antigen specificity and binding affinity. The terms "framework", "FW" and "FR" are used interchangeably herein.

The framework regions and CDRs have been precisely defined using a variety of methods (see Kabat, E.A., et al, (1991) Sequences ofProteins ofImmunological Interest (by the hot immunological protein sequence, 5 th edition, U.S. public health agency, national institutes of health, publication No. 91-3242; chothia, C. Et al, (1987) J.mol. Biol.196:901-917; and AbM definitions for the use of Oxford Molecular AbM antibody modeling software (Oxford Molecular's AbM antibody modeling software). See generally "Protein Sequence and Structure Analysis of Antibody Variable Domains" ("protein sequence and structural analysis of antibody variable domain") in antibody engineering laboratory Manual (Antibody Engineering Lab Manual) (Duebel, S. and Kontermann, R. plague, springer-Verlag, V.L.) in one embodiment, the use of AbM definition for heavy chain variable domain 1 and AbCDR for Kacdr 1 in one embodiment and for the use of Kabat end definition for CDR1 and in addition to three CDR end of the use of three CDR3 in another embodiment, the amino end definition for CDR1 and CDR2 in addition to three end definition for FR2, in accordance with the use of the amino end definition of the three CDR2, and the three end definition for FR 2.

As used herein, "immunoglobulin variable domain sequence" refers to an amino acid sequence capable of forming an immunoglobulin variable domain structure. For example, the sequence may include all or part of a naturally occurring variable domain amino acid sequence. For example, the sequence may or may not contain one, two or more N-or C-terminal amino acids, or may contain other changes that are compatible with protein structure formation.

The term "antigen binding region" refers to a portion of an antibody molecule that comprises determinants that form a binding interface with an antigen (e.g., APRIL) or epitope thereof. In the case of proteins (or protein mimics), the antigen binding region typically comprises one or more loops (e.g., loops of at least 4 amino acids or amino acid mimics) that form an antigen, e.g., an APRIL binding interface. 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 interfere with the binding of an anti-APRIL antibody molecule (e.g., an anti-APRIL antibody molecule provided herein) to a target (e.g., APRIL). The interference with binding may be direct or indirect (e.g., through allosteric modulation of the antibody molecule or target). The extent to which an antibody molecule interferes with the binding of other antibody molecules to a target and thus whether it can be referred to as competition, can be determined using a competitive binding test (e.g., FACS test, ELISA, or BIACORE test). In one embodiment, the competitive binding assay is a quantitative competitive assay. In one embodiment, a first anti-APRIL antibody molecule is considered to competitively bind to a second anti-APRIL antibody molecule when binding of the first anti-APRIL antibody molecule to the target is reduced in a competitive binding assay (e.g., the competitive assay described herein) as follows: a reduction of 10% or more, for example 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.

The term "monoclonal antibody" or "monoclonal antibody composition" as used herein refers to a preparation of antibody molecules having a single molecular composition. Monoclonal antibody compositions exhibit a single binding specificity and affinity for a particular epitope. Monoclonal antibodies can be prepared using hybridoma technology or methods that do not employ hybridoma technology (e.g., recombinant methods).

An "effective/potent human (effectively human)" protein is one that does not elicit a neutralizing antibody response (e.g., a human anti-murine antibody (HAMA) response). HAMA can be problematic in many situations (e.g., if the antibody molecule is repeatedly administered, for example, in the treatment of chronic or recurrent disease symptoms). HAMA responses can result in repeated antibody administration that may be ineffective due to increased serum antibody clearance (see, e.g., saleh et al, cancer immunol. Immunother.32:180-190 (1990)) and due to potential allergic reactions (see, e.g., loBuglio et al, hybrid mia, 5:5117-5123 (1986)).

The antibody molecule may be a polyclonal or monoclonal antibody. In some embodiments, the antibody may be recombinantly produced, e.g., by any suitable phage display or recombinant method.

Various phage display and combinatorial methods for producing antibodies are known in the art (as described below, e.g., ladner et al, U.S. Pat. No. 5,223,409; kang et al, international publication No. WO 92/18619; dower et al, international publication No. WO 91/17271; winter et al, international publication No. WO 92/20791; markland et al, international publication No. WO 92/15679; breitling et al, international publication No. WO 93/01188; mcCafferty et al, international publication No. WO 92/01047; garard et al, international publication No. WO 92/09690; ladner et al, international publication No. WO 90/02809; fuchs et al, (1991) Bio/Technology 9:13701372; hay et al, (1992) Hum Antibod Hybridomas:81-85; huse et al, (1989) Science 246:1275-1281; griffths et al, (1993) supra; hawkins et al, (1992) J Mol Biol 226:889; clackson et al, (1991) Nature 352:624; gram et al, (1992) PNAS 89:3576-3580; garrad et al, (1991) Bio/Technology9:13731377; 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 their entirety).

In one embodiment, the antibody molecule is a fully human antibody (e.g., an antibody produced by a mouse that has been genetically engineered to produce antibodies derived from human immunoglobulin sequences), or a non-human antibody, e.g., a rodent (mouse or rat), sheep, primate (e.g., monkey), camel antibody. In one embodiment, the non-human antibody is a rodent antibody (mouse or rat antibody). Methods of preparing rodent antibodies are known in the art.

Human monoclonal antibodies can be produced using transgenic mice carrying human immunoglobulin genes rather than a mouse system. Spleen cells from these transgenic mice immunized with the antigen of interest were used to generate hybridomas secreting human mAbs that have binding specificity for epitopes from human proteins (see, e.g., wood et al, international application No. WO 9I/00906, kucherlpati et al, PCT publication No. WO 91/10741; lonberg et al, international application No. WO 92/03918; kay et al, international application No. 92/03917; lonberg et al, 1994Nature 368:856-859; green, L.L. Et al, 1994Nature Genet.7:13-21; morrison, S.L. Et al, 1994Proc.Natl.Acad.Sci.USA 81:6851-6855; bruggeman et al, 1993Year Immunol 7:33-40; tuaillon et al, 1993PNAS 90:3720-3724; bruggeman et al, 1991Eur J Immunol 21:1323-1326).

An antibody may be one in which the variable region or portion thereof (e.g., CDR) is produced in a non-human organism (e.g., rat or mouse). Chimeric, CDR-grafted and humanized antibodies are encompassed by the present invention. The invention includes antibodies that are produced in a non-human organism (e.g., a rat or mouse) and subsequently modified (e.g., in a variable framework or constant region) to reduce antigenicity in humans.

Chimeric antibodies may be produced using any suitable recombinant DNA technology. Several are known in the art (see Robinson et al, international patent application publication No. WO1987/002671; akira, et al, european patent application 184,187; taniguchi, M., european patent application 171,496; morrison et al, european patent application 173,494; neuberger et al, international patent application publication No. WO 86/01533; cabilly et al, U.S. Pat. No. 4,816,567; cabily et al, european patent application 125,023; better et al, (1988 science240: 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, res. 999:1005-1005; wood et al, (1985) Nature 314:446-449; and 1988,JNatl Cancer Inst.80:1553-579).

At least one or two, but typically all three, recipient CDRs (of an immunoglobulin heavy or light chain) in a humanized or CDR-grafted antibody are replaced by donor CDRs. The antibody may be replaced with at least a portion of the non-human CDRs, or only some CDRs may be replaced with non-human CDRs. Only the number of CDRs required for the humanized antibody to bind lipopolysaccharide needs to be replaced. In one embodiment, the donor may be a rodent antibody, such as a rat or mouse antibody, and the recipient may be a human framework or a human consensus framework. In general, immunoglobulins that provide CDRs are referred to as "donors" and immunoglobulins that provide framework regions are referred to as "recipients". In some embodiments, the donor immunoglobulin is non-human (e.g., rodent). The recipient framework is typically a naturally occurring (e.g., human) framework or a consensus framework, or a sequence that is about 85% or more, e.g., 90%, 95%, 99% or more identical thereto.

As used herein, the term "consensus sequence" refers to a sequence consisting of the highest frequency of amino acids (or nucleotides) present in the family of related sequences (see, e.g., winnaker, from gene to clone (From Genes to Clones), verlagsgesellschaft publishing company, delbrueck helm (Weinheim, germany), 1987). In a family of proteins, each position in the consensus sequence is the most frequently occurring amino acid at that position in the family. If the frequency of occurrence of the two amino acids is the same, either one of them may be contained in the consensus sequence. "consensus framework" refers to a framework region in a consensus immunoglobulin sequence.

Many such methods are known in the art (see, e.g., morrison, S.L.,1985,Science 229:1202-1207, oi et al, 1986, bioTechniques4:214, and Queen et al, U.S. Pat. No. 5,585,089, U.S. Pat. No. 5,693,761, and U.S. Pat. No. 5,693,762, the entire contents of which are incorporated herein by reference) for humanizing antibodies using any suitable method.

CDR grafting or CDR substitution may be employed to generate humanized or CDR-grafted antibodies, replacing one, two or all CDRs in an immunoglobulin chain. See, for example, U.S. Pat. nos. 5,225,539; jones et al, 1986Nature 321:552-525; verhoey et al, 1988science 239:1534; beidler et al, 1988J.Immunol.141:4053-4060; winter US 5,225,539, the entire contents of which are incorporated herein by reference. Winter describes a CDR-grafting method that can be used to prepare humanized antibodies (British patent application GB 2188638A, filed on 26.3.1987; winter US 5,225,539), the entire contents of which are incorporated herein by reference.

Humanized antibodies in which specific amino acids are substituted, deleted or inserted are also provided. Criteria for selecting amino acids from a donor are described, for example, in U.S. Pat. No. 5,585,089, e.g., columns 12-16 of U.S. Pat. No. 5,585,089, the contents of which are incorporated herein by reference. Other techniques for humanizing antibodies are described in EP519596A1 to Padlan et al (published in 12, 23 1992).

In one embodiment, the antibody molecule has a heavy chain constant region selected from, for example: heavy chain constant regions of IgG1, igG2 (e.g., igG2 a), igG3, igG4, igM, igA1, igA2, igD, and IgE; specifically, a heavy chain constant region (e.g., of a human) selected from, for example, igG1, igG2, igG3, and IgG 4. In another embodiment, the antibody molecule has a light chain constant region selected from, for example, kappa or lambda (e.g., human) light chain constant regions. The constant region can be altered (e.g., mutated) to modify the properties of the antibody molecule (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function, and/or complement function). In one embodiment, the antibody molecule has an effector function and is capable of fixing complement. In another embodiment, the antibody molecule does not recruit effector cells or fix complement. In certain embodiments, the antibody molecule has reduced or no ability to bind to an Fc receptor. For example, an antibody may be an isoform or subtype, fragment or other mutant that does not support binding to Fc receptors, e.g., that has a mutagenized Fc receptor binding region or lacks an Fc receptor binding region.

In one embodiment, the constant region of the antibody molecule is altered. Methods for altering the constant regions of antibodies are known in the art. Antibody molecules having altered functions (e.g., altered affinity for effector ligands (e.g., fcrs on cells) or C1 components of complement) can be produced by replacing at least one amino acid residue in the constant portion of the antibody with a different residue (see, e.g., EP388,151A1, U.S. Pat. No. 5,624,821, and U.S. Pat. No. 5,648,260, the entire contents of which are incorporated herein by reference). Amino acid mutations that stabilize the structure of the antibody are also included, such as S228P in human IgG4 (EU nomenclature, S241P in Kabat nomenclature). Similar types of changes can be described which would attenuate or eliminate these functions if applied to immunoglobulins in mice or other species.

In one embodiment, the antibody molecule comprises an Fc region comprising one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 6, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more) of the mutations or combinations of mutations described in table 6.

TABLE 6 exemplary Fc mutations

In one embodiment, the Fc region comprises FcMut001. In one embodiment, the Fc region comprises FcMut002. In one embodiment, the Fc region comprises FcMut003. In one embodiment, the Fc region comprises FcMut004. In one embodiment, the Fc region comprises FcMut005. In one embodiment, the Fc region comprises FcMut006. In one embodiment, the Fc region comprises FcMut007. In one embodiment, the Fc region comprises FcMut008. In one embodiment, the Fc region comprises FcMut009. In one embodiment, the Fc region comprises FcMut010. In one embodiment, the Fc region comprises FcMut011. In one embodiment, the Fc region comprises FcMut012. In one embodiment, the Fc region comprises FcMut013. In one embodiment, the Fc region comprises FcMut014. In one embodiment, the Fc region comprises FcMut015. In one embodiment, the Fc region comprises FcMut016. In one embodiment, the Fc region comprises FcMut017. In one embodiment, the Fc region comprises FcMut018. In one embodiment, the Fc region includes FcMut019. In one embodiment, the Fc region comprises FcMut020. In one embodiment, the Fc region comprises FcMut021. In one embodiment, the Fc region comprises FcMut022. In one embodiment, the Fc region comprises FcMut023. In one embodiment, the Fc region comprises FcMut024. In one embodiment, the Fc region comprises FcMut026. In one embodiment, the Fc region comprises FcMut027. In one embodiment, the Fc region comprises FcMut028. In one embodiment, the Fc region comprises FcMut029. In one embodiment, the Fc region comprises FcMut030. In one embodiment, the Fc region comprises FcMut031. In one embodiment, the Fc region comprises FcMut032. In one embodiment, the Fc region comprises FcMut033. In one embodiment, the Fc region comprises FcMut034. In one embodiment, the Fc region comprises FcMut035. In one embodiment, the Fc region comprises FcMut036. In one embodiment, the Fc region comprises FcMut037. In one embodiment, the Fc region comprises FcMut038. In one embodiment, the Fc region comprises FcMut039. In one embodiment, the Fc region comprises FcMut040. In one embodiment, the Fc region includes FcMut041. In one embodiment, the Fc region comprises FcMut042. In one embodiment, the Fc region comprises FcMut043. In one embodiment, the Fc region comprises FcMut044. In one embodiment, the Fc region comprises FcMut045. In one embodiment, the Fc region comprises FcMut046. In one embodiment, the Fc region comprises FcMut047. In one embodiment, the Fc region comprises FcMut048. In one embodiment, the Fc region comprises FcMut049. In one embodiment, the Fc region comprises FcMut050. In one embodiment, the Fc region comprises FcMut051. In one embodiment, the Fc region comprises FcMut052. In one embodiment, the Fc region comprises FcMut053. In one embodiment, the Fc region comprises FcMut067. In one embodiment, the Fc region comprises FcMut068. In one embodiment, the Fc region comprises FcMut069. In one embodiment, the Fc region comprises FcMut070. In one embodiment, the Fc region includes FcMut071. In one embodiment, the Fc region comprises FcMut072. In one embodiment, the Fc region comprises FcMut073. In one embodiment, the Fc region comprises FcMut074. In one embodiment, the Fc region comprises FcMut075. In one embodiment, the Fc region comprises FcMut076. In one embodiment, the Fc region comprises FcMut077. In one embodiment, the Fc region comprises FcMut078. In one embodiment, the Fc region comprises FcMut079. In one embodiment, the Fc region comprises FcMut080. In one embodiment, the Fc region comprises FcMut081. In one embodiment, the Fc region comprises FcMut082. In one embodiment, the Fc region comprises FcMut083. In one embodiment, the Fc region comprises FcMut084. In one embodiment, the Fc region comprises FcMut085. In one embodiment, the Fc region comprises FcMut086. In one embodiment, the Fc region comprises FcMut087. In one embodiment, the Fc region comprises FcMut088. In one embodiment, the Fc region comprises FcMut089. In one embodiment, the Fc region comprises FcMut090. In one embodiment, the Fc region comprises FcMut091. In one embodiment, the Fc region comprises FcMut093. In one embodiment, the Fc region comprises FcMut094. In one embodiment, the Fc region comprises FcMut095. In one embodiment, the Fc region comprises FcMut096. In one embodiment, the Fc region comprises FcMut097. In one embodiment, the Fc region comprises FcMut098. In one embodiment, the Fc region comprises FcMut099. In one embodiment, the Fc region comprises FcMut100. In one embodiment, the Fc region comprises FcMut101. In one embodiment, the Fc region comprises FcMut102. In one embodiment, the Fc region comprises FcMut103. In one embodiment, the Fc region comprises FcMut104. In one embodiment, the Fc region comprises FcMut105. In one embodiment, the Fc region comprises FcMut106. In one embodiment, the Fc region comprises FcMut107. In one embodiment, the Fc region comprises FcMut108. In one embodiment, the Fc region comprises FcMut109. In one embodiment, the Fc region comprises FcMut110. In one embodiment, the Fc region comprises FcMut111. In one embodiment, the Fc region comprises FcMut112. In one embodiment, the Fc region comprises FcMut113. In one embodiment, the Fc region comprises FcMut114. In one embodiment, the Fc region comprises FcMut115. In one embodiment, the Fc region comprises FcMut116. In one embodiment, the Fc region comprises FcMut117. In one embodiment, the Fc region comprises FcMut118. In one embodiment, the Fc region comprises FcMut119. In one embodiment, the Fc region comprises FcMut120. In one embodiment, the Fc region comprises FcMut121. In one embodiment, the Fc region comprises FcMut122. In one embodiment, the Fc region comprises FcMut123. In one embodiment, the Fc region comprises FcMut124. In one embodiment, the Fc region comprises FcMut125. In one embodiment, the Fc region includes FcMut126. In one embodiment, the Fc region comprises FcMut127. In one embodiment, the Fc region comprises FcMut128. In one embodiment, the Fc region comprises FcMut129. In one embodiment, the Fc region includes FcMut130. In one embodiment, the Fc region comprises FcMut131. In one embodiment, the Fc region comprises FcMut132. In one embodiment, the Fc region comprises FcMut133. In one embodiment, the Fc region comprises FcMut134. In one embodiment, the Fc region comprises FcMut135. In one embodiment, the Fc region comprises FcMut136. In one embodiment, the Fc region comprises FcMut137. In one embodiment, the Fc region comprises FcMut138. In one embodiment, the Fc region comprises FcMut139. In one embodiment, the Fc region includes FcMut140. In one embodiment, the Fc region comprises FcMut141. In one embodiment, the Fc region comprises FcMut142. In one embodiment, the Fc region comprises FcMut143. In one embodiment, the Fc region comprises fccmutl 44. In one embodiment, the Fc region comprises FcMut145. In one embodiment, the Fc region includes FcMut146. In one embodiment, the Fc region comprises FcMut147. In one embodiment, the Fc region includes FcMut148. In one embodiment, the Fc region comprises FcMut149. In one embodiment, the Fc region includes FcMut150. In one embodiment, the Fc region comprises FcMut151. In one embodiment, the Fc region includes FcMut152. In one embodiment, the Fc region includes FcMut153. In one embodiment, the Fc region comprises FcMut154. In one embodiment, the Fc region comprises FcMut155. In one embodiment, the Fc region includes FcMut156. In one embodiment, the Fc region comprises fccmutl 57. In one embodiment, the Fc region includes FcMut158. In one embodiment, the Fc region comprises FcMut159. In one embodiment, the Fc region includes FcMut160. In one embodiment, the Fc region comprises FcMut161. In one embodiment, the Fc region includes FcMut162. In one embodiment, the Fc region comprises FcMut163. In one embodiment, the Fc region includes FcMut164. In one embodiment, the Fc region comprises FcMut165. In one embodiment, the Fc region includes FcMut166. In one embodiment, the Fc region comprises FcMut167. In one embodiment, the Fc region includes FcMut168. In one embodiment, the Fc region comprises FcMut169. In one embodiment, the Fc region includes FcMut170. In one embodiment, the Fc region includes FcMut171. In one embodiment, the Fc region comprises FcMut172. In one embodiment, the Fc region comprises FcMut173. In one embodiment, the Fc region includes FcMut174. In one embodiment, the Fc region comprises FcMut175. In one embodiment, the Fc region includes FcMut176. In one embodiment, the Fc region comprises FcMut177. In one embodiment, the Fc region comprises FcMut178. In one embodiment, the Fc region comprises FcMut179. In one embodiment, the Fc region comprises FcMut180. In one embodiment, the Fc region comprises FcMut181. In one embodiment, the Fc region includes FcMut182. In one embodiment, the Fc region comprises FcMut183. In one embodiment, the Fc region comprises FcMut184. In one embodiment, the Fc region comprises FcMut185. In one embodiment, the Fc region includes FcMut186. In one embodiment, the Fc region comprises FcMut187. In one embodiment, the Fc region comprises FcMut188. In one embodiment, the Fc region comprises FcMut189. In one embodiment, the Fc region includes FcMut190. In one embodiment, the Fc region includes FcMut191. In one embodiment, the Fc region includes FcMut192. In one embodiment, the Fc region includes FcMut193. In one embodiment, the Fc region includes FcMut194. In one embodiment, the Fc region comprises FcMut195. In one embodiment, the Fc region comprises FcMut196. In one embodiment, the Fc region comprises FcMut197. In one embodiment, the Fc region comprises FcMut198. In one embodiment, the Fc region comprises FcMut199. In one embodiment, the Fc region comprises FcMut200. In one embodiment, the Fc region comprises FcMut201. In one embodiment, the Fc region comprises FcMut202. In one embodiment, the Fc region comprises FcMut203. In one embodiment, the Fc region includes FcMut204. In one embodiment, the Fc region comprises FcMut205. In one embodiment, the Fc region includes FcMut206. In one embodiment, the Fc region comprises FcMut207. In one embodiment, the Fc region includes FcMut208. In one embodiment, the Fc region comprises FcMut209. In one embodiment, the Fc region includes FcMut210. In one embodiment, the Fc region includes FcMut211. In one embodiment, the Fc region includes FcMut212. In one embodiment, the Fc region comprises FcMut213. In one embodiment, the Fc region comprises FcMut214. In one embodiment, the Fc region comprises FcMut215. In one embodiment, the Fc region includes FcMut216. In one embodiment, the Fc region comprises FcMut217. In one embodiment, the Fc region comprises FcMut218. In one embodiment, the Fc region comprises FcMut219. In one embodiment, the Fc region includes FcMut220. In one embodiment, the Fc region comprises FcMut221. In one embodiment, the Fc region comprises FcMut222. In one embodiment, the Fc region comprises FcMut223. In one embodiment, the Fc region comprises FcMut224. In one embodiment, the Fc region comprises FcMut225. In one embodiment, the Fc region includes FcMut226. In one embodiment, the Fc region comprises FcMut227. In one embodiment, the Fc region comprises FcMut228. In one embodiment, the Fc region comprises FcMut229. In one embodiment, the Fc region comprises FcMut230. In one embodiment, the Fc region comprises FcMut231. In one embodiment, the Fc region comprises FcMut232. In one embodiment, the Fc region comprises FcMut233. In one embodiment, the Fc region includes FcMut234. In one embodiment, the Fc region includes FcMut242. In one embodiment, the Fc region comprises FcMut243. In one embodiment, the Fc region comprises FcMut244.

Other exemplary Fc mutations are described, for example, in International application publication No. WO2018/052556, U.S. patent application publication No. US2018/0037634, and Booth et al, MAbs.2018;10 (7): 1098-1110, the entire contents of which are incorporated herein by reference.

In one embodiment, the Fc region is altered to extend half-life. For example, the Fc region may comprise one or more of the following: fcMut183 (T256D-Q311V-a 378V), fcMut197 (H285N-T307Q-N315D), fcMut213 (H285D-T307Q-a 378V), fcMut215 (T307Q-Q311V-a 378V) or FcMut228 (T256D-N286D-T307R-Q311V-a 378V) (all numbering according to EU).

In one embodiment, the Fc region is altered to enhance ADCC. For example, the Fc region may comprise one or more of the following: A330L-I332E-S239D, F243L-R292P-Y300L-V305I-P396L, or S298A-E333A-K334A. In one embodiment, the defucosylation can be achieved by expression in a cell line (e.g., CHO) that knocks out fucosyltransferase (FucT 8).

In one embodiment, the Fc region is altered to enhance CDC. For example, the Fc region comprises S267E-H268F-S324T.

In one embodiment, the Fc region is altered to enhance Antibody Dependent Cell Phagocytosis (ADCP). For example, the Fc region comprises S239D-I332E-A330L.

In one embodiment, the amino acids in the antibody molecule are only standard amino acids. In one embodiment, the antibody molecule comprises naturally occurring amino acids; analogs, derivatives and analogs thereof; amino acid analogs having variant side chains; and/or all stereoisomers of any of the foregoing. The antibody molecule may comprise a peptide mimetic and a D-or L-optical isomer of an amino acid.

The polypeptides of the antibody molecules described herein may be linear or branched, may comprise modified amino acids, and may be interspersed with non-amino acids. Antibody molecules may also be modified; for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation or any other manipulation, such as coupling with a labeling component. The polypeptides may be isolated from natural sources, may be produced by recombinant techniques from prokaryotic or eukaryotic hosts, or may be the product of synthetic methods.

The antibody molecules described herein may be used alone in unconjugated form, or may be conjugated to substances such as toxins or moieties (e.g., therapeutic agents, radiation emitting compounds, plant, fungal, or bacterial origin molecules, or biological proteins (e.g., protein toxins) or particles (e.g., recombinant viral particles (e.g., by viral coating proteins)). For example, anti-APRIL antibodies may be conjugated to radioisotopes (e.g., alpha-, beta-, or gamma-radiation or beta-and gamma-radiation).

The antibody molecule may be derivatized or otherwise linked to other functional molecules (e.g., another peptide or protein). As used herein, a "derivatized" antibody molecule is an antibody molecule that has been modified. Methods of derivatization include, but are not limited to: fluorescent moieties, radionucleotides, toxins, enzymes or affinity ligands (e.g. biotin) are added. Thus, antibody molecules include derivatized and other modified forms of the antibodies described herein, including immunoadhesion molecules. For example, an antibody molecule may be functionally linked (by chemical coupling, 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 detection agent, a toxin, an agent, and/or a protein or peptide that can mediate the association of the antibody or antibody portion with other molecules (e.g., streptavidin core region or polyhistidine tag).

Certain types of derivatized antibody molecules may be produced by cross-linking two or more antibodies (of the same type or different types, e.g., to produce bispecific antibodies). Suitable crosslinking agents include heterobifunctional crosslinking agents (e.g., m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (e.g., disuccinimidyl suberate) crosslinking agents having two different reactive groups separated by a suitable spacer. Such cross-linking agents are available from pierce chemicals company (Pierce Chemical Company) (rocford, il).

Useful detectable agents that may be used to derivatize (or label) anti-dengue antibody molecules include fluorescent compounds, various enzymes, prosthetic groups, luminescent materials, bioluminescent materials, fluorescence emitting metal atoms (e.g., europium (Eu) and other lanthanide atoms), and radioactive materials (as described below). Exemplary fluorescent detection agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-naphthalene sulfonic acid chloride, phycoerythrin, and the like. Antibodies may also be derivatized with detectable enzymes, which may be, for example, alkaline phosphatase, horseradish peroxidase, beta-galactosidase, acetylcholinesterase, glucose oxidase, and the like. Where a detectable enzyme is used to derive an antibody, the antibody may be detected using other reagents added to the enzyme to produce a detectable reaction product. For example, in the presence of the detector horseradish peroxidase, hydrogen peroxide and diaminobenzidine are added to produce a detectable color reaction product. Prosthetic groups (e.g., streptavidin/biotin and avidin/biotin) can also be used to derivatize antibody molecules. For example, antibodies can be derivatized with biotin and detected by indirect assay of avidin or streptavidin binding. Examples of suitable fluorescent materials include umbelliferone, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; examples of the luminescent material include luminol; examples of bioluminescent materials include luciferase, luciferin and aequorin.

Labeled antibody molecules may be used, for example, diagnostically and/or experimentally, including (i) for isolating a predetermined antigen by standard techniques (such as affinity chromatography or immunoprecipitation) and (ii) for detecting a predetermined antigen (e.g., in a cell lysate or cell supernatant) to evaluate the expression pattern and abundance of a protein; (iii) For monitoring protein levels in tissues as part of a clinical trial, for example, for determining the efficacy of a given treatment regimen.

The antibody molecule may be conjugated to other molecular entities, typically labels or moieties, such as antimicrobial agents (e.g., antibacterial or bactericidal agents), immunomodulators, immunostimulants, cytotoxic or cytostatic agents. Radioisotopes may be used in detection or therapeutic applications. Radioisotopes that may be conjugated to antibody molecules include, but are not limited to, alpha-, beta-, or gamma-radiationBody, or beta-and gamma-emitters. Such radioisotopes 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, re% ¹⁸⁶ Re, bi% ²¹² Bi or Bi ²¹³ Bi, in ] ¹¹¹ In, technetium ] ⁹⁹ mTc, phosphorus% ³² P and rhodium ¹⁸⁸ Rh and sulfur ³⁵ S, C ¹⁴ C) The tritium is ³ H) The chromium is ⁵¹ Cr and chlorine% ³⁶ Cl, co% ⁵⁷ Co or ⁵⁸ Co, fe ⁵⁹ Fe and Se ⁷⁵ Se) or Ga% ⁶⁷ Ga). Radioisotopes useful as therapeutic agents include: yttrium (-) -A/D ⁹⁰ Y, lutetium ] ¹⁷⁷ Lu), actinium ²²⁵ Ac), praseodymium, astatine ²¹¹ At, re% ¹⁸⁶ Re, bi% ²¹² Bi or Bi ²¹³ Bi) and rhodium% ¹⁸⁸ Rh). Radioisotopes useful as markers, for example for diagnosis, include: iodine ¹³¹ I or ¹²⁵ I) The indium is ¹¹¹ In, technetium ] ⁹⁹ mTc, phosphorus% ³² p, C ¹⁴ C) And tritium% ³ H) Or one or more of the therapeutic isotopes listed above.

The present disclosure provides radiolabeled antibody molecules and methods of labeling thereof. In one embodiment, a method of labeling an antibody molecule is disclosed. The method comprises contacting an antibody molecule with a chelator to produce a conjugated antibody. The conjugated antibodies are conjugated to a radioisotope (e.g ¹¹¹ Indium (indium), ⁹⁰ Yttrium and its preparation ¹⁷⁷ Lutetium) radiolabeled to produce labeled antibody molecules.

In some aspects, the disclosure provides methods of making the antibody molecules disclosed herein. The method comprises the following steps: providing an antigen (e.g., APRIL) or fragment thereof; obtaining an antibody molecule that specifically binds to the antigen; the efficacy of the antibody molecule in modulating the activity of the antigen and/or biologically expressing the antigen (e.g., APRIL) is assessed. The method may further comprise administering to the subject (e.g., human) the antibody molecule, including derivatives thereof (e.g., humanized antibody molecules).

The present disclosure provides isolated nucleic acid molecules encoding the above antibody molecules, as well as vectors and host cells thereof. Nucleic acid molecules include, but are 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. Table 5 describes the amino acid sequences of other exemplary humanized antibody molecules.

Table 1. Amino acid sequences of heavy chain variable region (VH) and light chain variable region (VL) of exemplary anti-APRIL antibodies are provided below. The CDR bands defined according to the Kabat system are underlined and bolded, while the CDRs defined according to the Chothia system are italicized.

Table 2. Nucleotide sequences of heavy chain variable region (VH) and light chain variable region (VL) of exemplary antibody molecules.

Table 5. Amino acid sequences of the heavy chain variable region (VH) and the light chain variable region (VL) of exemplary humanized anti-APRIL antibodies are provided below.

In one embodiment, the antibody molecule comprises 1, 2 or 3 CDRs of a VH region of an antibody molecule described herein, e.g., in table 1 or 5 (e.g., any of monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439 or 4237, defined using Kabat or Chothia of CDRs. In one embodiment, the antibody molecule comprises 1, 2, or 3 CDRs of an antibody molecule described herein, e.g., in table 1 or 5 (e.g., any of monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439, or 4237), defined using Kabat or Chothia of the CDRs of the VL. In one embodiment, the antibody molecule comprises one or more (e.g., 2 or 3) CDRs of VH regions and/or VL regions of an antibody molecule described herein, e.g., any of table 1 or 5 (e.g., monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439, or 4237), defined using Kabat or chota of CDRs.

In one embodiment, the antibody molecule comprises 1, 2 or 3 VHCDRs as set forth in table 1 or 5. In one embodiment, the antibody molecule comprises 1, 2, or 3 VL CDRs as described in table 1 or 5. In one embodiment, the antibody molecule comprises one or more (e.g., 2 or 3) VH CDRs and/or one or more (e.g., 2 or 3) VL CDRs as set forth in table 1 or 5.

In one embodiment, the antibody molecule comprises 1, 2, 3 or 4 frameworks of the VH region of an antibody molecule described herein, e.g., in table 1 or 5 (e.g., any of monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439 or 4237). In one embodiment, the antibody molecule comprises 1, 2, 3, or 4 frameworks of the VL region of an antibody molecule described herein, e.g., in table 1 or 5 (e.g., any of monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439, or 4237). In one embodiment, the antibody molecule comprises one or more (e.g., 2, 3, or 4) frameworks of VH regions and/or one or more (e.g., 2, 3, or 4) frameworks of VL regions of an antibody molecule described herein, e.g., in table 1 or 5 (e.g., any of monoclonal antibodies 2218, 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, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439, or 4237).

In one embodiment, the antibody molecule comprises a heavy chain variable region of an antibody molecule described herein, e.g., any of table 1 or 5 (e.g., monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439, or 4237). In one embodiment, the antibody molecule comprises a light chain variable region of an antibody molecule described herein, e.g., any of table 1 or 5 (e.g., monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439, or 4237). In one embodiment, the antibody molecule comprises a heavy chain variable region and a light chain variable region of an antibody molecule described herein, e.g., any of table 1 or 5 (e.g., monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439, or 4237).

In one embodiment, the antibody molecule comprises a heavy chain variable region having an amino acid sequence set forth in table 1 or 5, or an amino acid sequence substantially identical thereto. In one embodiment, the antibody molecule comprises a light chain variable region having an amino acid sequence set forth in table 1 or 5, or an amino acid sequence substantially identical thereto. In one embodiment, the antibody molecule comprises a heavy chain variable region having an amino acid sequence (or substantially the same amino acid sequence) as set forth in table 1 or 5 and a light chain variable region having an amino acid sequence (or substantially the same amino acid sequence) as set forth in table 1 or 5.

In one embodiment, the antibody molecule comprises a heavy chain variable region encoded by, or substantially identical to, a nucleotide sequence set forth in table 2. In one embodiment, the antibody molecule comprises a light chain variable region encoded by, or substantially identical to, a nucleotide sequence set forth in table 2. In one embodiment, the antibody molecule comprises a heavy chain variable region encoded by (or substantially identical to) a nucleotide sequence set forth in table 2, and a light chain variable region encoded by (or substantially identical to) a nucleotide sequence set forth in table 2.

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, e.g., SEQ ID NO:320-322, or a functional portion thereof. In another embodiment, the heavy chain constant region is an IgG1 constant region, e.g., SEQ ID NO: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 the heavy chain constant region, the light chain constant region, and the heavy and light chain variable regions of the antibody molecules described in tables 1 or 5 herein. In certain embodiments, an antibody molecule comprises a heavy chain constant region, a light chain constant region, and a variable region comprising one, two, three, four, five, or six CDRs of an antibody molecule described in table 1 or 5.

Exemplary heavy chain constant regions are described below.

Exemplary IgG1 constant regions

>IGHG1＊01

>IGHG1＊03

>IGHG1＊04

Exemplary IgG2 constant regions

>IGHG2＊01

>IGHG2＊02

>IGHG2＊04

>IGHG2＊06

In one embodiment, the antibody molecule comprises 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence corresponding to SEQ ID NO:11 differ by no more than 1,2 or 3 amino acid residues, or have at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence corresponding to SEQ ID NO:12 differ by no more than 1,2 or 3 amino acid residues, or have at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising a nucleotide sequence identical to SEQ ID NO:13 differ by no more than 1,2 or 3 amino acid residues, or have at least 85, 90, 95, 99 or 100% homology thereto, or

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: LCDR1 comprising an amino acid sequence corresponding to SEQ ID NO:280 by no more than 1,2 or 3 amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99 or 100% homology thereto; LCDR2 comprising an amino acid sequence corresponding to SEQ ID NO:285 differ by no more than 1,2 or 3 amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99 or 100% homology thereto; or LCDR3 comprising a nucleotide sequence corresponding to SEQ ID NO:16 differ by no more than 1,2 or 3 amino acid residues, or have at least 85, 90, 95, 99 or 100% homology thereto.

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises: HCDR1 comprising SEQ ID NO:11, an amino acid sequence of seq id no; HCDR2 comprising SEQ ID NO:12, an amino acid sequence of seq id no; and HCDR3 comprising 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 (LCDR 1, LCDR2, and LCDR 3), wherein the light chain variable region comprises: LCDR1 comprising SEQ ID NO:280, and an amino acid sequence of LCDR 1; LCDR2 comprising SEQ ID NO:285 amino acid sequence; or LCDR3 comprising SEQ ID NO:16, and a sequence of amino acids.

(i) A heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence corresponding to SEQ ID NO:17 differ by no more than 1,2, or 3 amino acid residues, or have at least 85, 90, 95, 99, or 100% homology thereto; HCDR2 comprising an amino acid sequence corresponding to SEQ ID NO:282 by no more than 1,2 or 3 amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising a nucleotide sequence identical to SEQ ID NO:13 differ by no more than 1,2 or 3 amino acid residues, or have at least 85, 90, 95, 99 or 100% homology thereto, or

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises: HCDR1 comprising SEQ ID NO:17, an amino acid sequence of seq id no; HCDR2 comprising SEQ ID NO: 282; and HCDR3 comprising 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 (LCDR 1, LCDR2, and LCDR 3), wherein the light chain variable region comprises: LCDR1 comprising SEQ ID NO:280, an amino acid sequence of 280; LCDR2 comprising SEQ ID NO:285 amino acid sequence; or LCDR3 comprising SEQ ID NO:16, and a sequence of amino acids.

In one embodiment, the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 296. 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:296, and VL comprising the amino acid sequence of SEQ ID NO: 286.

In one embodiment, the antibody molecule comprises a polypeptide consisting of a polypeptide comprising SEQ ID NO:313, and a VH encoded by a nucleic acid of nucleotide sequence 313. In one embodiment, the antibody molecule comprises a polypeptide consisting of a polypeptide comprising SEQ ID NO:306, and a VL encoded by a nucleic acid of the nucleotide sequence of 306. In one embodiment, the antibody molecule comprises a polypeptide consisting of a polypeptide comprising SEQ ID NO:313 and a VH encoded by a nucleic acid comprising the nucleotide sequence of SEQ ID NO:306, and a VL encoded by a nucleic acid of the nucleotide sequence of 306.

In one embodiment, the antibody molecule further comprises a heavy chain constant region of IgG2, e.g., SEQ ID NO: 323-326.

In one embodiment, the antibody molecule comprises:

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, and VL comprising the amino acid sequence of SEQ ID NO: 286.

In one embodiment, the antibody molecule comprises a polypeptide consisting of a polypeptide comprising SEQ ID NO:308, and a VH encoded by a nucleic acid of nucleotide sequence 308. In one embodiment, the antibody molecule comprises a polypeptide consisting of a polypeptide comprising SEQ ID NO:305, and a VL encoded by a nucleic acid of the nucleotide sequence of 305. In one embodiment, the antibody molecule comprises a polypeptide consisting of a polypeptide comprising SEQ ID NO:308 and a VH encoded by a nucleic acid comprising the nucleotide sequence of SEQ ID NO:306, and a VL encoded by a nucleic acid of the nucleotide sequence of 306.

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: LCDR1 comprising an amino acid sequence corresponding to SEQ ID NO:280 by no more than 1,2 or 3 amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99 or 100% homology thereto; LCDR2 comprising an amino acid sequence corresponding to SEQ ID NO:281 differs by no more than 1,2 or 3 amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99 or 100% homology thereto; or LCDR3 comprising a nucleotide sequence corresponding to SEQ ID NO:16 differ by no more than 1,2 or 3 amino acid residues, or have at least 85, 90, 95, 99 or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2, and LCDR 3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of seq id NO:280, and an amino acid sequence of LCDR 1; LCDR2 comprising SEQ ID NO:281 amino acid sequence; or LCDR3 comprising SEQ ID NO:16, and a sequence of amino acids.

In one embodiment, the antibody molecule comprises:

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2, and LCDR 3), wherein the light chain variable region comprises: LCDR1 comprising SEQ ID NO:280, an amino acid sequence of 280; LCDR2 comprising SEQ ID NO:281 amino acid sequence; or LCDR3 comprising SEQ ID NO:16, and a sequence of amino acids.

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 comprising the amino acid sequence of SEQ ID NO: 284.

In one embodiment, the antibody molecule comprises a polypeptide consisting of a polypeptide comprising SEQ ID NO:308, and a VH encoded by a nucleic acid of nucleotide sequence 308. In one embodiment, the antibody molecule comprises a polypeptide consisting of a polypeptide comprising SEQ ID NO:305, and a VL encoded by a nucleic acid of the nucleotide sequence of 305. In one embodiment, the antibody molecule comprises a polypeptide consisting of a polypeptide comprising SEQ ID NO:308 and a VH encoded by a nucleic acid comprising the nucleotide sequence of SEQ ID NO:305, and a VL encoded by a nucleic acid of the nucleotide sequence of 305.

(i) A heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence corresponding to SEQ ID NO:93 differs by no more than 1,2 or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence corresponding to SEQ ID NO:94 differ by no more than 1,2 or 3 amino acid residues, or have at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising a nucleotide sequence identical to SEQ ID NO:95 by no more than 1,2 or 3 amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99 or 100% homology thereto, or

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: LCDR1 comprising an amino acid sequence corresponding to SEQ ID NO:96, or an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; LCDR2 comprising an amino acid sequence corresponding to SEQ ID NO:97 by no more than 1,2 or 3 amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99 or 100% homology thereto; or LCDR3 comprising a nucleotide sequence corresponding to SEQ ID NO:98 differ by no more than 1,2 or 3 amino acid residues, or have at least 85, 90, 95, 99 or 100% homology thereto.

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises: HCDR1 comprising SEQ ID NO:93, an amino acid sequence of 93; HCDR2 comprising SEQ ID NO:94, an amino acid sequence of seq id no; and HCDR3 comprising 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 (LCDR 1, LCDR2, and LCDR 3), wherein the light chain variable region comprises: LCDR1 comprising SEQ ID NO:96 amino acid sequence of LCDR 1; LCDR2 comprising SEQ ID NO:97, an amino acid sequence of 97; or LCDR3 comprising SEQ ID NO: 98.

(i) A heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence corresponding to SEQ ID NO:99 by no more than 1,2 or 3 amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence corresponding to SEQ ID NO:273 by no more than 1,2 or 3 amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising a nucleotide sequence identical to SEQ ID NO:95 by no more than 1,2 or 3 amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99 or 100% homology thereto, or

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: LCDR1 comprising an amino acid sequence corresponding to SEQ ID NO:96 by no more than 1,2 or 3 amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99 or 100% homology thereto; LCDR2 comprising an amino acid sequence corresponding to SEQ ID NO:97 by no more than 1,2 or 3 amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99 or 100% homology thereto; or LCDR3 comprising a nucleotide sequence corresponding to SEQ ID NO:98 differ by no more than 1,2 or 3 amino acid residues, or have at least 85, 90, 95, 99 or 100% homology thereto.

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises: HCDR1 comprising SEQ ID NO:99, an amino acid sequence of seq id no; HCDR2 comprising SEQ ID NO:273 amino acid sequence; and HCDR3 comprising 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 (LCDR 1, LCDR2, and LCDR 3), wherein the light chain variable region comprises: LCDR1 comprising SEQ ID NO:96, an amino acid sequence of 96; LCDR2 comprising SEQ ID NO:97, an amino acid sequence of 97; or LCDR3 comprising SEQ ID NO: 98.

In one embodiment, the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:225, and a sequence of amino acids. In one embodiment, the antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 229. In one embodiment, the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:225, and VL comprising the amino acid sequence of SEQ ID NO: 229.

In one embodiment, the antibody molecule comprises a polypeptide consisting of a polypeptide comprising SEQ ID NO:299, and a VH encoded by a nucleic acid of the nucleotide sequence of 299. In one embodiment, the antibody molecule comprises a polypeptide consisting of a polypeptide comprising SEQ ID NO:300, and a VL encoded by a nucleic acid of the nucleotide sequence of 300. In one embodiment, the antibody molecule comprises a polypeptide consisting of a polypeptide comprising SEQ ID NO:299 and VH encoded by a nucleic acid comprising the nucleotide sequence of SEQ ID NO:300, and a VL encoded by a nucleic acid of the nucleotide sequence of 300.

In one embodiment, the antibody molecule further comprises a heavy chain constant region of IgG1, e.g., SEQ ID NO: 320-322.

In one embodiment, the antibody molecules described herein have one or more (e.g., 2, 3, 4, 5, or all) of the following properties: (a) is a humanized antibody molecule; (b) At an EC of 60pM or less ₅₀ Binding to human APRIL as determined by ELISA; (c) IC with 0.5nM or less ₅₀ For example, in vitro inhibition of binding of human APRIL to TACI; (d) IC with 0.6nM or less ₅₀ For example, in vitro inhibition of binding of human APRIL to BCMI; (e) is IgG2 κ; or (f) have an Fc region engineered to reduce complement activation. In one embodiment, the antibody molecule comprises one or more (e.g., 2, 3, 4, 5, or all) CDRs, one or both of a heavy chain variable region or a light chain variable region, or one or both of a heavy chain or a light chain of any of antibody molecules 2419-1406, 2419-0205, or 2419-0206. In one embodiment, the antibody molecule is suitable for treating kidney disease, e.g., igA nephropathy. In another embodiment, the antibody molecule is useful for treating cancer, e.g., multiple myeloma.

In one embodiment, the antibody molecules described herein have one or more (e.g., 2, 3, 4, 5, or all) of the following properties: (a) is a humanized antibody molecule; (b) At an EC of 50pM or less ₅₀ Binding to human APRIL as determined by ELISA; (c) IC at 0.3nM or less _50， For example, inhibition of binding of human APRIL to TACI in vitro; (d) IC at 0.2nM or less ₅₀ For example, in vitro inhibition of binding of human APRIL to BCMA; (e) is IgG1 kappa; or (f) has higher BCMA neutralizing activity, e.g., has an IC of 0.1nM or less ₅₀ . In one embodiment, the antibody molecule comprises one or more (e.g., 2, 3, 4, 5, or all) CDRs, one or both of a heavy chain variable region or a light chain variable region, or one or both of a heavy chain or a light chain of antibody molecule 4035-062. In one embodiment, the antibody molecule is useful for treating cancer or autoimmune disease.

The antibody molecules described herein may have several advantageous properties. For example, the antibody molecules may be useful for the effective treatment, prevention or diagnosis of a disorder associated with APRIL, e.g., a disorder described herein, e.g., igA nephropathy.

In one embodiment, the antibody molecule is capable of binding, or substantially binds, human APRIL and mouse APRIL. In one embodiment, the antibody molecule is capable of binding, or substantially binds, human APRIL, but is incapable of binding, or substantially binds, mouse APRIL. In one embodiment, the antibody molecule has a high affinity (e.g., dissociation constant (K _D ) Less than about 100nM, typically about 10nM, more typically about 10-0.001nM, about 10-0.01nM, about 5-0.01nM, about 3-0.05nM, about 1-0.1nM, or more strongly, 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) binds to APRIL. In one embodiment, the antibody molecule binds to the K of APRIL _off Is slower than 1 multiplied by 10 ^-4 、5×10 ^-5 Or 1X 10 ^-5 s ^-1 . In one embodiment, the antibody molecule binds to the K of APRIL _on Faster than 1X 10 ⁴ 、5×10 ⁴ 、1×10 ⁵ Or 5X 10 ⁵ M ^-1 s ^-1 。

In one embodiment, the antibody molecule is capable of inhibiting, or substantially inhibiting, binding of human APRIL to TACI. In one embodiment, the antibody molecule is capable of inhibiting, or substantially inhibiting, binding of human APRIL to TACI. In one embodiment, the antibody molecule is capable of inhibiting, or substantially inhibiting, binding of human APRIL to BCMA. In one embodiment, the antibody molecule is capable of inhibiting, or substantially inhibiting, binding of human APRIL to TACI and BCMA. In one embodiment, the antibody molecule is capable of inhibiting, or substantially inhibiting, binding of human APRIL to TACI, but not 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 not 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 methods described herein (e.g., normalized to no antibody control).

In one embodiment, the antibody molecule inhibits 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 methods described herein (e.g., normalized to no antibody control).

In one embodiment, the antibody molecule does not substantially inhibit binding of human APRIL to human BCMA, e.g., inhibits binding of human APRIL to human BCMA by less than 10%, as determined by the methods described herein (e.g., normalized to an antibody free control).

In one embodiment, the antibody molecule binds a linear or conformational epitope on APRIL. In one embodiment, the antibody molecule binds to an epitope that is conserved between human APRIL and mouse APRIL. In one embodiment, the antibody molecule binds to an epitope described herein. In one embodiment, the antibody molecule binds to a second antibody molecule (e.g., a monoclonal antibody as described in table 1 or 5), or binds substantially to the same, similar, or overlapping epitope on APRIL. In one embodiment, the antibody molecule competes with a second antibody molecule (e.g., a monoclonal antibody described in table 1 or 5) for binding to APRIL.

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

In one embodiment, the antibody molecule binds to or substantially binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues from human APRIL at positions 105-114 and/or one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues from mouse APRIL at positions 96-105.

In one embodiment, the antibody molecule binds to 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 more) residues within an APRIL region defined in table 7. In one embodiment, the antibody molecule binds to or substantially binds to an epitope comprising, or consisting of, 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 in table 7. In one embodiment, the antibody molecule binds to or substantially binds to an epitope that overlaps with an epitope comprising or consisting of all of the human APRIL residues of table 7.

In one embodiment, the antibody molecule binds to 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, or more) residues within an APRIL region defined in table 8 of international application publication No. WO 2017/091683. In one embodiment, the antibody molecule binds to or substantially binds to, or consists of, an epitope comprising, 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 in table 8 of international application publication No. WO 2017/091683. In one embodiment, the antibody molecule binds to or substantially binds to an epitope that overlaps with an epitope comprising or consisting of all or a portion of the human APRIL residues of table 8 of international application publication No. WO 2017/091683.

In one embodiment, the epitope is a conformational epitope.

In one embodiment, the antibody molecule does not bind, or does not substantially bind, 1, 2 or all of Asp129, arg233 or His203 of human APRIL.

In one embodiment, the binding of the antibody molecule to APRIL (e.g., human APRIL) is inhibited, or the binding of the CRD2 domain of TACI (e.g., human TACI) to APRIL (e.g., human APRIL) is substantially inhibited. In one 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 all) of the human APRIL residues in table 3. 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, or all) of the human APRIL residues in 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 (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 in 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 (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 in table 8 of international application publication No. WO 2017/091683.

Exemplary anti-APRIL antibody molecules

The present disclosure provides, at least in part, antibody molecules that bind to APRIL (e.g., human and/or mouse APRIL) comprising one or more of the functional and structural properties disclosed herein. In one embodiment, the antibody molecule binds to and/or reduces (e.g., inhibits, blocks, or neutralizes) one or more activities of APRIL. In one embodiment, the antibody molecule binds to a region in APRIL that interacts with TACI (e.g., the CRD2 domain of TACI). In one embodiment, the antibody molecule binds to one or more residues within the region of human APRIL defined in any one of tables 3-4 or 7 or 8 of international application publication No. WO 2017/091683. Without wishing to be bound by theory, it is believed that in one embodiment, improved or optimal inhibition of APRIL activity may be achieved by targeting certain region(s) on APRIL (e.g., regions associated with interactions between CDR2 domains of APRIL and TACI). In one embodiment, the antibody molecule is selected from table 1 or 5, or competes with an antibody molecule selected from table 1 or 5 for binding to APRIL. In one embodiment, the antibody molecule binds to the same or overlapping epitope as that recognized by the antibody molecule selected from table 1 or 5. In one embodiment, the antibody molecule comprises 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 comprises one or more heavy chain CDRs and/or one or more light chain CDRs as set forth in table 1 or 5. In one embodiment, nucleic acid molecules encoding the antibody molecules, expression vectors, host cells, compositions (e.g., pharmaceutical compositions), kits, and methods for making the antibody molecules are also provided. The antibody molecules disclosed herein are useful (alone or in combination with other formulations or therapies) for the treatment, prevention and/or diagnosis of APRIL-associated disorders, such as IgA nephropathy.

In one embodiment, the antibody molecule has one or more of the following properties (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):

a) With high affinity (e.g., dissociation constant (K) _D ) Less than about 100nM, typically about 10nM, more typically about 10-0.001nM, about 10-0.01nM, about 5-0.01nM, about 3-0.05nM, about 1-0.1nM, or more strongly, 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) to human APRIL,

b) With high affinity (e.g., dissociation constant (K) _D ) Less than about 100nM, typically about 10nM, more typically about 10-0.001nM, about 10-0.01nM, about 5-0.01nM, about 3-0.05nM, about 1-0.1nM, or more strongly, 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) to mouse APRIL,

c) Does not bind mouse APRIL, or with low affinity (e.g., dissociation constant (K _D ) Greater than about 500nM, e.g., greater than about 1000 nM) binds mouse APRIL,

d) Does not bind mouse APRIL, or with low affinity (e.g., dissociation constant (K _D ) Greater than about 500nM, e.g., greater than about 1000nM) binds one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) cytokines (e.g., TNFa, CD40 (TNFSF 4), fasL (TNFSF 6), TRAIL (TNFSF 10), RANKL (TNFSF 1 1), theak (TNFSF 12), BAFF (TNFSF 13B), or LIGHT (TNFSF 14)) from a TNF superfamily (TNFSF) other than APRIL,

e) Binding 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) residues within the region of APRIL defined in table 3, or specifically binding to an epitope on APRIL, e.g., an epitope comprising 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) residues described in table 3,

f) An epitope that binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all) residues within the region of APRIL defined in table 4, or that specifically binds to APRIL, e.g., an epitope comprising one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all) residues described in table 4,

g) Binding to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all) residues within the region of APRIL defined in table 7, or specifically binding to an epitope on APRIL, e.g., an epitope comprising one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all) residues as set forth in table 7,

h) 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) residues within the region of APRIL defined in table 8 of international application publication No. WO2017/091683, or an epitope that specifically binds to APRIL, e.g., an epitope comprising 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) residues described in table 8 of international application publication No. WO2017/091683,

i) An epitope that specifically binds to APRIL, e.g., an epitope that is identical, similar or overlapping to an epitope recognized by a monoclonal antibody molecule described in Table 1 or 5 (e.g., any of monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439 or 4237),

j) Reducing (e.g., inhibiting, blocking, or neutralizing) one or more biological activities of APRIL (e.g., human APRIL, mouse APRIL, or both) in vitro, ex vivo, or in vivo,

k) Reducing (e.g., inhibiting, blocking, or neutralizing) the binding of human APRIL to TACI, e.g., at about 50nM or less, typically about 0.01-50nM, 0.1-25nM, 0.1-10nM, 0.5-5nM, or 1-5nM, e.g., an IC of less than about 40, 30, 20, 10, 5, 1, 0.5, 0.2, 0.1, 0.05, or 0.01nM ₅₀ For example, as determined by the methods described herein,

1) Reducing (e.g., inhibiting, blocking, or neutralizing) the binding of mouse APRIL to TACI, e.g., at about 100nM or less, typically about 0.01-75nM, 0.1-50nM, 0.1-25nM, 0.1-10nM, 0.5-5nM, or 1-5nM, e.g., an IC of less than about 80, 60, 40, 20, 10, 5, 1, 0.5, 0.2, 0.1, 0.05, or 0.01nM ₅₀ For example, as determined by the methods described herein,

m) reducing (e.g., inhibiting, blocking or neutralizing) the binding of human APRIL to BMCA, e.g., at about 50nM or less, typically about 0.01-50nM, 0.1-25nM, 0.1-10nM, 0.5-5nM or 1-5nM, e.g., an IC of less than about 40, 30, 20, 10, 5, 1, 0.5, 0.2, 0.1, 0.05 or 0.01nM ₅₀ For example, as determined by the methods described herein,

n) reducing (e.g., inhibiting, blocking or neutralizing) the binding of mouse APRIL to BMCA, e.g., at about 200nM or less, typically about 0.01-200nM, 0.1-150nM, 0.1-100nM, 0.1-50nM, 0.1-25nM, 0.1-10nM, 0.5-5nM or 1-5nM, e.g., less than about 150, 100, 50, 40, 20, 10, 5, 1, 0.5,IC of 0.2, 0.1, 0.05 or 0.01nM ₅₀ For example, as determined by the methods described herein,

o) shows the same or similar binding affinity or specificity, or both, as a monoclonal antibody molecule described in Table 1 or 5 (e.g., any of monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439 or 4237),

p) shows the same or similar binding affinity or specificity as a monoclonal antibody molecule comprising 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 light chain variable region of any of monoclonal antibodies 2218, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-033, 4439 or 4237),

q) shows a specific affinity or affinity for an antibody or both comprising one or more (e.g., 2 or 3) heavy chain CDRs and/or one or more (e.g., 2 or 3) light chain CDRs (e.g., any of monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439 or 4237) heavy chain CDRs and/or one or more (e.g., 2 or 3) light chain CDRs or both as set forth in table 1 or 5,

r) shows the same or similar binding affinity or specificity or both as antibody molecules comprising the amino acid sequences shown in Table 1 or 5,

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

t) inhibiting, e.g., competitively inhibiting, binding of a second antibody molecule to human APRIL, mouse APRIL, or both, wherein the second antibody molecule is an antibody molecule selected from table 1 or 5 (e.g., any of monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439, or 4237),

u) competes with a second antibody molecule for binding to human APRIL, mouse APRIL, or both, wherein the second antibody molecule is a monoclonal antibody selected from table 1 or 5 (e.g., any of monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439, or 4237),

v) having one or more biological properties selected from the group consisting of monoclonal antibodies of Table 1 or 5 (e.g., any of monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439, or 4237),

w) has one or more structural properties selected from the monoclonal antibodies of table 1 or 5 (e.g., any of monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439, or 4237), or

x) has one or more pharmacokinetic properties selected from the group consisting of monoclonal antibodies of table 1 or 5 (e.g., any of monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439, or 4237).

In one embodiment, the anti-APRIL antibody molecule:

(i) Binding, or substantially binding, human APRIL;

(ii) Binding, or substantially binding, mouse APRIL;

(iii) Inhibit, or substantially inhibit, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both); and

(iv) Inhibit, or substantially inhibit, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse 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 is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM,0.001nM to 0.1nM, 0.0010.0010 nM to 0.01nM, 0.01nM to 0nM EC of 0.01nM to 0.05nM, or 0.01nM to 0.1nM _s0 Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein.

In one embodiment, the antibody molecule is present in an amount of 100nM or less, e.g., 80nM or less, 60nM or less, 40nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 100nM, e.g., 0.001nM to 50nM,0.01nM to 20nM,0.1nM to 10nM, 0.2nM to 1nM to 0.5nM to 0.01nM, 0nM to 0.0010.01 nM to 0.01nM, 0nM to 0.01nM EC 0.01nM to 0nM,0.01nM to 0.0010.01 nM to 0nM to 0.01nM to 0.0010 nM to 0.01nM to 0nM or 0 ₅₀ Binds, or substantially binds, mouse APRIL, e.g., as determined by the methods described herein.

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

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., an IC of 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM ₅₀ Inhibit, or substantially inhibit, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), e.g., as determined by the methods described herein.

In one embodiment, the antibody molecule is an IgG antibody molecule, e.g., comprising a heavy chain constant region of IgG, e.g., selected from IgG1, igG2 (e.g., igG2 a), igG3, or IgG4, e.g., igG2 or IgG4. In one embodiment, the antibody molecule is an IgG1 antibody molecule, e.g., having an IgG1 constant region as described herein. In one embodiment, the antibody molecule is an IgG2 antibody molecule, e.g., having an IgG2 constant region as described herein. In one embodiment, the antibody molecule comprises a light chain constant region of a kappa or lambda light chain.

In one embodiment, the antibody molecule comprises an Fc region. In one embodiment, the Fc region includes one or more mutations at the interface between the CH2 and CH3 domains (e.g., to increase the binding affinity and/or half-life of the neonatal receptor FcRn of the antibody molecule). In one embodiment, the Fc region comprises one or more mutations, for example one or more (e.g., 2, 3, 4, 5, 6, or all) mutations selected from the group consisting of: T250Q, M252Y, S254T, T256E, M428L, H433K, N434F of IgG1, or a combination thereof. In one embodiment, the Fc region comprises 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 comprises one or more (e.g., 2, 3, 4, 5, 6, 7, or all) mutations selected from the group consisting of: E233P, L234V, L235A, G236, K322A, A327G, A330S, P1S, or any combination thereof.

In one embodiment, the antibody molecule is a humanized antibody molecule, e.g., comprising one or more framework regions derived from human framework germline sequences. In one embodiment, the antibody molecule comprises a heavy chain variable region (VH) as set forth in table 1 or 5. In one embodiment, the antibody molecule comprises the light chain variable region (VL) described in table 1 or 5. In one embodiment, the antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL) as set forth in table 1 or 5. In one embodiment, the antibody molecule comprises 1, 2 or 3 CDRs of a heavy chain variable region (VH) as set forth in table 1 or 5. In one embodiment, the antibody molecule comprises 1, 2, or 3 CDRs of a light chain variable region (VL) as set forth in table 1 or 5. In one embodiment, the antibody molecule comprises 1, 2 or 3 CDRs of a heavy chain variable region (VH) as set forth in table 1 or 5, and 1, 2 or 3 CDRs of a light chain variable region (VL) as set forth in table 1 or 5. In one embodiment, the antibody molecule comprises 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 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 61), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 62) or that has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3530 (e.g., SEQ ID NO: 63), or has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 67), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 45) or that has at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3530 (e.g., SEQ ID NO: 46), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 61); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 62); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3530 (e.g., SEQ ID NO: 63); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 67); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 45); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3530 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 64), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 65) or that has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3530 (e.g., SEQ ID NO: 63), or has at least 85, 90, 95, 99 or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 64); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 65); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3530 (e.g., SEQ ID NO: 63); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 67); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 45); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule comprises a VH comprising 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 thereto, from the amino acid sequence of the VH of monoclonal antibody 3530 (e.g., SEQ ID NO: 66). In one embodiment, the antibody molecule comprises a VL comprising 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 to, the amino acid sequence of VL of monoclonal antibody 3530 (e.g., SEQ ID NO: 70).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3530 (e.g., SEQ ID NO: 66), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3530 (e.g., SEQ ID NO: 70), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto. In one embodiment, the antibody molecule comprises: (i) A VH comprising the amino acid sequence of the VH of monoclonal antibody 3530 (e.g., SEQ ID NO: 66); and (ii) a VL comprising the amino acid sequence of the VL of monoclonal antibody 3530 (e.g., SEQ ID NO: 70).

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

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 61) by NO more than 1,2 or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 62) or that has at least 85, 90, 95, 99 or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3525 (e.g., SEQ ID NO: 63), or has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 44), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 45) or that has at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3525 (e.g., SEQ ID NO: 46), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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

In one embodiment, the antibody molecule comprises: (i) VH comprising three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises: HCDR1, comprising the amino acid sequence of HCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 61); HCDR2, which comprises the amino acid sequence of HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 62); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3525 (e.g., SEQ ID NO: 63); and a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2, and LCDR 3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 44); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 45); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3525 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 64) by NO more than 1,2 or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 65) or that has at least 85, 90, 95, 99 or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3525 (e.g., SEQ ID NO: 63), or has at least 85, 90, 95, 99 or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

(i) VH comprising one, two, or all of: HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 64) by NO more than 1,2 or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 65) or that has at least 85, 90, 95, 99 or 100% homology therewith; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 3525 (e.g., SEQ ID NO: 63) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 64); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 65); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3525 (e.g., SEQ ID NO: 63); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 44); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 45); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3525 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule comprises a VH comprising 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 thereto, from the amino acid sequence of VH of monoclonal antibody 3525 (e.g., SEQ ID NO: 66). In one embodiment, the antibody molecule comprises a VL comprising 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 to, the amino acid sequence of VL of monoclonal antibody 3525 (e.g., SEQ ID NO: 50).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3525 (e.g., SEQ ID NO: 66), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3525 (e.g., SEQ ID NO: 50), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto. In one embodiment, the antibody molecule comprises: (i) A VH comprising the amino acid sequence of the VH of monoclonal antibody 3525 (e.g., SEQ ID NO: 66); and (ii) a VL comprising the amino acid sequence of the VL of monoclonal antibody 3525 (e.g., SEQ ID NO: 50).

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

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 113) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 114) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 115), or has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 116), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 117) or that has at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 118), or that has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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

In one embodiment, the antibody molecule comprises: (i) VH comprising three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 113); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 114); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 115); and a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2, and LCDR 3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 116); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 117); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3833 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 119), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 120) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 115), or has at least 85, 90, 95, 99 or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 119); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 120); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 115); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 116); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 117); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In one embodiment, the antibody molecule comprises a VH comprising 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 to, the amino acid sequence of the VH of monoclonal antibody 3833 (e.g., SEQ ID NO: 121). In one embodiment, the antibody molecule comprises a VL comprising 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 to, the amino acid sequence of VL of monoclonal antibody 3833 (e.g., SEQ ID NO: 122).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3833 (e.g., SEQ ID NO: 121), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3833 (e.g., SEQ ID NO: 122), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto. In one embodiment, the antibody molecule comprises: (i) A VH comprising the amino acid sequence of the VH of monoclonal antibody 3833 (e.g., SEQ ID NO: 121); and (ii) a VL comprising the amino acid sequence of the VL of monoclonal antibody 3833 (e.g., SEQ ID NO: 122).

In one embodiment, the antibody molecule is a monoclonal antibody 3833. In one embodiment, the monoclonal antibody 3833 is a humanized monoclonal antibody 3833. In one embodiment, the antibody molecule comprises a polypeptide comprising SEQ ID NO:246-250, comprising the amino acid sequence of any one of SEQ ID NOs: 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 123) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 124) by NO more than 1,2 or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3631 (e.g., SEQ ID NO: 125) or has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 126), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 127), or that has at least 85, 90, 95, 99, or 100% homology therewith; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3631 (e.g., SEQ ID NO: 128), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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

In one embodiment, the antibody molecule comprises: (i) VH comprising three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 123); HCDR2, comprising the amino acid sequence of HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 124); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3631 (e.g., SEQ ID NO: 125); and a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2, and LCDR 3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 126); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 127); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3631 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 129), or that has at least 85, 90, 95, 99, or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 130), or that has at least 85, 90, 95, 99 or 100% homology therewith; or HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 125), or has at least 85, 90, 95, 99, or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 126), or that has at least 85, 90, 95, 99, or 100% homology thereto; LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 127), or that has at least 85, 90, 95, 99, or 100% homology therewith; or LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3631 (e.g., SEQ ID NO: 128), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 129); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 130); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3631 (e.g., SEQ ID NO: 125); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 126); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 127); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In one embodiment, the antibody molecule comprises a VH comprising 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 thereto, from the amino acid sequence of VH of monoclonal antibody 3631 (e.g., SEQ ID NO: 131). In one embodiment, the antibody molecule comprises a VL comprising 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 thereto, from the amino acid sequence of VL of monoclonal antibody 3631 (e.g., SEQ ID NO: 132).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3631 (e.g., SEQ ID NO: 131), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3631 (e.g., SEQ ID NO: 132), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto. In one embodiment, the antibody molecule comprises: (i) A VH comprising the amino acid sequence of the VH of monoclonal antibody 3631 (e.g., SEQ ID NO: 131); and (ii) a VL comprising the amino acid sequence of the VL of monoclonal antibody 3631 (e.g., SEQ ID NO: 132).

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

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 133), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 134), or that has at least 85, 90, 95, 99 or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 135), or has at least 85, 90, 95, 99, or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 136), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 127), or that has at least 85, 90, 95, 99, or 100% homology therewith; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 137), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

(i) VH comprising one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 133), or that has at least 85, 90, 95, 99, or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 134), or that has at least 85, 90, 95, 99 or 100% homology therewith; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 135) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

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

In one embodiment, the antibody molecule comprises: (i) VH comprising three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises: HCDR1, comprising the amino acid sequence of HCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 133); HCDR2, comprising the amino acid sequence of HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 134); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 135); and a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2, and LCDR 3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 136); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 127); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3732 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 138), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 139), or that has at least 85, 90, 95, 99 or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 135), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 138); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 139); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 135); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 136); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 127); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In one embodiment, the antibody molecule comprises a VH comprising 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 to, the amino acid sequence of the VH of monoclonal antibody 3732 (e.g., SEQ ID NO: 140). In one embodiment, the antibody molecule comprises a VL comprising 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 to, the amino acid sequence of VL of monoclonal antibody 3732 (e.g., SEQ ID NO: 141).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3732 (e.g., SEQ ID NO: 140), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3732 (e.g., SEQ ID NO: 141), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto. In one embodiment, the antibody molecule comprises: (i) A VH comprising the amino acid sequence of the VH of monoclonal antibody 3732 (e.g., SEQ ID NO: 140); and (ii) a VL comprising the amino acid sequence of the VL of monoclonal antibody 3732 (e.g., SEQ ID NO: 141).

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

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4540, 4540-063 or 4540-033 (e.g. SEQ ID NO: 154), or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4540, 4540-063 or 4540-033 (e.g. SEQ ID NO: 155), or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 4540, 4540-063 or 4540-033 (e.g. SEQ ID NO: 156), or having at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99, or 100% homology to, the amino acid sequence of LCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO: 116), 4540-063 (e.g., SEQ ID NO: 274), or 4540-033 (e.g., SEQ ID NO: 274); (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO: 157), 4540-063 (e.g., SEQ ID NO: 275), or 4540-033 (e.g., SEQ ID NO: 275), or having at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 158), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

(i) VH comprising one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4540, 4540-063 or 4540-033 (e.g. SEQ ID NO: 154), or having at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4540, 4540-063 or 4540-033 (e.g. SEQ ID NO: 155), or having at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibodies 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 156), or has at least 85, 90, 95, 99, or 100% homology thereto, an

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

In one embodiment, the antibody molecule comprises: (i) VH comprising three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 4540, 4540-063 or 4540-033 (e.g. SEQ ID NO: 154); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 4540, 4540-063 or 4540-033 (e.g. SEQ ID NO: 155); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibodies 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 comprises three light chain complementarity determining regions (LCDR 1, LCDR2, and LCDR 3), wherein the light chain variable region comprises: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO: 116), 4540-063 (e.g., SEQ ID NO: 274), or 4540-033 (e.g., SEQ ID NO: 274); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO: 157), 4540-063 (e.g., SEQ ID NO: 275), or 4540-033 (e.g., SEQ ID NO: 275); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibodies 4540, 4540-063, or 4540-033 (e.g., 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 light chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO: 159), 4540-063 (e.g., SEQ ID NO: 276), or 4540-033 (e.g., SEQ ID NO: 159), or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO: 160), 4540-063 (e.g., SEQ ID NO: 277), or 4540-033 (e.g., SEQ ID NO: 278), or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 4540, 4540-063 or 4540-033 (e.g. SEQ ID NO: 156), or having at least 85, 90, 95, 99 or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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

In one embodiment, the antibody molecule comprises a VH comprising 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 thereto, from the amino acid sequence of a VH of 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). In one embodiment, the antibody molecule comprises a VL comprising 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 thereto, from the amino acid sequence of a VL of monoclonal antibody 4540 (e.g., SEQ ID NO: 162), 4540-063 (e.g., SEQ ID NO: 261), or 4540-033 (e.g., SEQ ID NO: 261).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of 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), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto, and (ii) VL comprising 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 VL of monoclonal antibody 4540 (e.g., SEQ ID NO: 162), 4540-063 (e.g., SEQ ID NO: 261), or 4540-033 (e.g., SEQ ID NO: 261), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto. In one embodiment, the antibody molecule comprises: (i) VH comprising the amino acid sequence of VH of 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) VL comprising the amino acid sequence of VL of monoclonal antibody 4540 (e.g., SEQ ID NO: 162), 4540-063 (e.g., SEQ ID NO: 261) or 4540-033 (e.g., SEQ ID NO: 261).

In one embodiment, the antibody molecule is monoclonal antibody 4540, 4540-063 or 4540-033. In one embodiment, the monoclonal antibody is a humanized monoclonal antibody 4540 (e.g., antibodies 4540-063 or 4540-033). In one embodiment, the antibody molecule comprises a polypeptide comprising SEQ ID NO:254-258 comprising the amino acid sequence of any one of SEQ ID NOs: 259-261, or both.

In one embodiment, the antibody molecule binds to 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 or more) residues within a human APRIL region defined in any one of tables 3-4 or 7 or table 8 of international application publication No. WO 2017/091683.

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

In one embodiment, the antibody molecule binds to 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 more) residues within the human APRIL region defined in table 7. In one embodiment, the antibody molecule binds to or substantially binds to an epitope comprising, or consisting of, 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 in table 7. In one embodiment, the antibody molecule binds to or substantially binds to an epitope that overlaps with an epitope comprising or consisting of all of the human APRIL residues of table 7.

In one embodiment, the antibody molecule binds to 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, or more) residues within the human APRIL region defined in table 8 of international application publication No. WO 2017/091683. In one embodiment, the antibody molecule binds to or substantially binds to, or consists of, an epitope comprising, 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 in table 8 of international application publication No. WO 2017/091683. In one embodiment, the antibody molecule binds to or substantially binds to an epitope that overlaps with an epitope comprising or consisting of all or a portion of the human APRIL residues of table 8 of international application publication No. WO 2017/091683.

In one embodiment, the antibody molecule binds to or substantially binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues from human APRIL at positions 105-114 and/or one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues from mouse APRIL at positions 96-105. In one embodiment, the antibody molecule does not bind, or does not substantially bind, 1, 2 or all of Asp129, arg233 or His203 of human APRIL. In one embodiment, the epitope is a conformational epitope.

In one embodiment, the binding of the antibody molecule to APRIL (e.g., human APRIL) is inhibited, or the binding of the CRD2 domain of TACI (e.g., human TACI) to APRIL (e.g., human APRIL) is substantially inhibited. In one 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 all) of the human APRIL residues in table 3. 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, or all) of the human APRIL residues in table 4. In yet another embodiment, binding of the antibody molecule to human APRIL inhibits, or substantially inhibits, binding of human TACT 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 human APRIL residues in 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 (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 in table 8 of international application publication No. WO 2017/091683. In another embodiment, binding of the antibody molecule to human APRIL inhibits, or substantially inhibits, binding of human BCMA 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 in table 8 of international application publication No. WO 2017/091683.

In one embodiment, the anti-APRIL antibody molecule binds to or substantially binds to, 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) of the human APRIL residues of any of tables 3-4 or 7 or 8 of international application publication No. WO 2017/091683. In one embodiment, the antibody molecule binds or substantially binds to a conformational epitope.

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

In one embodiment, the antibody molecule binds to or substantially binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues from human APRIL at positions 105-114 and/or one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues from mouse APRIL at positions 96-105. In one embodiment, the antibody molecule does not bind, or does not substantially bind, 1, 2 or all of Asp129, arg233 or His203 of human APRIL.

In one embodiment, the antibody molecule binds to or substantially binds to, or consists of, an epitope comprising, one or more (e.g., 2, 3, 4, 5, 6, 7, 6, 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) of the human APRIL residues in table 8 of international application publication No. WO 2017/091683.

In one embodiment, the antibody molecule binds to or substantially binds to one or more (e.g., 2, 3, 4, 5, or all) of the amino acid residues of human APRIL 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 (e.g., 2, 3, or all) of the amino acid residues of human APRIL selected from V181, S226, I228, or N237. In one embodiment, the antibody molecule binds to or substantially binds to one or more (e.g., 2, 3, or all) of the amino acid residues of human APRIL selected from F176, V181, Q190, or I228. In one embodiment, the antibody molecule does not bind or substantially does not bind one or both of the amino acid residues of human APRIL selected from Y208 or N237. In one embodiment, the antibody molecule binds to or substantially binds to one or more (e.g., 2 or all) of the amino acid residues of human APRIL selected from V174, R206, or Y208. In one embodiment, the antibody molecule does not bind or substantially does not bind one or more (e.g., 2, 3, or all) of the amino acid residues of human APRIL 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 is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0.01nM or 0.01nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein.

In one embodiment, the antibody molecule is present at 100nM or less, e.g., 80nM or less, 60nM or less, 40nM or less, 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less An EC of 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, 0.002nM or less, or 0.001nM or less, for example, 0.001nM to 100nM, for example, 0.001nM to 50nM,0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM,1nM to 5nM,0.001nM to 0.1nM,0.001nM to 0.01nM,0.001nM to 0.0050.01 nM,0.01nM to 0.05, or 0.01nM to 0.1nM ₅₀ Binds, or substantially binds, mouse APRIL, e.g., as determined by the methods described herein.

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

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

In one embodiment, the binding of the antibody molecule to APRIL (e.g., human APRIL) is inhibited, or the binding of the CRD2 domain of TACI (e.g., human TACI) to APRIL (e.g., human APRIL) is substantially inhibited. In 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 all) of the human APRIL residues in table 3. In one embodiment, binding of the antibody molecule to human APRIL inhibits, or substantially inhibits, binding of human TACT to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all) of the human APRIL residues in 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 (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 in 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 (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 in table 8 of international application publication No. WO 2017/091683. In another embodiment, binding of the antibody molecule to human APRIL inhibits, or substantially inhibits, binding of human BCMA 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 in table 8 of international application publication No. WO 2017/091683.

In one embodiment, the antibody molecule inhibits or substantially inhibits binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both). In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nMIC of 1nM,0.1nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM ₅₀ Inhibit, or substantially inhibit, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), e.g., as determined by the methods 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., comprising a heavy chain constant region of IgG, e.g., selected from IgG1, igG2 (e.g., igG2 a), 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 light chain constant region of a kappa or lambda light chain.

In one embodiment, the antibody molecule comprises an Fc region. In one embodiment, the Fc region includes one or more mutations at the interface between the CH2 and CH3 domains (e.g., to increase the binding affinity and/or half-life of the neonatal receptor FcRn of the antibody molecule). In one embodiment, the Fc region comprises one or more mutations, for example one or more (e.g., 2, 3, 4, 6, or all) mutations selected from the group consisting of: T250Q, M252Y, S254T, T256E, M428L, H433K, N434F of IgG1, or a combination thereof. In one embodiment, the Fc region comprises 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 comprises one or more (e.g., 2, 3, 4, 6, 7, or all) mutations selected from the group consisting of: E233P, L234V, L235A, G236, K322A, A327G, A330S, P1S, or any combination thereof.

In one embodiment, the antibody molecule is a humanized antibody molecule, e.g., as described in table 1 or 5, e.g., comprising one or more framework regions derived from human framework germline sequences.

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

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 2218 (e.g., SEQ ID NO: 4), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 2218 (e.g., SEQ ID NO: 5), or that has at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 2218 (e.g., SEQ ID NO: 6), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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

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

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

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

In one embodiment, the antibody molecule comprises:

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 2218 (e.g., SEQ ID NO: 1) by NO more than 7,2 or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of monoclonal antibody 2218 (e.g., SEQ ID NO: 2) by NO more than 1,2 or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; and HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 2218 (e.g., SEQ ID NO: 3), or has at least 85, 90, 95, 99, or 100% homology thereto, and (ii) VL comprising: LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 2218 (e.g., SEQ ID NO: 4), or that has at least 85, 90, 95, 99, or 100% homology thereto; LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 2218 (e.g., SEQ ID NO: 5), or that has at least 85, 90, 95, 99, or 100% homology thereto; and LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 2218 (e.g., SEQ ID NO: 6), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises a VH comprising 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 to, the amino acid sequence of VH of monoclonal antibody 2218 (e.g., SEQ ID NO: 9). In one embodiment, the antibody molecule comprises a VL comprising 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 to, the amino acid sequence of VL of monoclonal antibody 2218 (e.g., SEQ ID NO: 10).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 2218 (e.g., SEQ ID NO: 9), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 2218 (e.g., SEQ ID NO: 10), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto. In one embodiment, the antibody molecule comprises: (i) VH comprising the amino acid sequence of VH of monoclonal antibody 2218 (e.g., SEQ ID NO: 9); and (ii) a VL comprising the amino acid sequence of VL of monoclonal antibody 2218 (e.g., SEQ ID NO: 10).

In one embodiment, the antibody molecule is monoclonal antibody 2218. In one embodiment, monoclonal antibody 2218 is a humanized monoclonal antibody 2218. In one embodiment, the antibody molecule comprises a polypeptide comprising SEQ ID NO:190-201, comprising 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 2419 (e.g., SEQ ID NO: 11) or an antibody related to 2419, or has at least 85, 90, 95, 99, or 100% homology therewith; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 2419 (e.g., SEQ ID NO: 12) or an antibody related to 2419, or has at least 85, 90, 95, 99, or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 2419 (e.g., SEQ ID NO: 13) or 2419-related antibody, or has at least 85, 90, 95, 99, or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 2419 (e.g., SEQ ID NO: 14) or 2419-associated antibody, or that has at least 85, 90, 95, 99, or 100% homology therewith; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 2419 (e.g., SEQ ID NO: 15) or 2419-associated antibody, or that has at least 85, 90, 95, 99, or 100% homology therewith; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 2419 (e.g., SEQ ID NO: 16) or 2419-associated antibody, or has at least 85, 90, 95, 99, or 100% homology therewith.

In one embodiment, the antibody molecule comprises:

(i) VH comprising one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 2419 (e.g., SEQ ID NO: 11) or an antibody related to 2419, or has at least 85, 90, 95, 99, or 100% homology therewith; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 2419 (e.g., SEQ ID NO: 12) or an antibody related to 2419, or has at least 85, 90, 95, 99, or 100% homology therewith; or HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 2419 (e.g., SEQ ID NO: 13) or 2419-related antibody, or has at least 85, 90, 95, 99, or 100% homology therewith, an

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 11) or a 2419-related antibody HCDR1; HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 2419 (e.g., SEQ ID NO: 12) or a 2419-related antibody; and HCDR3 comprising the amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 13) or a 2419-related antibody; and

(ii) VL, comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 2419 (e.g., SEQ ID NO: 14) or 2419-related antibody; LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 2419 (e.g., SEQ ID NO: 15) or 2419-related antibody; and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 2419 (e.g., SEQ ID NO: 16) or 2419-related 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 2419 (e.g., SEQ ID NO: 17) or an antibody related to 2419, or has at least 85, 90, 95, 99, or 100% homology therewith; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 2419 (e.g., SEQ ID NO: 18) or an antibody related to 2419, or has at least 85, 90, 95, 99, or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 2419 (e.g., SEQ ID NO: 13) or 2419-related antibody, or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

(i) VH comprising one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 2419 (e.g., SEQ ID NO: 17) or an antibody related to 2419, or has at least 85, 90, 95, 99, or 100% homology therewith; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 2419 (e.g., SEQ ID NO: 18) or an antibody related to 2419, or has at least 85, 90, 95, 99, or 100% homology therewith; or HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 2419 (e.g., SEQ ID NO: 13) or 2419-related antibody, or has at least 85, 90, 95, 99, or 100% homology therewith, an

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 17) or a 2419-related antibody HCDR1; HCDR2 comprising the amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 18) or a 2419-related antibody; and HCDR3 comprising the amino acid sequence of monoclonal antibody 2419 (e.g., SEQ ID NO: 13) or a 2419-related antibody; and

In one embodiment, the antibody molecule comprises a VH comprising 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 thereto, from the amino acid sequence of a monoclonal antibody 2419 (e.g., SEQ ID NO: 19) or a VH of a 2419-related antibody. In one embodiment, the antibody molecule comprises a VL comprising 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 thereto, from the amino acid sequence of a VL of a monoclonal antibody 2419 (e.g., SEQ ID NO: 20) or 2419-related antibody.

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 2419 (e.g., SEQ ID NO: 19) or 2419-related antibody, or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 2419 (e.g., SEQ ID NO: 20) or 2419-related antibody, or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto.

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

In one embodiment, the antibody molecule is monoclonal antibody 2419. In one embodiment, monoclonal antibody 2419 is a humanized monoclonal antibody 2419. In one embodiment, the antibody molecule is a 2419-related antibody, e.g., any of 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, e.g., as described in table 1 or 5. In one embodiment, the antibody molecule comprises a polypeptide comprising SEQ ID NO:209-214, 283, 288, 289, 291, 292, 294, 296 or 317, comprising the amino acid sequence of any one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 21), or that has at least 85, 90, 95, 99 or 100% homology therewith; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO: 32), or that has at least 85, 90, 95, 99 or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 2922 (e.g., SEQ ID NO: 33), or has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 34), or that has at least 85, 90, 95, 99, or 100% homology therewith; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO: 35), or that has at least 85, 90, 95, 99, or 100% homology therewith; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 2922 (e.g., SEQ ID NO: 36), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 21); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO: 32); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 2922 (e.g., SEQ ID NO: 33); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 34); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO: 35); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 2922 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 37), or that has at least 85, 90, 95, 99 or 100% homology therewith; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO: 38), or that has at least 85, 90, 95, 99 or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 2922 (e.g., SEQ ID NO: 33), or has at least 85, 90, 95, 99 or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 37); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO: 38); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 2922 (e.g., SEQ id no: 33); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 34); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO: 35); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 2922 (e.g., SEQ ID NO: 36).

In one embodiment, the antibody molecule comprises a VH comprising 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 thereto, from the amino acid sequence of the VH of monoclonal antibody 2922 (e.g., SEQ ID NO: 39). In one embodiment, the antibody molecule comprises a VL comprising 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 to, the amino acid sequence of VL of monoclonal antibody 2922 (e.g., SEQ ID NO: 40).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 2922 (e.g., SEQ ID NO: 39), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 2922 (e.g., SEQ ID NO: 40), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto. In one embodiment, the antibody molecule comprises: (i) VH comprising the amino acid sequence of VH of monoclonal antibody 2922 (e.g., SEQ ID NO: 39); and (ii) a VL comprising the amino acid sequence of the VL of monoclonal antibody 2922 (e.g., SEQ ID NO: 40).

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

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3327 (e.g., SEQ ID NO: 51) by NO more than 1,2 or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO: 52), or that has at least 85, 90, 95, 99 or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3327 (e.g., SEQ ID NO: 53), or has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 3327 (e.g., SEQ ID NO: 54), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO: 55), or that has at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3327 (e.g., SEQ ID NO: 56), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

(i) VH comprising one, two, or all of: HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3327 (e.g., SEQ ID NO: 51) by NO more than 1,2 or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO: 52), or that has at least 85, 90, 95, 99 or 100% homology therewith; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 3327 (e.g., SEQ ID NO: 53) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3327 (e.g., SEQ ID NO: 51); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO: 52); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3327 (e.g., SEQ ID NO: 53); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3327 (e.g., SEQ ID NO: 54); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO: 55); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3327 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3327 (e.g., SEQ ID NO: 57), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO: 58) or that has at least 85, 90, 95, 99 or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3327 (e.g., SEQ ID NO: 53), or has at least 85, 90, 95, 99 or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3327 (e.g., SEQ ID NO: 57); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO: 58); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3327 (e.g., SEQ ID NO: 53); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3327 (e.g., SEQ ID NO: 54); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO: 55); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3327 (e.g., SEQ ID NO: 56).

In one embodiment, the antibody molecule comprises a VH comprising 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 thereto, from the amino acid sequence of VH of monoclonal antibody 3327 (e.g., SEQ ID NO: 59). In one embodiment, the antibody molecule comprises a VL comprising 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 to, the amino acid sequence of VL of monoclonal antibody 3327 (e.g., SEQ ID NO: 60).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3327 (e.g., SEQ ID NO: 59), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3327 (e.g., SEQ ID NO: 60), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto. In one embodiment, the antibody molecule comprises: (i) A VH comprising the amino acid sequence of the VH of monoclonal antibody 3327 (e.g., SEQ ID NO: 59); and (ii) a VL comprising the amino acid sequence of VL of monoclonal antibody 3327 (e.g., SEQ ID NO: 60).

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

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 (LCDRl, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 67), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 45) or that has at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3530 (e.g., SEQ ID NO: 46), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

(i) VH, comprising: HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 61) by NO more than 1,2 or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 62) or that has at least 85, 90, 95, 99 or 100% homology therewith; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 3525 (e.g., SEQ ID NO: 63) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 61); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 62); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3525 (e.g., SEQ ID NO: 63); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 44); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 45); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3525 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule comprises:

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 2621 (e.g., SEQ ID NO: 21), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO: 22), or that has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 2621 (e.g. SEQ ID NO: 23) or has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 2621 (e.g., SEQ ID NO: 24), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO: 25) or that has at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 2621 (e.g., SEQ ID NO: 26), or that has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 2621 (e.g., SEQ ID NO: 21); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO: 22); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 2621 (e.g., SEQ ID NO: 23); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 2621 (e.g., SEQ ID NO: 24); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO: 25); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 2621 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 2621 (e.g., SEQ ID NO: 27), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO: 28) or that has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 2621 (e.g. SEQ ID NO: 23) or has at least 85, 90, 95, 99 or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 2621 (e.g., SEQ ID NO: 27); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO: 28); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 2621 (e.g., SEQ ID NO: 23); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 2621 (e.g., SEQ ID NO: 24); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO: 25); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 2621 (e.g., SEQ ID NO: 26).

In one embodiment, the antibody molecule comprises a VH comprising 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 to, the amino acid sequence of VH of monoclonal antibody 2621 (e.g., SEQ ID NO: 29). In one embodiment, the antibody molecule comprises a VL comprising 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 to, the amino acid sequence of VL of monoclonal antibody 2621 (e.g., SEQ ID NO: 30).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 2621 (e.g., SEQ ID NO: 29), or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 2621 (e.g., SEQ ID NO: 30), or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto. In one embodiment, the antibody molecule comprises: (i) A VH comprising the amino acid sequence of the VH of monoclonal antibody 2621 (e.g., SEQ ID NO: 29); and (ii) a VL comprising the amino acid sequence of the VL of monoclonal antibody 2621 (e.g., SEQ ID NO: 30).

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

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3125 (e.g., SEQ ID NO: 11) by NO more than 1,2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology therewith; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO: 42) by NO more than 1,2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3125 (e.g., SEQ ID NO: 43) or has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 3125 (e.g., SEQ ID NO: 44), or that has at least 85, 90, 95, 99, or 100% homology therewith; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO: 45) or that has at least 85, 90, 95, 99, or 100% homology therewith; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3125 (e.g., SEQ ID NO: 46), or has at least 85, 90, 95, 99, or 100% homology therewith.

In one embodiment, the antibody molecule comprises:

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

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3125 (e.g., SEQ ID NO: 11); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO: 42); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3125 (e.g., SEQ id no: 43); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3125 (e.g., SEQ ID NO: 44); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO: 45); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3125 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3125 (e.g., SEQ ID NO: 47) by NO more than 1,2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology therewith; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO: 48) by NO more than 1,2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3125 (e.g., SEQ ID NO: 43) or has at least 85, 90, 95, 99 or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3125 (e.g., SEQ ID NO: 47); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO: 48); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3125 (e.g., SEQ ID NO: 43); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3125 (e.g., SEQ ID NO: 44); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO: 45); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3125 (e.g., SEQ ID NO: 46).

In one embodiment, the antibody molecule comprises a VH comprising 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 thereto, from the amino acid sequence of VH of monoclonal antibody 3125 (e.g., SEQ ID NO: 49). In one embodiment, the antibody molecule comprises a VL comprising 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 to, the amino acid sequence of VL of monoclonal antibody 3125 (e.g., SEQ ID NO: 50).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3125 (e.g., SEQ ID NO: 49), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3125 (e.g., SEQ ID NO: 50), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto. In one embodiment, the antibody molecule comprises: (i) A VH comprising the amino acid sequence of the VH of monoclonal antibody 3125 (e.g., SEQ ID NO: 49); and (ii) a VL comprising the amino acid sequence of the VL of monoclonal antibody 3125 (e.g., SEQ ID NO: 50).

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

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDRl comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 93), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 94), or that has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 4035 or 4035-062 (e.g. SEQ ID NO: 95), or has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 96), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 97), or that has at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 98), or that has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 93); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 94); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 95); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 96); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 97); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 99), or that has at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4035 (e.g., SEQ ID NO: 100) or 4035-062 (e.g., SEQ ID NO: 273), or that has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 4035 or 4035-062 (e.g. SEQ ID NO: 95), or has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDRl, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 96), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 97), or that has at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 98), or that has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 99); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 4035 (e.g., SEQ ID NO: 100) or 4035-062 (e.g., SEQ ID NO: 273); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 95); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 96); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 97); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 98).

In one embodiment, the antibody molecule comprises a VH comprising 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 thereto, from the amino acid sequence of a VH of monoclonal antibody 4035 (e.g., SEQ ID NO: 101) or 4035-062 (e.g., SEQ ID NO: 225). In one embodiment, the antibody molecule comprises a VL comprising 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 thereto, from the amino acid sequence of a VL of monoclonal antibody 4035 (e.g., SEQ ID NO: 102) or 4035-062 (e.g., SEQ ID NO: 229).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 4035 (e.g., SEQ ID NO: 101) or 4035-062 (e.g., SEQ ID NO: 225), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 4035 (e.g., SEQ ID NO: 102) or 4035-062 (e.g., SEQ ID NO: 229), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto. In one embodiment, the antibody molecule comprises: (i) VH comprising the amino acid sequence of VH of monoclonal antibody 4035 (e.g., SEQ ID NO: 101) or 4035-062 (e.g., SEQ ID NO: 225), and (ii) VL comprising the amino acid sequence of VL of monoclonal antibody 4035 (e.g., SEQ ID NO: 102) or 4035-062 (e.g., SEQ ID NO: 229).

In one embodiment, the antibody molecule is monoclonal antibody 4035. In one embodiment, the monoclonal antibody is a humanized monoclonal antibody 4035 (e.g., antibody 4035-062). In another embodiment, the antibody molecule is antibody 4035-062. In one embodiment, the antibody molecule comprises a polypeptide comprising SEQ ID NO:220-227 or 262-265, comprising the amino acid sequence of any one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3934 (e.g., SEQ ID NO: 103) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO: 104) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3934 (e.g., SEQ ID NO: 105), or that has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of monoclonal antibody 3934 (e.g., SEQ ID NO: 106) by NO more than 1,2, or 3 amino acid residues, or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO: 107), or that has at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3934 (e.g., SEQ ID NO: 108), or that has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3934 (e.g., SEQ ID NO: 103); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO: 104); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3934 (e.g., SEQ ID NO: 105); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3934 (e.g., SEQ ID NO: 106); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO: 107); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3934 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3934 (e.g., SEQ ID NO: 109) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO: 110) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3934 (e.g., SEQ ID NO: 105), or that has at least 85, 90, 95, 99 or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3934 (e.g., SEQ ID NO: 109); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO: 110); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3934 (e.g., SEQ ID NO: 105); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3934 (e.g., SEQ ID NO: 106); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO: 107); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3934 (e.g., SEQ ID NO: 108).

In one embodiment, the antibody molecule comprises a VH comprising 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 to, the amino acid sequence of VH of monoclonal antibody 3934 (e.g., SEQ ID NO: 111). In one embodiment, the antibody molecule comprises a VL comprising 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 to, the amino acid sequence of VL of monoclonal antibody 3934 (e.g., SEQ ID NO: 112).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3934 (e.g., SEQ ID NO: 111), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3934 (e.g., SEQ ID NO: 112), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto. In one embodiment, the antibody molecule comprises: (i) A VH comprising the amino acid sequence of the VH of monoclonal antibody 3934 (e.g., SEQ ID NO: 111); and (ii) a VL comprising the amino acid sequence of VL of monoclonal antibody 3934 (e.g., SEQ ID NO: 112).

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

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 112) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 113) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 114), or has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 115), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 116) or that has at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 117), or that has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 113); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 114); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 115); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 116); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 117); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In one embodiment, the antibody molecule comprises:

(i) VH comprising one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 119), or that has at least 85, 90, 95, 99, or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 120) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO-115), or having at least 85, 90, 95, 99, or 100% homology therewith, an

In one embodiment, the antibody molecule comprises:

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 123); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 124); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3631 (e.g., SEQ ID NO: 125); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 126); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 127); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3631 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 129), or that has at least 85, 90, 95, 99, or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 130), or that has at least 85, 90, 95, 99 or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 125), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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 (LCDRl, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 136), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 127), or that has at least 85, 90, 95, 99, or 100% homology therewith; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 137), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 133); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 134); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 135); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 136); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 127); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In one embodiment, the antibody molecule comprises:

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

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 4338 (e.g., SEQ ID NO: 11) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO: 142) by NO more than 1,2 or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO: 143), or has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 4338 (e.g., SEQ ID NO:144 or 146), or that has at least 85, 90, 95, 99, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO:107 or 147), or that has at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO:145 or 148), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 4338 (e.g., SEQ ID NO: 11); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO: 142); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO: 143); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 4338 (e.g., SEQ ID NO:144 or 146); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO:107 or 147); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 4338 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 4338 (e.g., SEQ ID NO: 149) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO: 150) by NO more than 1,2 or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO: 143), or has at least 85, 90, 95, 99 or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 4338 (e.g., SEQ ID NO: 149); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO: 150); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO: 143); and (ii) VL comprising: LCDRl comprising the amino acid sequence of LCDR1 of monoclonal antibody 4338 (e.g., SEQ ID NO:144 or 146); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO:107 or 147); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO:145 or 148).

In one embodiment, the antibody molecule comprises a VH comprising 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 to, the amino acid sequence of VH of monoclonal antibody 4338 (e.g., SEQ ID NO: 151). In one embodiment, the antibody molecule comprises a VL comprising 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 to, the amino acid sequence of VL of monoclonal antibody 4338 (e.g., SEQ ID NO:152 or 153).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 4338 (e.g., SEQ ID NO: 151), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 4338 (e.g., SEQ ID NO:152 or 153), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto. In one embodiment, the antibody molecule comprises: (i) VH comprising the amino acid sequence of VH of monoclonal antibody 4338 (SEQ ID NO: 150); and (ii) a VL comprising the amino acid sequence of VL of monoclonal antibody 4338 (SEQ ID NO:152 or 153).

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

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDRl comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4540, 4540-063 or 4540-033 (e.g. SEQ ID NO: 154), or has at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4540, 4540-063 or 4540-033 (e.g. SEQ ID NO: 155), or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 4540, 4540-063 or 4540-033 (e.g. SEQ ID NO: 156), or having at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues, or that has at least 85, 90, 95, 99, or 100% homology thereto, from the amino acid sequence of LCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO: 116), 4540-063 (e.g., SEQ ID NO: 274), or 4540-033 (e.g., SEQ ID NO: 274); (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO: 157), 4540-063 (e.g., SEQ ID NO: 275), or 4540-033 (e.g., SEQ ID NO: 275), or having at least 85, 90, 95, 99, or 100% homology thereto; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 158), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

In one embodiment, the antibody molecule comprises:

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 163), or that has at least 85, 90, 95, 99, or 100% homology therewith; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO: 164), or that has at least 85, 90, 95, 99 or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 4237 (e.g., SEQ ID NO: 165), or has at least 85, 90, 95, 99 or 100% homology thereto.

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 (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: (i) LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 166), or that has at least 85, 90, 95, 99, or 100% homology therewith; (ii) LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO: 167), or that has at least 85, 90, 95, 99, or 100% homology therewith; or (iii) LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 4237 (e.g., SEQ ID NO: 168), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 163); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO: 164); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 4237 (e.g., SEQ ID NO: 165); and (ii) VL comprising: LCDR1 comprising the amino acid sequence of LCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 166); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO: 167); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 4237 (e.g., 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 169) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO: 170) or that has at least 85, 90, 95, 99 or 100% homology therewith; or (iii) HCDR3 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 4237 (e.g., SEQ ID NO: 165), or has at least 85, 90, 95, 99 or 100% homology thereto.

In one embodiment, the antibody molecule comprises:

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

In one embodiment, the antibody molecule comprises: (i) VH comprising: HCDR1 comprising the amino acid sequence of HCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 169); HCDR2 comprising the amino acid sequence of HCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO: 170); and HCDR3 comprising the amino acid sequence of HCDR3 of monoclonal antibody 4237 (e.g., SEQ ID NO: 165); and (ii) VL comprising: LCDRl comprising the amino acid sequence of LCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 166); LCDR2 comprising the amino acid sequence of LCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO: 167); and LCDR3 comprising the amino acid sequence of LCDR3 of monoclonal antibody 4237 (e.g., SEQ ID NO: 168).

In one embodiment, the antibody molecule comprises a VH comprising 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 to, the amino acid sequence of the VH of monoclonal antibody 4237 (e.g., SEQ ID NO: 171). In one embodiment, the antibody molecule comprises a VL comprising 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 to, the amino acid sequence of VL of monoclonal antibody 4237 (e.g., SEQ ID NO: 172).

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 4237 (e.g., SEQ ID NO: 171), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 4237 (e.g., SEQ ID NO: 172), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto. In one embodiment, the antibody molecule comprises: (i) A VH comprising the amino acid sequence of the VH of monoclonal antibody 4237 (e.g., SEQ ID NO: 171); and (ii) a VL comprising the amino acid sequence of the VL of monoclonal antibody 4237 (e.g., SEQ ID NO: 172).

In one embodiment, the antibody molecule is monoclonal antibody 4237. In one embodiment, monoclonal antibody 4237 is a humanized monoclonal antibody 4237. In one embodiment, the antibody molecule comprises a polypeptide comprising SEQ ID NO: VH of any one of amino acid sequences 235-240, comprising SEQ ID NO:241-245, or both.

In another embodiment, the anti-APRIL antibody molecule:

(i) Binding, or substantially binding, human APRIL;

(ii) Inhibit, or substantially inhibit, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both);

(iii) Inhibit, or substantially inhibit, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both); and

(iv) 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 within a human APRIL region defined in any of tables 3-4 or 7 or 8 of international application publication No. WO 2017/091683.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or lessSmall, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM,0.5nM to 5nM, or an IC of 1nM to 5nM ₅₀ Inhibit, or substantially inhibit, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), e.g., as determined by the methods described herein.

In one embodiment, the antibody molecule binds or substantially binds to an epitope comprising 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 to or substantially binds to one or more APRIL residues from the C-D loop (e.g., the loop connecting β -sheets C and D), the G-H loop (e.g., the loop connecting β -sheets G and H), or both. In one embodiment, the antibody molecule binds to or substantially binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues from human APRIL at positions 105-114 and/or one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues from mouse APRIL at positions 96-105. In one embodiment, the antibody molecule does not bind, or binds with low affinity, 1, 2 or all of Asp129, arg233 or His203 of human APRIL.

(i) A heavy chain variable region (VH) comprising 1, 2 or all of: HCDR1 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues from the amino acid sequence of HCDR1 of a monoclonal antibody selected from the group consisting of antibodies 2218, 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, 4035-062, 3934, 4338, 4439 or 4237, or that has at least 85%, 90%, 95%, 99% or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues from the amino acid sequence of HCDR2 of the (same) monoclonal antibody, or that has at least 85%, 90%, 95%, 99% or 100% homology therewith; or HCDR3 comprising an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues from the amino acid sequence of HCDR3 of the (same) monoclonal antibody, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto, or

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

(i) VH comprising 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 the amino acid sequence of VH of a monoclonal antibody selected from antibodies 2218, 2419-0105, 2419-0205, 2419-0206, 2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3125, 2621, 4035-062, 3934, 4338, 4439, or 4237, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto; or (b)

(ii) VL comprising 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 the amino acid sequence of VL of the (same) monoclonal antibody, or that has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto.

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, e.g., comprising one or more framework regions derived from human framework germline sequences.

In one embodiment, the antibody molecule is an IgG antibody molecule, e.g., comprising a heavy chain constant region of IgG, e.g., selected from IgG1, igG2 (e.g., igG2 a), 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 the light chain constant region of a K or lambda light chain.

In one embodiment, the antibody molecule comprises an Fc region. In one embodiment, the Fc region includes one or more mutations at the interface between the CH2 and CH3 domains (e.g., to increase the binding affinity and/or half-life of the neonatal receptor FcRn of the antibody molecule). In one embodiment, the Fc region comprises one or more mutations, for example one or more (e.g., 2, 3, 4, 6, or all) mutations selected from the group consisting of: T250Q, M252Y, S254T, T256E, M428L, H433K, N434F of IgG1, or a combination thereof. In one embodiment, the Fc region comprises 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 comprises one or more (e.g., 2, 3, 4, 6, 7, or all) mutations selected from the group consisting of: E233P, L234V, L235A, G236, K322A, A327G, A330S, P331S, or any combination thereof.

In one embodiment, the anti-APRIL antibody:

a) Competing with an antibody molecule comprising the heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3) and the light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3) of any of monoclonal antibodies 2218, 2419-0105, 2419-0205, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439 or 4237) described, for example, in table 1 or 5; or (b)

b) An epitope that binds or substantially binds to an epitope that overlaps fully or partially with an epitope of an antibody molecule comprising a heavy chain complementarity determining region (HCDR 1, HCDR2, and HCDR 3) and a light chain complementarity determining region (LCDR 1, LCDR2, and LCDR 3) of any one of the following monoclonal antibodies: 2218 (e.g., SEQ ID NO:1-6 according to Chothia numbering or SEQ ID NO:3-8 according to Kabat numbering), 2419 (e.g., SEQ ID NO:11-16 according to Chothia numbering or SEQ ID NO:13-18 according to Kabat numbering), 2419-0105 (e.g., 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 (e.g., 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), 2419-0206 (e.g., SEQ ID NO:11-13, 16, 17, 280 and 285 according to Chothia numbering or SEQ ID NO:13, 16, 17, 280 and 285 according to Chothia numbering), 2419-0406 (e.g., SEQ ID NO:11-13, 16, 280 and 285 according to Chothia numbering), 2419-0206 (e.g., SEQ ID NO:11-13, 16, 17, 280 and 280 according to Kabat numbering), 2419-0206 (e.g., SEQ ID NO:11-13, 16, 17, 280 and 280 according to Chothia numbering), 2419-0206 (e.g., SEQ ID NO:11-13, 16, 280 and 280 according to Chothia numbering) or SEQ ID NO: 280-285 according to Chothia numbering), 2419-285 (e.g., 16, 280 and 280 according to Chothia numbering) (e.g., 16, etc.). SEQ ID NO:11-13, 16, 280 and 293 according to Chothia numbering or SEQ ID NO:13 16, 17, 280, 282, and 293 are numbered according to Kabat), 2419-1205 (e.g., 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), 2419-1210 (e.g., SEQ ID NO:11-13, 16, 314 and 315 according to Chothia numbering or SEQ ID NO:13 16, 17, 282, 314, and 315 are numbered according to Kabat), 2419-1305 (e.g., 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), 2419-1306 (e.g., SE0 ID NO:11-13, 16, 280 and 285 according to Chothia numbering or SEQ ID NO:13 16, 17, 280, 282, and 285 are numbered according to Kabat), 2419-1310 (e.g., SEQ ID NO:11-13, 16, 314 and 315 according to Chothia numbering or SEQ ID NO:13 16, 17, 282, 314, and 315 are numbered according to Kabat), 2419-1406 (e.g., SEQ ID NO:11-13, 16, 280 and 285 according to Chothia numbering or SEQ ID NO:13 16, 17, 280, 282, and 285 are numbered according to Kabat), 2922 (e.g., SEQ ID NO:21 and 32-36 according to Chothia numbering or SEQ ID NO:33-38 according to Kabat numbering), 3327 (e.g., SEQ ID NO:51-56 according to Chothia numbering or SEQ ID NO:53-58 according to Kabat numbering), 3530 (e.g., SEQ ID NO:61-63, 67, 45 and 46 according to Chothia numbering or SEQ ID NO:63-65, 67, 45, and 46 according to Kabat numbering), 3525 (e.g., SEQ ID NO:44-46 and 61-63 according to Chothia numbering or SEQ ID NO:44-46 and 63-65 according to Kabat numbering), 3125 (e.g., SEQ ID NO:11 and 42-46 according to Chothia numbering or SEQ ID NO:43-48 according to Kabat numbering), 2621 (e.g., SEQ ID NO:21-26 according to Chothia numbering or SEQ ID NO:23-28 according to Kabat numbering), 4035 (e.g., SEQ ID NO:93-98 according to Chothia numbering or SEQ ID NO:95-100 according to Kabat numbering), 4035-062 (e.g., SEQ ID NO:93-98 according to Chothia numbering or SEQ ID NO:95-99 and 273 are numbered according to Kabat), 3934 (e.g., 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 Chothia numbering or SEQ ID NO:115-120 according to Kabat numbering), 3631 (e.g., SEQ ID NO:123-128 according to Chothia numbering or SEQ ID NO:125-130 according to Kabat numbering), 3732 (e.g., SEQ ID NO:127 and 133-137 according to Chothia numbering or SEQ ID NO:127 and 135-139 according to Kabat numbering), 4338 (e.g., SEQ ID NO:11 107 and 142-145, or SEQ ID NO:11 142, 143, and 146-148 are numbered according to Chothia; or SEQ ID NO:107 143-145 and 149-150, or SEQ ID NO:143 and 146-150 according to Kabat numbering), 4540 (e.g., SEQ ID NO:116 and 154-158 according to Chothia numbering or SEQ ID NO:116 and 156-160 according to Kabat numbering), 4540-063 (e.g., SEQ ID NO:154-156, 158, 274 and 275 according to Chothia numbering or SEQ ID NO:156 158 and 274-277 according to Kabat numbering), 4540-033 (e.g., SEQ ID NO:154-156, 158, 274 and 275 according to Chothia numbering or SEQ ID NO:156 158, 159, 274, 275 and 278 are numbered according to Kabat), 4439 (e.g., SEQ ID NO:146-148 and 266-268 according to Chothia numbering or SEQ ID NO:146-148 and 269-270 according to Kabat numbering), or 4237 (e.g., SEQ ID NO:163-168 according to Chothia numbering or SEQ ID NO:165-170 according to Kabat numbering), e.g., as described in table 1 or 5.

In one embodiment, the antibody molecule competes for binding with 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of an antibody molecule comprising HCDR1, HCDR2, HCDR3, HCDR1, LCDR2, and LCDR3 of any of monoclonal antibodies 2218, 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, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4439, or 4237.

In one embodiment, the antibody molecule binds or substantially binds an epitope that overlaps fully or partially with an epitope of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of an antibody molecule comprising an HCDR1, HCDR2, 2419-1210, 2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4506340-0633, 4439, or 4237 of any of monoclonal antibodies 2218, 2419-0605, 2419-0806, 2419-1204, 2419-1205, 2419-241, 3525, 2419-3125, 2621, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 450639, 4439, and LCDR3.

In one embodiment of the present invention, in one embodiment, comprises a monoclonal antibody 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439 or 4237 HCDR1, HCDR2, HCDR3, LCDR 1) the antibody molecules of LCDR2 and LCDR3 comprise the heavy chain variable region and the light chain variable region of any of monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439 or 4237.

In one embodiment of the present invention, in one embodiment, comprises a monoclonal antibody 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439, HCDR2, HCDR3, HCDR2 or 4237 the antibody molecules of LCDR1, LCDR2 and LCDR3 are monoclonal antibodies 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4539, 4439 or 4237.

In one embodiment, the antibody molecule is a humanized monoclonal antibody 2218, 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, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540-063, 4540-033, 4439 or 4237. In one embodiment, the antibody molecule comprises a heavy chain variable region (VH) having an amino acid sequence set forth in table 1 or 5. In one embodiment, the antibody molecule comprises a light chain variable region (VL) having an amino acid sequence set forth in table 1 or 5. In one embodiment, the antibody molecule comprises a heavy chain variable region (VH) having an amino acid sequence set forth in table 1 or 5 and a light chain variable region (VL) having an amino acid sequence set forth 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 is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 50nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.0010.01 nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein.

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

In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., EC at 1000nM or greater, e.g., 2000nM or greater _s0 For example, as determined by the methods 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) to BCMA (e.g., human BCMA, mouse BCMA, or both).

In one embodiment, the binding of the antibody molecule to APRIL (e.g., human APRIL) is inhibited, or the binding of the CRD2 domain of TACI (e.g., human TACI) to APRIL (e.g., human APRIL) is substantially inhibited.

In 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 all) of the human APRIL residues in table 3. In one 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, or all) of the human APRIL residues in 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 (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 in 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 (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 in table 8 of international application publication No. WO 2017/091683.

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

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM to 5nM,0.1nM to 5nM, 0.0.2 nM to 5nM, 0.01nM to 50nM ₅₀ Inhibit, or substantially inhibit, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), e.g., as determined by the methods described herein.

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

In one embodiment, the antibody molecule binds to 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 or more) residues within a human APRIL region defined in any one of tables 3-4 or 7 or table 8 of international application publication No. WO 2017/091683. In one embodiment, the antibody molecule binds or substantially binds to a conformational epitope.

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

In one embodiment, the antibody molecule is an IgG antibody molecule, e.g., comprising a heavy chain constant region of IgG, e.g., selected from IgG1, igG2 (e.g., igG2 a), 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 light chain constant region of a kappa or lambda light chain.

In one embodiment, the antibody molecule is a humanized antibody molecule, e.g., comprising one or more framework regions derived from human framework germline sequences. In one embodiment, the antibody molecule comprises 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 single chain Fv fragment (scFv).

In one embodiment, the anti-APRIL antibody molecule is a synthetic, isolated, or humanized anti-APRIL antibody molecule described herein.

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 2218 (e.g., SEQ ID NO:1 or 7), or that has at least 85, 90, 95, 99, or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 2218 (e.g., SEQ ID NO:2 or 8), or has at least 85, 90, 95, 99, or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 2218 (e.g., SEQ ID NO: 3) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

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

In one embodiment, the antibody molecule comprises: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 2218 (e.g., SEQ ID NO: 9), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 2218 (e.g., SEQ ID NO: 10), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:71 (or a nucleotide sequence substantially identical thereto) or a VH encoded by SEQ ID NO:72 (or a nucleotide sequence substantially identical thereto).

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0.01nM or 0.01nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 1nM or less, e.g., about 0.6nM ₅₀ Bind human APRIL. In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., EC at 1000nM or greater, e.g., 2000nM or greater ₅₀ For example, as determined by the methods described herein.

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

In one embodiment, the antibody molecule is present at 50nM or less, e.g., 40nM or less, 30nM or less, 20An IC of nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM _s0 Inhibit, or substantially inhibit, binding of human APRIL to human TACI, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 1nM or less, e.g., about 0.74nM ₅₀ Inhibit binding of human APRIL to human TACI.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM to 5nM,0.1nM to 5nM, 0.0.2 nM to 5nM, 0.01nM to 50nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human BCMA, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 0.5nM or less, e.g., about 0.22nM ₅₀ Inhibit binding of human APRIL to human BCMA.

(i) A heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two or all of: HCDR1 comprising the amino acid sequence of G-Y-T-F-T-D-Y (SEQ ID NO: 11); HCDR2 comprising the amino acid sequence of Y-P-L-R-G-S (SEQ ID NO: 12); ext> orext> HCDRext> 3ext> comprisingext> theext> aminoext> acidext> sequenceext> ofext> Hext> -ext> Gext> -ext> Aext> -ext> Yext> -ext> Yext> -ext> Sext> -ext> Next> -ext> Aext> -ext> Fext> -ext> Dext> -ext> Yext> (ext> SEQext> IDext> NOext>:ext> 13ext>)ext>,ext> orext>

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2, and LCDR 3), wherein the light chain variable region comprises one, two, or all of: LCDR1 comprising an amino acid sequence of X1-X2-S-X4-S-V-D-N-D-G-I-R-F-X14-H (SEQ ID NO: 327), wherein X1 is R or K; x2 is A or S; x4 is E or Q; and X14 is M or L; LCDR2 comprising the amino acid sequence of R-A-S-X4-X5-X6-X7 (SEQ ID NO: 328), wherein X4 is N or T; x5 is L or R; x6 is E or A; and X7 is S or T; or LCDR3 comprising the amino acid sequence of Q-Q-S-N-K-D-P-Y-T (SEQ ID NO: 16).

(i) A heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two or all of: HCDR1 comprising the amino acid sequence of D-Y-T-I-H (SEQ ID NO: 17); HCDR2 comprising 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), wherein X12 is N, S or A and X13 is E, P or Q; x14 is K or S; x16 is K or Q; and X17 is D or G; ext> orext> HCDRext> 3ext> comprisingext> theext> aminoext> acidext> sequenceext> ofext> Hext> -ext> Gext> -ext> Aext> -ext> Yext> -ext> Yext> -ext> Sext> -ext> Next> -ext> Aext> -ext> Fext> -ext> Dext> -ext> Yext> (ext> SEQext> IDext> NOext>:ext> 13ext>)ext>,ext> orext>

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 is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0.01nM or 0.01nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 0.01nM or less, e.g., about 0.001-0.005nM or 0.002-0.004nM, e.g., about 0.001, 0.002, 0.003, 0.004 or 0.005nM ₅₀ Bind human APRIL. In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., EC at 1000nM or greater, e.g., 2000nM or greater ₅₀ For example, as determined by the methods described herein.

In one embodiment, the antibody molecule is present in an amount of 50nM or less, e.g., 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM, 0.5nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM of IC ₅₀ Inhibiting, or substantially inhibiting, binding of human APRIL to human TACI, e.g., as described hereinDetermined by the method. In one embodiment, the antibody molecule is present in an IC of 0.5nM or less, e.g., about 0.1-0.5nM or 0.2-0.4nM, e.g., about 0.1, 0.2, 0.3, 0.4 or 0.5nM ₅₀ Inhibit binding of human APRIL to human TACI.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM to 5nM,0.1nM to 5nM, 0.0.2 nM to 5nM, 0.01nM to 50nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human BCMA, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 0.5nM or less, e.g., about 0.1-0.5nM or 0.2-0.4nM, e.g., about 0.1, 0.2, 0.3, 0.4 or 0.5nM ₅₀ Inhibit binding of human APRIL to human BCMA.

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 2419 (e.g., SEQ ID NO:11 or 17), or that has at least 85, 90, 95, 99, or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 2419 (e.g., SEQ ID NO:12 or 18), or has at least 85, 90, 95, 99, or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 2419 (e.g., SEQ ID NO: 13) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, and

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

In one embodiment, the antibody molecule comprises: (i) VH comprising an amino acid sequence that differs by NO more than 1,2,3,4,5,6,7,8, 19, 10, 11, 12, 13, 14, or 15 amino acid residues from the amino acid sequence of VH of monoclonal antibody 2419 (e.g., SEQ ID NO: 9), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising an amino acid sequence that differs by NO more than 1,2,3,4,5,6,7,8,9, 20, 11, 12, 13, 14, or 15 amino acid residues from the amino acid sequence of VL of monoclonal antibody 2419 (e.g., SEQ ID NO: 10), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:73 (or a nucleotide sequence substantially identical thereto) or a VH encoded by SEQ ID NO:74 (or a nucleotide sequence substantially identical thereto).

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

In one embodiment, the antibody molecule is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0.01nM or 0.01nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 1nM or less, e.g., about 0.8nM, about 0.003nM, or about 0.002nM ₅₀ Bind human APRIL. In one embodiment, the antibody molecule does not bind, or binds with low affinity to mouse APRIL, e.g., with an EC of 500nM or greater ₅₀ 。

In one embodiment, the antibody molecule is present in an amount of 50nM or less, e.g., 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM, 0.5nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM of IC _s0 Inhibit, or substantially inhibit, binding of human APRIL to human TACI, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present at 1nM or less, e.g., about 0.74An IC of nM, about 0.4nM, 0.3nM or 0.2nM _s0 Inhibit binding of human APRIL to human TACI.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM to 5nM,0.1nM to 5nM, 0.0.2 nM to 5nM, 0.01nM to 50nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human BCMA, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 5nM or less, e.g., about 4nM, about 2nM, or about 1nM, or 0.5nM or less, e.g., about 0.22nM, about 1nM, about 0.7nM, about 0.3nM, about 0.2nM, or about 0.1nM ₅₀ Inhibit binding of human APRIL to human BCMA.

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of an antibody associated with 2419 (e.g., SEQ ID NO:11 or 17), or has at least 85, 90, 95, 99, or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of an antibody associated with 2419 (e.g., SEQ ID NO:12, 282, 287 or 290), or has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR3 of a 2419-related antibody (e.g., SEQ ID NO: 13), or has at least 85, 90, 95, 99, or 100% homology therewith, an

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

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 thereto, from the amino acid sequence of VH of 2419-related antibody (e.g., SEQ ID NO:283, 288, 289, 291, 292, 294, 296, or 317); or (ii) a VL comprising 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 thereto, from the amino acid sequence of VL of 2419-related antibodies (e.g., SEQ ID NOs: 284, 286, 295, or 316).

In one embodiment, the antibody molecule comprises a VH nucleotide sequence of a 2419-related antibody (e.g., nucleotide sequence of SEQ ID NO:304, 307, 308, 309, 310, 311, 313, or 319) (or substantially the same nucleotide sequence thereof) encoding a VH or a VL nucleotide sequence of a 2419-related antibody (e.g., nucleotide sequence of SEQ ID NO:305, 306, 312, or 318) (or substantially the same nucleotide sequence thereof), or both.

In one embodiment, the 2419-related antibody molecule is selected from the group consisting of 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-related antibody is a humanized antibody molecule. In one embodiment, the antibody molecule comprises a polypeptide comprising SEQ ID NO:209-214, 283, 288, 289, 291, 292, 294, 296 or 317, comprising the amino acid sequence of any one 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 is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0.01nM or 0.01nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 1nM or less, e.g., about 0.8nM, about 0.003nM, or about 0.002nM ₅₀ Bind human APRIL.

In one embodiment, the antibody molecule does not bind, or binds with low affinity to mouse APRIL, e.g., with an EC of 500nM or greater ₅₀ 。

In one embodiment, the antibody molecule inhibits or substantially inhibits binding of APRIL (e.g., human APRIL) to TACI (e.g., human TACI), BCMA (e.g., human BCMA), or both. In one embodiment, the antibody molecule is present in an amount of 50nM or less, e.g., 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or lessSmaller, 1nM or smaller, 0.8nM or smaller, 0.6nM or smaller, 0.4nM or smaller, 0.2nM or smaller, 0.1nM or smaller, 0.05nM or smaller, 0.02nM or smaller, or 0.01nM or smaller, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human TACI, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 1nM or less, e.g., about 0.74nM, about 0.4nM, 0.3nM or 0.2nM ₅₀ Inhibit binding of human APRIL to human TACI.

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO:21 or 37), or that has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO:32 or 38), or that has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 33) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 34), or that has at least 85, 90, 95, 99, or 100% homology therewith; LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO: 35), or that has at least 85, 90, 95, 99, or 100% homology therewith; or LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 2922 (e.g., SEQ ID NO: 36), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 2922 (e.g., SEQ ID NO: 39), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 2922 (e.g., SEQ ID NO: 40), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:77 (or a nucleotide sequence substantially identical thereto) or a VH encoded by SEQ ID NO:78 (or a nucleotide sequence substantially identical thereto), or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0.01nM or 0.01nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 5nM or less, e.g., about 3.3nM ₅₀ Bind human APRIL. In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., EC at 1000nM or greater, e.g., 2000nM or greater ₅₀ For example, as determined by the methods described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits binding of APRIL (e.g., human APRIL) to TACI (e.g., human TACI), BCMA (e.g., human BCMA), or both. In one embodiment, the antibody molecule is present in an amount of 50nM or less, e.g., 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or lessSmaller, or 0.01nM or less, e.g., IC of 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human TACI, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 50nM or less, e.g., about 31.64nM ₅₀ Inhibit binding of human APRIL to human TACI.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM to 5nM,0.1nM to 5nM, 0.0.2 nM to 5nM, 0.01nM to 50nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human BCMA, e.g., as determined by the methods described herein. In some embodiments, such ICs ₅₀ Is 50nM or less. In one embodiment, the antibody molecule is present in an IC of 25nM or less, e.g., about 21.96nM ₅₀ Inhibit binding of human TACI to human BCMA.

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 51,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3327 (e.g., SEQ ID NO:1 or 57), or that has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO:2 or 58) or has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 3327 (e.g., SEQ ID NO: 3) by NO more than 1, 52, or 53 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, and

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

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3327 (e.g., SEQ ID NO: 59), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3327 (e.g., SEQ ID NO: 60), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

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

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

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule is present in an amount of 100nM or less, e.g., 80nM or less, 60nM or less, 40nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 100nM, e.g., 0.001nM to 50nM,0.01nM to 20nM,0.1nM to 10nM, 0.2nM to 1nM to 0.5nM to 0.01nM, 0nM to 0.0010.01 nM to 0.01nM, 0nM to 0.01nM EC 0.01nM to 0nM,0.01nM to 0.0010.01 nM to 0nM to 0.01nM to 0.0010 nM to 0.01nM to 0nM or 0 ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., EC at 1000nM or greater, e.g., 2000nM or greater ₅₀ For example, as determined by the methods described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits binding of APRIL (e.g., human APRIL) to TACI (e.g., human TACI), BCMA (e.g., human BCMA), or both. In one embodiment, the antibody molecule is present in an amount of 50nM or less, e.g., 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM, 0.5nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM of IC ₅₀ Inhibition, or baseBinding of human APRIL to human TACI is inhibited herein, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 5nM or less, e.g., about 3.16nM ₅₀ Inhibit binding of human APRIL to human TACI.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM to 5nM,0.1nM to 5nM, 0.0.2 nM to 5nM, 0.01nM to 50nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human BCMA, e.g., as determined by the methods described herein. In some embodiments, such ICs ₅₀ Is about 50nM or less. In one embodiment, the antibody molecule is present in an IC of 5nM or less, e.g., about 2.35nM ₅₀ Inhibit binding of human APRIL to human BCMA.

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4035 (e.g., SEQ ID NO:93 or 99), or that has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4035 (e.g., SEQ ID NO:94 or 100), or that has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 4035 (e.g., SEQ ID NO: 95) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 4035 (e.g., SEQ ID NO: 96), or that has at least 85, 90, 95, 99, or 100% homology thereto; LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 4035 (e.g., SEQ ID NO: 97), or that has at least 85, 90, 95, 99, or 100% homology thereto; or LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 4035 (e.g., SEQ ID NO: 98), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 4035 (e.g., SEQ ID NO: 101), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 4035 (e.g., SEQ ID NO: 102), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:173 or a VH encoded by (or substantially identical to) the nucleotide sequence of SEQ ID NO:174 (or a nucleotide sequence substantially identical thereto), or both.

In one embodiment, the antibody molecule is monoclonal antibody 4035. In one embodiment, monoclonal antibody 4035 is a humanized monoclonal antibody 4035. In one embodiment, the antibody molecule comprises a polypeptide comprising SEQ ID NO:220-227 or 262-265, comprising the amino acid sequence of any one 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 is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0.01nM or 0.01nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 0.01nM or less, e.g., about 0.001nM to 0.002nM ₅₀ Bind human APRIL. In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., EC at 1000nM or greater, e.g., 2000nM or greater ₅₀ For example, as determined by the methods described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits binding of APRIL (e.g., human APRIL) to TACI (e.g., human TACI), BCMA (e.g., human BCMA), or both. In one embodiment, the antibody molecule is present in an amount of 50nM or less, e.g., 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM, 0.5nM to 0.5nM, 0.01nM to 0.01nM IC of 5nM, or 1nM to 5nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human TACI, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 5nM or less, e.g., about 3.16nM, or about 0.1-0.5nM or 0.2-0.4nM ₅₀ Inhibit binding of human APRIL to human TACI.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM to 5nM,0.1nM to 5nM, 0.0.2 nM to 5nM, 0.01nM to 50nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human BCMA, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 5nM or less, e.g., about 2.35nM, or about 0.1-0.5nM or 0.1-0.2nM ₅₀ Inhibit binding of human APRIL to human BCMA.

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4035-062 (e.g., SEQ ID NO:93 or 99), or that has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4035-062 (e.g. SEQ ID NO:94 or 273), or that has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 4035-062 (e.g., SEQ ID NO: 95), or has at least 85, 90, 95, 99, or 100% homology thereto, an

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 4035-062 (e.g., SEQ ID NO: 96), or that has at least 85, 90, 95, 99, or 100% homology thereto; LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 4035-062 (e.g., SEQ ID NO: 97), or that has at least 85, 90, 95, 99, or 100% homology thereto; or LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 4035-062 (e.g., SEQ ID NO: 98), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 4035-062 (e.g., SEQ ID NO: 225), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 4035-062 (e.g., SEQ ID NO: 229), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:299 or a VH encoded by (or substantially identical to) a nucleotide sequence of SEQ ID NO:300 (or a nucleotide sequence substantially identical thereto), or both.

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

In one placeIn one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0.01nM or 0.01nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 0.01nM or less, e.g., about 0.001nM to 0.002nM ₅₀ Bind human APRIL. In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., EC at 1000nM or greater, e.g., 2000nM or greater ₅₀ For example, as determined by the methods described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits binding of APRIL (e.g., human APRIL) to TACI (e.g., human TACI), BCMA (e.g., human BCMA), or both. In one embodiment, the antibody molecule is present in an amount of 50nM or less, e.g., 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM, 0.5nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM of IC ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human TACI, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present at 1nM or less,for example, about 0.1-0.5nM or 0.2-0.4nM ₅₀ Inhibit binding of human APRIL to human TACI.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM to 5nM,0.1nM to 5nM, 0.0.2 nM to 5nM, 0.01nM to 50nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human BCMA, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 1nM or less, e.g., about 0.1-0.5nM or 0.1-0.2nM ₅₀ Inhibit binding of human APRIL to human BCMA.

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two or all of: HCDR1 comprising the amino acid sequence of I-Y-D-V-H (SEQ ID NO: 99); HCDR2 comprising the amino acid sequence of V-I-W-S-D-G-S-T-D-Y-N-X12-X13-X14-X15-S (SEQ ID NO: 342), wherein X12 is A or P and X13 is A or S; x14 is F or L; and X15 is I or K; or HCDR3 comprising the amino acid sequence of 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 comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two or all of: LCDR1 comprising the amino acid sequence of R-A-S-K-N-I-Y-S-Y-L-A (SEQ ID NO: 96) LCDR2 comprising the amino acid sequence of N-A-K-T-L-P-E (SEQ ID NO: 97); or LCDR3 comprising the amino acid sequence of Q-H-H-Y-G-T-P-L-T (SEQ ID NO: 98).

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

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 comprises:

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

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

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3934 (e.g., SEQ ID NO: 111), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, and (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3934 (e.g., SEQ ID NO: 112), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:175 (or a nucleotide sequence substantially identical thereto) or a VH encoded by SEQ ID NO:176 (or a nucleotide sequence substantially identical thereto), or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, 0.0 nM or less 02nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM,1nM to 5nM,0.001nM to 0.1nM,0.001nM to 0.01nM,0.001nM to 0.005nM,0.01nM to 0.05nM, or 0.01nM to 0.1nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., EC at 1000nM or greater, e.g., 2000nM or greater ₅₀ For example, as determined by the methods described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits binding of APRIL (e.g., human APRIL) to TACI (e.g., human TACI), BCMA (e.g., human BCMA), or both. In one embodiment, the antibody molecule is present in an amount of 50nM or less, e.g., 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM, 0.5nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM of IC ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human TACI, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 5nM or less, e.g., about 3.16nM ₅₀ Inhibit binding of human APRIL to human TACI.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.IC of 1nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human BCMA, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 5nM or less, e.g., about 2.35nM ₅₀ Inhibit binding of human APRIL to human BCMA.

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 4338 (e.g., SEQ ID NO:11 or 149) by NO more than 1,2 or 3 amino acid residues, or that has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO:142 or 150), or that has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO: 143) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

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

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 4338 (e.g., SEQ ID NO: 151), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 4338 (e.g., SEQ ID NO:152 or 153), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:183 or a VH encoded by (or substantially identical to) a nucleotide sequence of SEQ ID NO:184 or 185 (or a nucleotide sequence substantially identical thereto), or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0.01nM or 0.01nM EC ₅₀ Binding, or substantially binding, to human APRIL, e.g. asAs determined by the methods described herein. In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., EC at 1000nM or greater, e.g., 2000nM or greater ₅₀ For example, as determined by the methods described herein.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM to 5nM,0.1nM to 5nM, 0.0.2 nM to 5nM, 0.01nM to 50nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human BCMA, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present at 5nM or less, e.g., about 2.3IC of 5nM ₅₀ Inhibit binding of human APRIL to human BCMA.

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO:163 or 169), or that has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO:164 or 170), or that has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 165) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, and

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 166), or that has at least 85, 90, 95, 99, or 100% homology therewith; LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO: 167), or that has at least 85, 90, 95, 99, or 100% homology therewith; or LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 4237 (e.g., SEQ ID NO: 168), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 4237 (e.g., SEQ ID NO: 171), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 4237 (e.g., SEQ ID NO: 172), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:188 (or a nucleotide sequence substantially identical thereto) or a VH encoded by SEQ ID NO:189 (or a nucleotide sequence substantially identical thereto), or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0.01nM or 0.01nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods 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 1000nM or greater, e.g., 200EC of 0nM or greater ₅₀ For example, as determined by the methods described herein.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM to 5nM,0.1nM to 5nM, 0.0.2 nM to 5nM, 0.01nM to 50nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human BCMA, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 5nM or less, e.g., about 2.35nM ₅₀ Inhibit binding of human APRIL to human BCMA.

(i) A heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises 1, 2 or all of: HCDR1 comprising an amino acid sequence of G-Y-X3-X4-T-X6-X7-Y (SEQ ID NO: 330), wherein X3 is S or T; x4 is I or F; x6 is S or absent; and X7 is G, D or S; HCDR2 comprising the amino acid sequence of X3-X4-X5-X6-X7-X8 (SEQ ID NO: 331), wherein X3 is absent and is 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 HCDR3 comprising the amino acid sequence of X1-X2-X3-X4-Y-X6-X7-X8-X9-F-X11-X12 (SEQ ID NO: 332), wherein X1 is Y, E or H; x2 is absent 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), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3), wherein the light chain complementarity determining regions comprise one, two or all of: LCDR1 comprising an amino acid sequence of X1-A-S-X4-S-V-X7-X8-X9-G-X11-X12-X13-X14-X15 (SEQ ID NO: 333), wherein 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 comprising the amino acid sequence of X1-A-S-N-X5-X6-X7 (SEQ ID NO: 334), wherein X1 is A, R or H; x5 is Q or L; x6 is G or E; and X7 is S, P or T; or LCDR3 comprising an amino acid sequence of X1-Q-S-X4-X5-X6-P-X8-T (SEQ ID NO: 335), wherein X1 is Q or L; x4 is K, R or N; x5 is 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 one of 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 is administered in a dose of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM,1nM to 5nM,0.001nM to 0.1nM,0.001nM to 0.01nM,0.001nM to 0.005nM,0.01nM to 0.05nM, or 0.01nM to 0.1nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., EC at 1000nM or greater, e.g., 2000nM or greater ₅₀ For example, as determined by the methods described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits binding of APRIL (e.g., human APRIL) to TACI (e.g., human TACI), BCMA (e.g., human BCMA), or both. In one embodiment, the antibody molecule is present in an IC of 50nM or less, e.g., 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, or 0.1nM or less, e.g., 0.1nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.5nM to 5nM, or 1nM to 5nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human TACI, e.g., as determined by the methods described herein.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nMIC of 1nM,0.1nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human BCMA, e.g., as determined by the methods described herein.

(i) A heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR 1, HCDR2, and HCDR 3), wherein the heavy chain variable region comprises 1, 2, or all of: HCDR1 comprising the amino acid sequence of X6-X7-Y-X9-X10-X11 (SEQ ID NO: 336), wherein 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 comprising the amino acid sequence of X1-I-X3-X4-X5-X6-X7-X8-X9-X10-Y-N-X13-X14-X15-K-X17 (SEQ ID NO: 337), wherein X1 is Y, R or W; x3 is absent and is 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 HCDR3 comprising the amino acid sequence of X1-X2-X3-X4-Y-X6-X7-X8-X9-F-X11-X12 (SEQ ID NO: 332), wherein X1 is Y, E or H; x2 is absent 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

In one embodiment, the antibody molecule is any one of 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 is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0.01nM or 0.01nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., EC at 1000nM or greater, e.g., 2000nM or greater ₅₀ For example, as determined by the methods described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits binding of APRIL (e.g., human APRIL) to TACT (e.g., human TACI), BCMA (e.g., human BCMA), or both. In one embodiment, the antibody molecule is present in an amount of 50nM or less, e.g., 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM,0.5nM to 5nM, or 1nM to 1nMIC of 5nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human TACI, e.g., as determined by the methods described herein.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM to 5nM,0.1nM to 5nM, 0.0.2 nM to 5nM, 0.01nM to 50nM ₅₀ Inhibit, or substantially inhibit, binding of human APRIL to human BCMA, e.g., as determined by the methods described herein.

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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO:61 or 64), or that has at least 85, 90, 95, 99, or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO:62 or 65) or has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 3530 (e.g., SEQ ID NO: 63) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

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

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3530 (e.g., SEQ ID NO: 66), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3530 (e.g., SEQ ID NO: 70), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:83 or a VH encoded by (or substantially identical to) a nucleotide sequence of SEQ ID NO:84 (or a nucleotide sequence substantially identical thereto), 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 is present at 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or lessSmall, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM,1nM to 5nM,0.001nm to 0.1nM,0.001nm to 0.01nM,0.001nm to 0.005nM,0.01nM to 0.05nM, or EC of 0.01nM to 0.1nM ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 5nM or less, e.g., about 2.7nM _s0 Bind human APRIL.

In one embodiment, the antibody molecule inhibits or substantially inhibits binding of APRIL (e.g., human APRIL) to TACI (e.g., human TACI), BCMA (e.g., human BCMA), or both. In one embodiment, the antibody molecule is present in an amount of 50nM or less, e.g., 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05n An IC of M or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM ₅₀ Inhibit, or substantially inhibit, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, or both), e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 5nM or less, e.g., about 4.95nM ₅₀ Inhibit binding of human APRIL to human TACI.

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM to 5nM,0.1nM to 5nM, 0.0.2 nM to 5nM, 0.01nM to 50nM ₅₀ Inhibit, or substantially inhibit, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 1nM or less, e.g., about 0.68nM ₅₀ Inhibit binding of human APRIL to human BCMA.

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO:61 or 64), or that has at least 85, 90, 95, 99, or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO:62 or 65) or has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 3525 (e.g., SEQ ID NO: 63) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

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

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3525 (e.g., SEQ ID NO: 66), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3525 (e.g., SEQ ID NO: 50), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:83 or a VH encoded by (or substantially identical to) a nucleotide sequence of SEQ ID NO:80 (or a nucleotide sequence substantially identical thereto), or both.

In one embodiment, the antibody molecule is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0.01nM or 0.01nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 5nM or less, e.g., about 2.5nM _s0 Bind human APRIL.

In one embodiment, the antibody molecule is present in an amount of 100nM or less, e.g., 80nM or less, 60nM or less, 40nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 100nM, e.g., 0.001nM to 50nM,0.01nM to 20nM,0.1nM to 10nM, 0.2nM to 1nM to 0.5nM to 0.01nM, 0nM to 0.0010.01 nM to 0.01nM, 0nM to 0.01nM EC 0.01nM to 0nM,0.01nM to 0.0010.01 nM to 0nM to 0.01nM to 0.0010 nM to 0.01nM to 0nM or 0 _s0 Binds, or substantially binds, mouse APRIL, e.g.,as determined by the methods described herein.

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

In one embodiment, the antibody molecule is present in an amount of 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM to 5nM,0.1nM to 5nM, 0.0.2 nM to 5nM, 0.01nM to 50nM ₅₀ Inhibit, or substantially inhibit, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 1nM or less, e.g., about 0.85nM ₅₀ Inhibit binding of human APRIL to human BCMA.

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO:113 or 119), or that has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO:114 or 120), or that has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 115) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

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

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3833 (e.g., SEQ ID NO: 121), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3833 (e.g., SEQ ID NO: 122), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:177 or a VH encoded by (or substantially identical to) the nucleotide sequence of SEQ ID NO:178 (or a nucleotide sequence substantially identical thereto), or both.

In one embodiment, the antibody molecule is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM,0.01nM to 0.01nM or 0.01nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 5nM or less, e.g., about 2.5nM ₅₀ Bind human APRIL.

In one embodiment, the antibody molecule is present in an amount of 100nM or less, e.g., 80nM or less, 60nM or less, 40nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 100nM, e.g., 0.001nM to 50nM,0.01nM to 20nM,0.1nM to 10nM, 0.2nM to 1nM to 0.5nM to 0.01nM, 0nM to 0.0010.01 nM to 0.01nM, 0nM to 0.01nM EC 0.01nM to 0nM,0.01nM to 0.0010.01 nM to 0nM to 0.01nM to 0.0010 nM to 0.01nM to 0nM or 0 _s0 Binds, or substantially binds, mouse APRIL, e.g., as determined by the methods described herein.

In one embodiment, the antibody molecule is present at 200nM or less, 100nM or less, 50nM or less, 40nM or less, 30nM or lessSmaller, 20nM or smaller, 10nM or smaller, 9nM or smaller, 8nM or smaller, 7nM or smaller, 6nM or smaller, 5nM or smaller, 4nM or smaller, 3nM or smaller, 2nM or smaller, 1nM or smaller, 0.8nM or smaller, 0.6nM or smaller, 0.4nM or smaller, 0.2nM or smaller, 0.1nM or smaller, 0.05nM or smaller, 0.02nM or smaller, or 0.01nM or smaller, for example, 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM,0.1nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM IC ₅₀ Inhibit, or substantially inhibit, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both), e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of 1nM or less, e.g., about 0.85nM ₅₀ Inhibit binding of human APRIL to human BCMA.

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO:123 or 129), or that has at least 85, 90, 95, 99, or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO:124 or 130), or that has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 3631 (e.g., SEQ ID NO: 125) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 126), or that has at least 85, 90, 95, 99, or 100% homology thereto; LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 127), or that has at least 85, 90, 95, 99, or 100% homology therewith; or LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3631 (e.g., SEQ ID NO: 128), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3631 (e.g., SEQ ID NO: 131), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3631 (e.g., SEQ ID NO: 132), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:179 (or a nucleotide sequence substantially identical thereto) or a VH encoded by SEQ ID NO:180 (or a nucleotide sequence substantially identical thereto), or both.

In one embodiment, the antibody molecule is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or lessAn EC of 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM,1nM to 5nM,0.001nM to 0.1nM,0.001nM to 0.01nM,0.001nM to 0.005nM,0.01nM to 0.005nM, or 0.01nM to 0.1nM ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 5nM or less, e.g., about 2.5nM ₅₀ Bind human APRIL.

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

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO:133 or 138), or that has at least 85, 90, 95, 99, or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO:134 or 139), or that has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 135) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 136), or that has at least 85, 90, 95, 99, or 100% homology thereto; LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 127), or that has at least 85, 90, 95, 99, or 100% homology therewith; or LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 137), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3732 (e.g., SEQ ID NO: 140), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3732 (e.g., SEQ ID NO: 141), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:181 (or a nucleotide sequence substantially identical thereto) or a VH encoded by SEQ ID NO:182 (or a nucleotide sequence substantially identical thereto), or both.

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

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4540 (e.g. SEQ ID NO:154 or 159), or that has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4540 (e.g. SEQ ID NO:155 or 160) or has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 4540 (e.g., SEQ ID NO: 156) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, an

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

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 4540 (e.g., SEQ ID NO: 161), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 4540 (e.g., SEQ ID NO: 162), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:186 (or a nucleotide sequence substantially identical thereto) or a VH encoded by SEQ ID NO:187 (or a nucleotide sequence substantially identical thereto), or both.

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

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4540-063 (e.g. SEQ ID NO:154 or 276), or that has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4540-063 (e.g. SEQ ID NO:155 or 277), or having at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99, or 100% homology with, the amino acid sequence of HCDR3 of monoclonal antibodies 4540-063 (e.g., SEQ ID NO: 156), an

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

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 4540-063 (e.g., SEQ ID NO: 258), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 4540-063 (e.g., SEQ ID NO: 261), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:301 or a VH encoded by (or substantially identical to) a nucleotide sequence of SEQ ID NO:302 (or a nucleotide sequence substantially identical thereto), or both.

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

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4540-033 (e.g. SEQ ID NO:154 or 159), or having at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4540-033 (e.g. SEQ ID NO:155 or 278), or having at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR3 of monoclonal antibody 4540-033 (e.g., SEQ ID NO: 156), or has at least 85, 90, 95, 99, or 100% homology thereto, an

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

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 4540-033 (e.g., SEQ ID NO: 256), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 4540-033 (e.g., SEQ ID NO: 261), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:303 or a VH encoded by (or substantially identical to) a nucleotide sequence of SEQ ID NO:302 (or a nucleotide sequence substantially identical thereto), or both.

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

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the VH comprises one, two or all of: HCDR1 comprising the amino acid sequence of D-Y-Y-X4-N (SEQ ID NO: 343), wherein X4 is I or M; HCDR2 comprising the amino acid sequence of W-I-F-P-G-S-G-S-T-Y-Y-X12-X13-K-X15-X16-G (SEQ ID NO: 344), wherein X12 is N or A and X13 is E or Q; x15 is F or L; and X16 is K or Q; or HCDR3 comprising the amino acid sequence of 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 comprises three light chain complementarity determining regions (LCDR 1, LCDR2, and LCDR 3), wherein VL comprises one, two, or all of: LCDR1 comprising an amino acid sequence of X1-A-S-Q-D-I-N-K-Y-I-A (SEQ ID NO: 345), wherein X1 is K or Q; LCDR2 comprising an amino acid sequence of Y-T-S-T-L-X6-X7 (SEQ ID NO: 346), wherein X6 is Q or E and X7 is S or T; or LCDR3 comprising the amino acid sequence of L-Q-Y-D-N-L-L-T (SEQ ID NO: 158).

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 (HCDR 1, HCDR2 and HCDR 3), wherein the VH comprises one, two or all of: HCDR1 comprising the amino acid sequence of G-Y-T-F-A-D-Y (SEQ ID NO: 154); HCDR2 comprising the amino acid sequence of F-P-G-S-G-S (SEQ ID NO: 155); or HCDR3 comprising the amino acid sequence of G-D-S-G-R-A-M-D-Y (SEQ ID NO: 156), and

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

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 monoclonal antibody 4540-033.

In one embodiment, the antibody molecule is present in an EC of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, or 0.1nM or less, e.g., 0.01nM to 20nM, e.g., 0.1nM to 10nM,0.5nM to 5nM, or 1nM to 5nM ₅₀ Combined, or substantially combinedHuman APRIL, for example, as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 5nM or less, e.g., about 2.5nM _s0 Bind human APRIL.

In one embodiment, the antibody molecule is in an EC of 100nM or less, e.g., 80nM or less, 60nM or less, 40nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, or 0.1nM or less, e.g., 0.01nM to 20nM, e.g., 0.1nM to 10nM,0.5nM to 5nM, or 1nM to 5nM ₅₀ Binds, or substantially binds, mouse APRIL, e.g., as determined by the methods described herein.

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

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

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 2621 (e.g., SEQ ID NO:21 or 27), or that has at least 85, 90, 95, 99, or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 2621 (e.g. SEQ ID NO:22 or 28) or that has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 2621 (e.g., SEQ ID NO: 23) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, and

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

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 2621 (e.g., SEQ ID NO: 29), or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 2621 (e.g., SEQ ID NO: 30), or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:75 (or a nucleotide sequence substantially identical thereto) or a VH encoded by SEQ ID NO:76 (or a nucleotide sequence substantially identical thereto), or both.

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

In one embodiment, the antibody molecule is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM,1nM to 5nM,0.001nM to 0.1nM,0.001nM to 0.01nM,0.001nM to 0.005nM,0.01nM to 0.05nM, or 0.01nM to 0.1nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 1nM or less, e.g., about 0.7nM ₅₀ Bind human APRIL. In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., EC at 1000nM or greater, e.g., 2000nM or greater ₅₀ For example, as determined by the methods described herein.

In one embodiment, the antibody molecule inhibits or substantially inhibits binding of APRIL (e.g., human APRIL) to TACI (e.g., human TACI). In one embodiment, the antibody molecule is present in an amount of 50nM or less, e.g., 40nM or less, 30nM or less, 20nM or less, 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, or 0.01nM or less, e.g., 0.01nM to 50nM,0.1nM to 25nM,0.1nM to 10nM,0.1nM to 5nM,0.1nM to 1nM, 0.5nM to 0.5nM,0.5nM to 5nM, or 1nM to 5nM of IC ₅₀ Inhibit, or substantially inhibit, binding of APRIL (e.g., human APRIL) to TACI (e.g., human TACI), e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is present in an IC of about 1nM or less ₅₀ Inhibit binding of human APRIL to human TACI.

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

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of monoclonal antibody 3125 (e.g., SEQ ID NO:11 or 47) by NO more than 1,2 or 3 amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO:42 or 48) or has at least 85, 90, 95, 99 or 100% homology therewith; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 3125 (e.g., SEQ ID NO: 43) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology therewith, an

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

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 3125 (e.g., SEQ ID NO: 49), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 3125 (e.g., SEQ ID NO: 50), or an amino acid sequence having at least 85, 90, 95, 96, 97, 98, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:79 or a VH encoded by (or substantially identical to) a nucleotide sequence of SEQ ID NO:80 (or a nucleotide sequence substantially identical thereto), or both.

In one embodiment, the antibody molecule binds or substantially binds to human APRIL. In one embodiment, the antibody molecule is present in an amount of 20nM or less, e.g., 10nM or less, 9nM or less, 8nM or less, 7nM or less, 6nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.8nM or less, 0.6nM or less, 0.4nM or less, 0.2nM or less, 0.1nM or less, 0.05nM or less, 0.02nM or less, 0.01nM or less, 0.005nM or less, or 0.002nM or less, or 0.001nM or less, e.g., 0.001nM to 20nM, e.g., 0.01nM to 20nM,0.1nM to 10nM,0.5nM to 5nM, 0.001to 0.1nM, 0.0010.1 nM to 0.001nM, 0.01nM to 0.01nM, 0.01nM to 0nM, 0.01nM to 0.01nM or 0.01nM EC ₅₀ Bind, or substantially bind, to human APRIL, e.g., as determined by the methods described herein. In one embodiment, the antibody molecule is in an EC of 20nM or less, e.g., about 13nM ₅₀ Bind human APRIL. In one embodiment, the antibody molecule does not bind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., EC at 1000nM or greater, e.g., 2000nM or greater ₅₀ For example, as determined by the methods described herein.

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

In one 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 (HCDR 1, HCDR2 and HCDR 3), wherein the heavy chain variable region comprises one, two, or all of: HCDR1 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR1 of monoclonal antibody 4439 (e.g., SEQ ID NO:266 or 269), or that has at least 85, 90, 95, 99 or 100% homology thereto; HCDR2 comprising an amino acid sequence that differs by NO more than 1,2 or 3 amino acid residues from the amino acid sequence of HCDR2 of monoclonal antibody 4439 (e.g., SEQ ID NO:267 or 270), or that has at least 85, 90, 95, 99 or 100% homology thereto; or HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of monoclonal antibody 4439 (e.g., SEQ ID NO: 268) by NO more than 1,2, or 3 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, and

(ii) A light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDRl, LCDR2 and LCDR 3), wherein the light chain variable region comprises one, two, or all of: LCDR1 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR1 of monoclonal antibody 4439 (e.g., SEQ ID NO: 146), or that has at least 85, 90, 95, 99, or 100% homology thereto; LCDR2 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR2 of monoclonal antibody 4439 (e.g., SEQ ID NO: 147), or that has at least 85, 90, 95, 99, or 100% homology thereto; or LCDR3 comprising an amino acid sequence that differs by NO more than 1,2, or 3 amino acid residues from the amino acid sequence of LCDR3 of monoclonal antibody 4439 (e.g., SEQ ID NO: 148), or has at least 85, 90, 95, 99, or 100% homology thereto.

In one embodiment, the antibody molecule comprises one or both of the following: (i) VH comprising 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 the amino acid sequence of VH of monoclonal antibody 4439 (e.g., SEQ ID NO: 271), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto, or (ii) VL comprising 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 the amino acid sequence of VL of monoclonal antibody 4439 (e.g., SEQ ID NO: 272), or an amino acid sequence that is at least 85, 90, 95, 96, 97, 98, 99, or 100% homologous thereto.

In one embodiment, the antibody molecule comprises a polypeptide consisting of SEQ ID NO:297 or a VH encoded by (or substantially identical to) the nucleotide sequence of SEQ ID NO:298 (or a nucleotide sequence substantially identical thereto), or both.

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

In one embodiment, the antibody molecule binds to 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, or more) residues within the human APRIL region defined in table 8 of international application publication No. WO 2017/091683. In one embodiment, the antibody molecule binds to or substantially binds to, or consists of, an epitope comprising, 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 in table 8 of international application publication No. WO 2017/091683. In one embodiment, the antibody molecule binds to or substantially binds to an epitope that overlaps with an epitope comprising or consisting of all or a portion of the human APRIL residues of table 8 of international application publication No. WO 2017/091683. In one embodiment, the antibody molecule binds or substantially binds to an epitope comprising APRIL residues from two monomers, e.g., one or more residues from monomer a and monomer B, as shown in table 8 of international application publication No. WO 2017/091683.

In one embodiment, the antibody molecule is a humanized antibody molecule, e.g., as described in table 5, e.g., comprising one or more framework regions derived from a human framework germline sequence.

Animal model

The antibody molecules described herein can be evaluated in vivo, for example, using various animal models. For example, animal models can be used to test the efficacy of the antibody molecules described herein in inhibiting APRIL and/or treating or preventing a condition described herein (e.g., igA nephropathy). Animal models can also be used, for example, to study side effects, measure the concentration of antibody molecules in situ, and demonstrate the correlation between APRIL function and the disorders described herein (e.g., igA nephropathy).

Exemplary animal models of IgA nephropathy that can be used to evaluate the antibody molecules described herein include, but are not limited to, ddY mouse models of idiopathic IgA nephropathy (Imai et al, kidney int.1985;27 (5): 756-761); a mouse model using an inert protein or a common viral pathogen as a stimulatory antigen (Emantacitor et al, curr.Protoc.Immunol.2001, month 5; chapter 15: unit 15.11), a rat model of a non-infectious protein antigen (Emantacitor et al, curr.Protoc.Immunol.2001, month 5; chapter 15: unit 15.11); chronic mouse models of IgA immune complex-associated kidney disease (Montinaro et al, nephrol. Dial. Transplant.1995;10 (11): 2035-2042); gne M712T mice as a model of human glomerulopathy (Kakani et al, am. JPathol.2012;180 (4): 1431-1440); mouse IgA nephropathy model with MBP-20-peptide fusion protein (Zhang et al, anat. Rec. (Hoboken). 2010;293 (10): 1729-1737); and IgA immune complex nephritis (Rifai et al, JEXp Med.1979;150 (5): 1161-1173). Other animal models of IgA nephropathy are described, for example, in Tomino et al, j. Neprol.2008; 21 (4): 463-467; endo ren. Fail.1997;19 (3): 347-371; and Rifai Kidney int.1987;31 (1): 1-7.

Exemplary animal models of other conditions described herein are also known in the art. Exemplary types of animals 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 composition and kit/kit

In some aspects, the disclosure provides compositions, e.g., pharmaceutically acceptable compositions, comprising an antibody molecule described herein (e.g., a humanized antibody molecule described herein) formulated with a pharmaceutically acceptable carrier.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible. The carrier may be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion). In certain embodiments, less than about 5% (e.g., less than about 4%, 3%, 2%, or 1%) of the antibody molecules in the pharmaceutical composition are present in the form of aggregates. In other embodiments, at least about 95% (e.g., at least about 96%, 97%, 98%, 98.5%, 99%, 99.5%, 99.8% or more) of the antibody molecules in the pharmaceutical composition are present in monomeric form. In some embodiments, the aggregate or monomer level is determined by chromatography, such as high performance size exclusion chromatography (HP-SEC).

The compositions described herein may be in various forms. These include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes, and suppositories. The appropriate form depends on the targeted mode of administration and the therapeutic application. Generally suitable compositions are in the form of injectable or infusible solutions. One of the suitable modes of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In some embodiments, the antibody molecule is administered by intravenous infusion or injection. In certain embodiments, the antibody is administered by intramuscular or subcutaneous injection.

The terms "parenteral administration" and "administration by parenteral route" as used herein mean forms of administration other than enteral and topical administration, typically by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraocular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular (subarachnoid), subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

Therapeutic compositions should generally be sterile and stable under the conditions of manufacture and storage. The compositions may be formulated as solutions, microemulsions, dispersions, liposomes or other ordered structures suitable for high antibody concentrations. Sterile injectable solutions can be prepared by incorporating the active compound (i.e., an antibody or antibody portion) in the required amount in a suitable solvent with one or a combination of the ingredients enumerated above, as required, followed by filtered sterilization. In general, dispersions can be prepared by adding the active agent to a sterile vehicle which contains an alkaline dispersion medium and the other required ingredients described above. In the preparation of sterile powders for sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Proper fluidity of the solution may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by the inclusion in the composition of substances which delay absorption, for example, monostearates and gelatins.

The antibody molecules described herein can be administered by a variety of methods. Several are known in the art, and for many therapeutic, prophylactic or diagnostic applications, a suitable route/mode of administration is intravenous injection or infusion. For example, the antibody molecule may be administered by intravenous infusion at a rate of less than 10 mg/min; preferably less than or equal to 5 mg/min to a dosage of about 1 to 100 mg/square meter, preferably about 5 to 50 mg/square meter, about 7 to 25 mg/square meter, more preferably about 10 mg/square meter. Those skilled in the art will appreciate that the route and/or mode of administration will vary depending upon the desired result. In certain embodiments, the active compounds may be prepared with a carrier that will protect the compound from rapid release, such as controlled release formulations, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid may be used. Many methods of preparing such formulations are patented or known to those skilled in the art. See, e.g., sustained and Controlled Release Drug Delivery Systems (sustained release drug delivery system, J.R. Robinson, marcel Dekker, new York, 1978).

In certain embodiments, the antibody molecule may be administered orally (e.g., with an inert diluent or an absorbable edible carrier). The antibody molecules (and other components as desired) may also be contained in hard or soft shell gelatin capsules, compressed into tablets, or directly incorporated into the diet of the subject. For oral therapeutic administration, the antibody molecules may be mixed with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. In order to administer antibody molecules via other forms of parenteral routes of administration, it may be desirable to coat a compound with a material or co-administer a material with the compound to prevent inactivation of the compound. Medical devices may also be employed to administer therapeutic, prophylactic or diagnostic compositions, several such devices being known in the art.

The dosing regimen is adjusted to provide the desired response (e.g., therapeutic, prophylactic or diagnostic response). For example, a single bolus may be administered, multiple divided doses over a period of time, or the dose may be proportionally reduced or increased depending on the urgency of the treatment regimen. It is particularly advantageous to formulate parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, a unit dosage form refers to physically discrete units suitable as unitary dosages for subjects to be treated, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the desired pharmaceutical carrier. The specification of the dosage unit form in the present invention is dependent on or directly dependent on (a) the unique characteristics of the antibody and the particular therapeutic, prophylactic or diagnostic effect to be achieved, and (b) the inherent limitations of this antibody molecule formulation-related art with respect to managing the sensitivity of the individual.

An exemplary non-limiting range of therapeutically, prophylactically, or diagnostically effective amount of an antibody molecule is about 0.1 to 50mg/kg of subject body weight, for example, about 0.1 to 30mg/kg, for example, about 1 to 30, 1 to 15, 1 to 10, 1 to 5, 5 to 10, or 1 to 3mg/kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, or 50mg/kg. For example, the antibody molecule may 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 a dosage of about 1 to 100 mg/square meter, such as about 5 to 50 mg/square meter, about 7 to 25 mg/square meter, about 10 mg/square meter. It should be noted that the dosage value may vary depending on the type and severity of the condition to be alleviated. It will be appreciated that for each particular subject, the particular dosage regimen should be adjusted over time in accordance with the individual needs and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or embodiment of the claimed compositions.

The pharmaceutical compositions herein may comprise a "therapeutically effective amount," "prophylactically effective amount," or "diagnostically effective amount" of an antibody molecule described herein.

"therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic result at the necessary dosage and duration. The therapeutically effective amount of the 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 or antibody portion to elicit a desired response in the individual. A therapeutically effective amount of the antibody molecule has a therapeutic benefit that outweighs any toxic or detrimental effects. A "therapeutically effective dose" generally results in at least about 20%, such as at least about 40%, at least about 60%, or at least about 80% inhibition of a measurable parameter relative to an untreated subject. The measurable parameter may be, for example, hematuria, urine color, urine foam, pain, swelling (edema) of hands and feet, or hypertension. The ability of an antibody molecule to inhibit a measurable parameter can be evaluated in an animal model system for predicting therapeutic efficacy in treating or preventing IgA nephropathy. Alternatively, such properties of the composition may be assessed (e.g., by an in vitro assay) by examining the ability of the antibody molecule to inhibit APRIL.

"prophylactically effective amount" refers to an amount effective to achieve the desired prophylactic result at the necessary dosage and duration. In general, since a prophylactic dose is used in a subject at or before an early stage of the disease, a prophylactically effective amount will be less than a therapeutically effective amount.

A "diagnostically effective amount" refers to an amount which, in accordance with a dosage and schedule of necessity, achieves the desired diagnostic effect. Generally, a diagnostically effective amount is an amount in which a disorder, such as a disorder described herein (e.g., igA nephropathy), can be diagnosed in vitro, ex vivo, or in vivo.

The present disclosure also includes kits/kits comprising the antibody molecules described herein. The kit may include one or more other components including: instructions for use; other agents, such as labels, therapeutic agents, or agents for chelating or otherwise coupling, antibody molecules coupled to labels or therapeutic agents, or radioprotective compositions; a device or other material for preparing antibody molecules for administration; a pharmaceutically acceptable carrier; and an appliance or other material for administering to a subject.

Nucleic acid

The invention also features nucleic acids comprising nucleotide sequences encoding antibody molecules (e.g., heavy and light chain variable regions and CDRs of an antibody molecule), as described herein.

For example, the disclosure features first and second nucleic acids encoding heavy and light chain variable regions, respectively, of an antibody molecule (e.g., an antibody molecule of table 1 or 5) or a portion of an antibody molecule (e.g., a variable region of table 2) selected from one or more antibody molecules disclosed herein. The nucleic acid may comprise a nucleotide sequence encoding any one of the amino acid sequences in the tables herein, or a sequence substantially identical thereto (e.g., a sequence at least about 85%,90%,95%,99% or more identical to a sequence set forth in the tables herein, or a sequence not differing therefrom by more than 3,6, 15, 30 or 45 nucleotides).

In certain embodiments, a nucleic acid can comprise a nucleotide sequence encoding at least one, two, or three CDRs from a heavy chain variable region having an amino acid sequence set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%,90%,95%,99% or more identical thereto, and/or having one or more substitutions, e.g., 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 an amino acid sequence set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%,90%,95%,99% or more identical thereto, and/or having one or more substitutions, e.g., 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 a heavy chain and a light chain variable region having an amino acid sequence set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%,90%,95%,99% or more identical thereto, and/or having one or more substitutions, e.g., conservative substitutions).

In certain embodiments, a nucleic acid can comprise a nucleotide sequence encoding at least one, two, or three CDRs from a heavy chain variable region, the nucleic acid having a nucleotide sequence as set forth in table 2, a sequence substantially homologous thereto (e.g., a sequence at least about 85%,90%,95%,99% or more identical thereto, and/or capable of hybridizing under stringent conditions as described herein). In some embodiments, a nucleic acid can comprise a nucleotide sequence encoding at least one, two, or three CDRs from a light chain variable region, the nucleic acid having a nucleotide sequence as set forth in table 2, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%,90%,95%,99% or more identical thereto, and/or capable of hybridizing under stringent conditions as described herein). In certain embodiments, a nucleic acid can comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs from the heavy and light chain variable regions, the nucleic acid having a nucleotide sequence as set forth in table 2, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%,90%,95%,99% or more identical thereto, and/or capable of hybridizing under stringent conditions as described herein).

In certain embodiments, the nucleic acid comprises or is substantially homologous to a nucleotide sequence set forth in table 2 (e.g., a sequence at least about 85%,90%,95%,99% or more identical thereto, and/or is capable of hybridizing under stringent conditions as described herein). In some embodiments, the nucleic acid comprises a portion of the nucleotide sequence shown in table 2 or a sequence substantially homologous thereto (e.g., a sequence at least about 85%,90%,95%,99% or more identical thereto, and/or capable of hybridizing under stringent conditions as described herein). The moiety may encode, for example, a variable region (e.g., VH or VL); one, two or three or more CDRs; or one, two, three, four or more frame regions.

The nucleic acids described herein include deoxyribonucleotides or ribonucleotides or analogs thereof. The polynucleotide may be single-stranded or double-stranded, and if single-stranded, may be the coding strand or the non-coding (antisense) strand. Polynucleotides may include modified nucleotides, such as methylated nucleotides and nucleotide analogs. The nucleotide sequence may be interspersed with non-nucleotide components. The polynucleotide may be further modified after polymerization, such as by coupling to a labeling component. The nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin, i.e., non-naturally occurring or associated with another polynucleotide in a non-natural arrangement.

In certain aspects, features of the application include host cells and vectors comprising the nucleic acids described herein. The nucleic acid may be present in a single vector or in separate vectors in the same host cell or in a non-same host cell, as described in detail below.

Carrier body

Further provided herein are vectors comprising nucleotide sequences encoding the antibody molecules described herein.

In one embodiment, the vector comprises nucleotides encoding an antibody molecule described herein (e.g., as described in table 1 or 5). In another embodiment, the vector comprises a nucleotide sequence described herein (e.g., in table 2). Vectors include, but are not limited to, viruses, plasmids, cosmids, lambda phage, or Yeast Artificial Chromosomes (YACs).

A wide variety of carrier systems may be employed. For example, one class of vectors utilizes DNA elements derived from animal viruses such as bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, baculovirus, retrovirus (rous sarcoma virus, MMTV or MOMLV) or SV40 virus. Another class of vectors utilizes RNA elements derived from RNA viruses such as Semliki forest virus, eastern equine encephalitis virus, and flavivirus.

In addition, cells that have stably integrated DNA into their chromosomes can be selected by introducing one or more markers that enable selection of transfected host cells. The markers may provide an auxotrophic host with, for example, auxotroph, biocide (e.g., antibiotic) resistance, or resistance to heavy metals such as copper, and the like. The selectable marker gene may be directly linked to the DNA sequence to be expressed or introduced into the same cell by co-transformation. Other elements may also be required for optimal synthesis of mRNA. These elements may include splicing signals, transcriptional promoters, enhancers, and termination signals.

Once the expression vector or DNA sequence containing the construct is prepared for expression, the expression vector may be transfected or introduced into a suitable host cell. This can be accomplished using a variety of techniques, such as protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, viral transfection, gene guns, lipid-based transfection, or other conventional techniques. In the case of protoplast fusion, cells can be grown in medium and screened for appropriate activity.

Methods and conditions for culturing the resulting transfected cells and recovering the resulting antibody molecules are known to those skilled in the art and may be varied or optimized based on the description herein, depending on the particular expression vector and mammalian host cell used.

Cells

The disclosure also provides cells (e.g., host cells) comprising nucleic acids encoding antibody molecules as described herein. For example, a host cell can comprise a nucleic acid molecule having a nucleotide sequence set forth in table 2, a sequence substantially homologous thereto (e.g., a sequence having at least about 85%,90%,95%,99% or more identity thereto, and/or a sequence capable of hybridizing under stringent conditions as described herein) or a portion of one of the nucleic acids. In addition, the host cell may comprise a nucleic acid molecule encoding an amino acid sequence of table 1 or 5, a sequence substantially homologous thereto (e.g., a sequence at least about 80%,85%,90%,95%,99% or more identical thereto), or a portion of one of the sequences.

In some embodiments, the host cell is genetically engineered to comprise a nucleic acid encoding an antibody molecule described herein.

In certain embodiments, the host cell is genetically engineered with an expression cassette. The term "expression cassette" refers to a nucleotide sequence capable of affecting expression of a gene in a host compatible with such sequences. Such expression cassettes may include a promoter, an open reading frame with or without an intron, and a termination signal. Other factors necessary or helpful to achieve expression, such as inducible promoters, may also be employed.

The present disclosure also provides host cells comprising the vectors described herein.

The cells may be, but are not limited to: eukaryotic cells, bacterial cells, insect cells or human cells. 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 (e.g., host cell) is an isolated cell.

Use of antibody molecules

The antibody molecules described herein and the pharmaceutical compositions described herein have therapeutic, prophylactic and/or diagnostic uses in vitro, ex vivo and in vivo.

In one embodiment, the antibody molecule reduces (e.g., 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 subject, such as a human subject, for example, in vivo, to reduce (e.g., inhibit, block, or neutralize) one or more biological activities of APRIL. In one embodiment, the antibody molecule inhibits or substantially inhibits binding of APRIL (e.g., human APRIL) to TACI, BCMA, or both. Thus, in one aspect, the disclosure provides methods of treating, preventing, or diagnosing a disorder in a subject, e.g., a disorder described herein (e.g., igA nephropathy (IgAN) or a disorder associated with IgAN (e.g., advanced Chronic Kidney Disease (CKD)), igAN after transplantation, pediatric IgAN, allergic purpura (HSP) or cutaneous vasculitis, igAN with crescentic Glomerulonephritis (GN)), igA vasculitis, igA dermatitis (e.g., igA dermatitis herpetiformis, igA bullous skin disease), igM-mediated neuropathy (e.g., anti-MAG peripheral neuropathy or IgM-mediated neuropathy associated with anti-GM 1 antibodies), waldenstrom Macroglobulinemia (WM), or lupus nephritis), comprising administering to the subject an antibody molecule described herein, thereby treating, preventing, or diagnosing the disorder. For example, the present disclosure provides a method comprising contacting an antibody molecule described herein with cells in culture (e.g., in vitro or ex vivo), or administering an antibody molecule described herein to a subject (e.g., in vivo) to treat, prevent, or diagnose a disorder, e.g., an APRIL-associated disorder (e.g., igA nephropathy (IgAN) or a disorder associated with IgAN (e.g., end stage Chronic Kidney Disease (CKD), igAN after transplantation, pediatric IgAN, allergic purpura (HSP) or cutaneous vasculitis, igAN with crescentic Glomerulonephritis (GN)), igA vasculitis, igA dermatitis (e.g., igA herpetiformis, igA bullous dermatoses), igM-mediated neuropathy (e.g., anti-MAG peripheral neuropathy or IgM-mediated neuropathy associated with anti-GM 1 antibodies), waldenstrom Macroglobulinemia (WM), or lupus nephritis.

The term "subject" as used herein is intended to include both human and non-human animals. In one embodiment, the subject is a human subject, e.g., having or in a condition described herein (e.g., igA nephropathy (IgAN) or a condition associated with IgAN (e.g., advanced Chronic Kidney Disease (CKD), igAN, pediatric IgAN, allergic purpura (HSP) or cutaneous vasculitis, igAN with crescent Glomerulonephritis (GN)), or is in a condition described herein (e.g., igA nephropathy (IgAN) or a condition associated with IgAN (e.g., advanced Chronic Kidney Disease (CKD), igAN, pediatric IgAN, allergic purpura (HSP) or cutaneous vasculitis, igAN with crescent Glomerulonephritis (GN) after transplantation, the term "non-human animal" includes mammals and non-mammals, e.g., non-human primate, in some embodiments, subjects are humans, methods and compositions described herein are useful for treating a subject suffering from a disorder described herein, e.g., igA nephropathy (IgAN) or a condition associated with IgAN, e.g., advanced Chronic Kidney Disease (CKD), igAN, pediatric IgAN, allergic purpura (HSP) or cutaneous vasculitis, igAN with crescentic Glomerulonephritis (GN), igA vasculitis, igA dermatitis (e.g., igA dermatitis, igA bullous dermatoses), igA Glomerulonephritis (GN), human patients with IgM-mediated neuropathy, such as anti-MAG peripheral neuropathy or IgM-mediated neuropathy associated with anti-GM 1 antibodies, waldenstrom Macroglobulinemia (WM) or lupus nephritis.

Patients suffering from a disorder described herein (e.g., igA nephropathy (IgAN) or a disorder associated with IgAN (e.g., advanced Chronic Kidney Disease (CKD)), igAN after transplantation, pediatric IgAN, allergic purpura (HSP) or cutaneous vasculitis, igAN with crescentic Glomerulonephritis (GN), igA vasculitis, igA dermatitis (e.g., igA dermatitis herpetiformis, igA bullous dermatoses), igM-mediated neuropathy (e.g., anti-MAG peripheral neuropathy or IgM-mediated neuropathy associated with anti-GM 1 antibodies), waldenstrom Macroglobulinemia (WM) or lupus nephritis) include those who have developed the disorder, but are (at least temporarily) asymptomatic, exhibit symptoms of the disorder, or have a disorder associated with or associated with the disorder.

Methods of treating or preventing diseases

The antibody molecules described herein are useful for treating or preventing a disorder associated with APRIL or a symptom thereof.

Exemplary diseases or conditions that may be associated with APRIL include, but are not limited to, igA nephropathy (IgAN) or conditions associated with IgAN (e.g., advanced Chronic Kidney Disease (CKD), igAN after transplantation, pediatric IgAN, allergic purpura (HSP) or cutaneous vasculitis, igAN with crescentic Glomerulonephritis (GN), diabetic nephropathy, igM-mediated kidney disease (e.g., anti-MAG peripheral kidney disease or IgM-mediated kidney disease associated with anti-GM 1 antibody), cancer (e.g., hematological cancer (e.g., B-cell non-hodgkin lymphoma, chronic lymphocytic leukemia, hodgkin lymphoma, multiple myeloma, Macroglobulinemia, and lymphoplasmacytic lymphoma) or solid tumors (e.g., colorectal cancer, breast cancer (e.g., breast cancer), esophageal cancer (e.g., esophageal adenocarcinoma), brain cancer (e.g., glioblastoma) and cancer (e.g., renal cell carcinoma), immunoproliferative diseases (e.g., monoclonal IgA hypergammaglobemia), vasculitis (e.g., renal vasculitis, allergic purpura (IgA-related vasculitis), post-streptococcal glomerulonephritis), autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, igA dermatitis (e.g., igA dermatitis herpetiformis), linear IgA bullous disease/linear immunoglobulin a (IgA) skin diseases, igA-mediated epidermolysis bullosa, igA pemphigus, celiac disease, and alcoholic cirrhosis).

In one embodiment, associated with APRILThe condition is IgA nephropathy (IgAN) or a condition associated with IgAN (e.g., late stage Chronic Kidney Disease (CKD), igAN after transplantation, pediatric IgAN, allergic purpura (HSP) or cutaneous vasculitis, igAN with crescentic Glomerulonephritis (GN), igA vasculitis, igA dermatitis (e.g., igA dermatitis herpetiformis, igA bullous dermatoses), igM-mediated neuropathy (e.g., anti-MAG peripheral neuropathy or IgM-mediated neuropathy associated with anti-GM 1 antibodies), waldenstrom Macroglobulinemia (WM) or lupus nephritis in one embodiment, the condition is IgA nephropathy (IgAN) in one embodiment, the condition is IgA nephropathy in a subject with more late stage Chronic Kidney Disease (CKD) (eGFR. Gtoreq.30 or 45), in one embodiment, the disorder is IgA nephropathy in a subject with crescent Glomerulonephritis (GN), in one embodiment, the disorder is IgA vasculitis, in one embodiment, the disorder is IgA dermatitis (e.g., dermatitis herpetiformis, igA bullous dermatoses), in one embodiment, the disorder is IgM mediated nephropathy (e.g., igM-resistant or GM 1-associated IgM-resistant) in one embodiment, the disorder is IgA vasculitis Macroglobulinemia (WM). In one embodiment, the disorder is lupus nephritis.

The frequency of administration of the antibody molecules described herein should generally maintain a therapeutically effective level of the antibody molecule in the patient's system until the patient is rehabilitated. For example, the antibody molecules can be administered at a frequency sufficient to achieve a serum concentration of at least about 1, 2, 5, 10, 20, 30, or 40 antibody molecules binding each APRIL molecule. In one embodiment, the antibody molecule is 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 of administering various antibody molecules are known in the art and are described below. The appropriate dosage of antibody molecule to be used will depend on the age and weight of the subject and the particular drug being used.

In one embodiment, the antibody molecule is administered intravenously to a subject (e.g., a human subject). In one embodiment, the antibody molecule is administered to a subject at the following doses: 0.1mg/kg to 50mg/kg, for example, 0.2mg/kg to 25mg/kg, 0.5mg/kg to 10mg/kg, 0.5mg/kg to 5mg/kg, 0.5mg/kg to 3mg/kg, 0.5mg/kg to 2.5mg/kg, 0.5mg/kg to 2mg/kg, 0.5mg/kg to 1.5mg/kg, 0.5mg/kg to 1mg/kg, 1mg/kg to 1.5mg/kg, 1mg/kg to 2mg/kg, 1mg/kg to 2.5mg/kg, 1mg/kg to 3mg/kg, 1mg/kg to 2.5mg/kg, or 1mg/kg to 5mg/kg. In one embodiment, the antibody molecule is administered to the subject at the following fixed doses: 10mg to 1000mg, for example, 10mg to 500mg, 10mg to 250mg, 10mg to 150mg, 10mg to 100mg, 10mg to 50mg, 250mg to 500mg, 150mg to 500mg, 100mg to 500mg, 50mg to 500mg, 25mg to 250mg, 50mg to 150mg, 50mg to 100mg, 100mg to 150mg, 100mg to 200mg, or 150mg to 250mg. In one embodiment, the antibody molecule is administered to the subject at a dose of about 100mg, about 200mg, about 400mg, about 600mg, about 800mg, or about 1000mg, or about 1200mg, e.g., subcutaneously. In one embodiment, the antibody molecule is administered subcutaneously to the subject at a dose of about 200 mg. In one embodiment, the antibody molecule is administered subcutaneously to a subject at a dose of about 400 mg. In one embodiment, the antibody molecule is administered subcutaneously to a subject at a dose of about 600 mg. In one embodiment, the antibody molecule is administered subcutaneously to the subject at a dose of about 800 mg. In one embodiment, the antibody molecule is administered in a unit dose of 100mg/mL to 300mg/mL, e.g., 200 mg/mL. In one embodiment, the antibody molecule is administered by subcutaneous injection of about 0.5mL to 5mL, e.g., 1mL,1.5mL,2mL,2.5mL,3mL,3.5mL,4mL,4.5mL,5mL,5.5mL, or 6 mL. In one embodiment, the antibody molecule is administered at a dose of 200mg by one 1mL subcutaneous injection. In one embodiment, the antibody molecule is administered at a dose of 400mg by one 2mL subcutaneous injection. In one embodiment, the antibody molecule is administered at a dose of 600mg by one 2mL subcutaneous injection and one 1mL subcutaneous injection. 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 or once every three months. In one embodiment, the antibody molecule is administered in a single subcutaneous dose, e.g., over a period of at least 1, 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, 33, 34, 35, or 36 weeks. In one embodiment, the antibody molecule is administered at 0.5mg/kg to 3mg/kg or 50mg to 150mg once a week, twice a week, once every two weeks or once every four weeks.

The antibody molecule may be used alone or conjugated to a second agent, such as a bacterial agent, toxin, or protein (e.g., a second anti-APRIL antibody molecule). The method comprises the following steps: administering to a subject in need of such treatment an antibody molecule alone or conjugated to a second agent. Antibody molecules may be delivered with a variety of therapeutic agents (e.g., toxins or mixtures thereof).

IgA nephropathy

IgA nephropathy (also known as Berger disease, berger syndrome, igA nephritis, igAN or bipharyngeal glomerulonephritis) is the most common chronic glomerular disease worldwide. Conservative epidemiological estimates indicate global morbidity of about 5-50 cases/million (children) and 10-40 cases/million (adults). The disease incidence shows regional preference, the prevalence of asia and america is high, and the disease burden in japan and china is particularly high. In japan, the number of IgA nephropathy cases confirmed by biopsy is estimated to be about 35 ten thousand. In the united states, this prediction is about 10 tens of thousands, and therefore it is the most commonly diagnosed 1 glomerular disease in adults. Although IgA nephropathy is a relatively inert disease, it can lead to End Stage Renal Disease (ESRD), i.e., 20-50% of patients develop renal failure over a 20-30 year time span. Given the need to confirm disease by renal biopsy, which can be severely underestimated, renal biopsy is practiced differently in a variety of clinical settings. The disease has complex pathogenesis, including genetic, epidemiological and potential environmental factors, affecting the etiology, pathology and progression of the disease. It also has different clinical manifestations, ranging from asymptomatic to end-stage renal failure (ESRD). There is currently no disease-specific treatment for primary disease or disease progression.

The etiology of this disease, as the name suggests, has been established. Briefly, the disorder is caused by IgA deposition, usually in the form of a mesangial immune complex. Molecular characterization of these specific immunoglobulins has been performed. These IgAs belong to the A1 subclass (IgA 1 vs. IgA 2), are mainly polymeric (have J chain mediated linkages), and there is clearly a different o-glycosylation at the hinge region between the CH1 and CH2 domains. In particular, these o-glycans heterogeneously lack β1,3 galactose linkages and are therefore commonly referred to as galactose-deficient IgA1 (or gdIgA 1). Since the pathogenesis of the disease may involve a polygenic, multi-hit (hit) mechanism to induce renal pathology and abnormal physiology, igA1 may be regarded as a so-called autoantigen, representing the first key "target" in the multi-target model of IgA nephropathy. A group of autoantibodies to this disease has also been identified, which are associated with immunoglobulins (principally IgG), specifically recognizing this differentially glycosylated epitope and promoting the formation of immune complexes (representing the so-called "2 nd shot"). It should also be noted that IgA itself is prone to aggregation due to misfolding, conformational changes and potential changes in the N-glycosylation state of CH2/CH3 glycans.

Without wishing to be bound by theory, it is believed that in one embodiment, abnormally glycosylated IgA1 levels are associated with diseases and clinical outcomes of IgA nephropathy. Aberrant glycosylated IgA1 has been described directly from kidney biopsies, and increased production of aberrant glycosylated IgA1 was observed in B cells (tonsils, PBMCs) of IgA nephropathy patients. Galactose-deficient IgA1 levels in serum of IgA nephropathy patients are correlated with disease progression (Zhao et al, kidney int.2012;82 (7): 790-6). Differential lectin staining showed elevated levels of abnormally glycosylated IgA1 in serum and glomeruli of IgA nephropathy patients relative to healthy controls (Allen et al, kidney int.2001;60 (3): 969-73).

Based on this ongoing disease model, igA nephropathy may be properly regarded as an autoimmune disease with strong and severe extra-renal involvement. The identification and validation of selected immune targets has been proposed to play a key role in disease pathogenesis, namely IgA production and subsequent production of autoreactive antibodies to the target, representing a logical therapeutic strategy. For this reason, APRIL (TNFSF 13) represents a particular field of interest. Other reasons for targeting APRIL include emerging genetic data based on multiplex, comprehensive whole genome association (GWAS) studies, and IgA-related genetic diseases, such as IgA-hypogammaglobulinemia-related Common Variable Immunoglobulin Deficiency (CVID), whose loci map to TNFRSF13B (TACI) defects, directly related to the role of APRIL-TACI interactions in regulating IgA synthesis.

IgA nephropathy is usually asymptomatic in the early stages. This disease may not be noticed for many years, and sometimes proteins and erythrocytes in urine are found in routine examination and are not first diagnosed without being seen under a microscope (microscopic hematuria). When kidney function is impaired, signs and symptoms of IgA nephropathy include, for example, cola or brown urine (caused by red blood cells in urine); repeated occurrence of cola or brown urine, sometimes even with blood in the urine, often occurs during or after upper respiratory tract infections or other types of infections; back side pain below ribs (flank); foam in the urine pool water caused by proteins in the urine; swelling of hands and feet (edema); also hypertension. In one embodiment, the sign or symptom includes, for example, one or more of hematuria, proteinuria, albuminuria, hypertension, or early kidney disease (e.g., in need of dialysis or transplantation). In one embodiment, the sign or symptom is associated with one or more of, for example, aberrant glycosylated IgA1, autoantibody formation, deposition of a nephrogenic immune complex in the kidney, or inflammation and loss of kidney function.

Classical manifestations of IgA nephropathy (about 40-50% of cases, more common in young people) are narcolepsy, usually beginning within one or two days of nonspecific upper respiratory tract infection (and thus pharyngeal infection). Unusual infections of the gastrointestinal or urinary system can be used as irritants. All of these infections share a common activation of mucosal defenses, resulting in the production of IgA antibodies. These episodes may occur irregularly every few months, with most patients eventually regressing. Renal function is usually maintained normal, but acute renal failure occasionally occurs.

A small proportion of IgA nephropathy patients (about 20-30% of cases, usually the elderly) have microscopic hematuria and proteinuria (less than 2 g/day). These patients may not have any symptoms and will only be clinically discovered when the physician decides to collect a urine sample. Thus, such diseases are often diagnosed in situations where urine screening is necessary, such as in Japanese schoolchildren.

Some IgA nephropathy patients (about 5% each) have the following disease manifestations: nephrotic syndrome (e.g., 3-3.5 g protein loss in urine, poor prognosis); acute renal failure (e.g., as a complication of acute haematuria, when it usually recovers, or due to rapidly progressive glomerulonephritis, chronic renal failure is often caused); chronic renal failure (e.g., asymptomatic in the past, manifested by anemia, hypertension, and other renal failure symptoms, a patient may have long-term microscopic undiscovered hematuria and/or proteinuria).

Various systemic diseases may be associated with IgA nephropathy, such as liver failure, celiac disease, rheumatoid arthritis, reactive arthritis, ankylosing spondylitis and HIV. Diagnosis of IgA nephropathy and searching for any related diseases incidentally revealed this potentially severe systemic disease. Occasionally symptoms of allergic purpura appear at the same time. Some HLA alleles along with complement phenotype are suspected to be genetic factors.

IgA nephropathy can be diagnosed by various examinations such as urine examination, blood examination (e.g., showing elevated levels in creatinine blood in waste), iodophthalate clearance test, renal imaging examination (e.g., ultrasound, X-ray or cystoscopy), renal biopsy, or a combination of both.

For adult patients with simple hematuria, renal ultrasound and cystoscopy are typically first performed to determine the source of bleeding. These tests will exclude kidney stones and bladder cancer, which are two other common urinary system causes that lead to hematuria. In children and young people, the history and relevance of respiratory tract infections can lead to suspicion of IgA nephropathy. Renal biopsy is often the necessary means of diagnosis. Biopsy specimens showed proliferation of mesangial, immunofluorescence and visible IgA deposition under electron microscopy. However, patients with simple microscopic hematuria (i.e., without associated proteinuria and normal renal function) typically do not have biopsies, as this is associated with a good prognosis. Urine tests show erythrocytes, usually of the erythropoietic type. Proteinuria, typically less than 2 grams per day, may also be present. Other renal causes of simple hematuria include, for example, thin basal membrane disease and Alport syndrome, the latter being a genetic disorder associated with hearing impairment and eye problems. Other blood tests that aid in diagnosis include CRP or ESR, complement levels, ANA, and LDH. Protein electrophoresis and immunoglobulin levels may show an increase in IgA in 50% of all patients.

Treatment with various drugs can slow the progression of the disease and help control symptoms such as hypertension, urine protein (proteinuria) and swelling of hands and feet (edema). Typical treatments for IgA nephropathy include, for example, hypertensive drugs (e.g., angiotensin Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs)), omega-3 fatty acids, immunosuppressants (e.g., corticosteroid drugs such as prednisone), statin therapy, mycophenolate mofetil, cyclosporine, mizoribine, cyclophosphamide (e.g., in combination with an anti-platelet/anticoagulant, or in combination with a steroid and azathioprine), renal dialysis, or renal transplantation. In Floego and Eitner J.am.Soc.Nephrol.22: exemplary treatments for IgA nephropathy are also described in 1785-1794, 2011. Typical therapies for other IgA nephropathy are described herein in the "combination therapy" section.

Without wishing to be bound by theory, it is believed that in one embodiment, targeting APRIL selectively reduces IgA. APRIL-/-mice have normal T and B lymphocyte development and normal T and B cell proliferation in vitro, but reduced serum IgA levels (Castigli et al Proc NatlAcad Sci USA.2004;101 (11): 3903-8). The discovery of novel risk loci for IgA nephropathy involves genes involved in immunization against enteric pathogens (Kiryluk et al, nat Genet.2014;46 (11): 1187-96). In IgA nephropathy patients, serum levels of APRIL and B cell production are elevated and correlated with abnormally glycosylated IgA levels (Zhai et al Medicine (Baltimore).2016; 95 (11): e 3099). Plasma APRIL levels (TNFSF 13) are associated with chronic kidney disease progression in IgA kidney disease (Han et al, JAm Soc Nephrol.2016;27 (2): 439-53). anti-APRIL antibody treatment reduced mouse serum IgA, cleared kidney membranes, reduced inflammatory cell infiltration and glomerular injury (Kim et al, PLoS one.2015;10 (9): e 0137044). The anti-APRIL antibodies maintain immune cell homeostasis in bone marrow and spleen (Kim et al, PLoS one.2015;10 (9): e 0137044).

APRIL (TNFSF 13) is a rational biological and therapeutic target for the treatment of IgA nephropathy. Without wishing to be bound by theory, it is believed that in one embodiment the efficacy of the antibody molecules described herein with respect to the targeted modulation of APRIL-mediated immune biological mechanisms is directly related to the treatment of IgA nephropathy. The anti-APRIL antibody molecules described herein (e.g., humanized anti-APRIL antibody molecules), such as having high biological activity and/or low complement activation, can be used to treat IgA nephropathy. In one embodiment, the antibody molecule has picomolar APRIL binding affinity and sub-nanomolar receptor blocking activity for TACI and BCMA, e.g., in vitro. In another embodiment, the antibody molecule functionally interferes with APRIL-mediated downstream cell signaling pathways via the classical nfkb activation pathway. In one embodiment, the antibody molecule is designed, e.g., as an IgG2 subtype, for clinically alleviating exacerbation of antibody-dependent complement recruitment, e.g., in the kidney of IgA nephropathy patients. In one embodiment, the antibody molecules described herein may have improved safety compared to more depleting B cell-based therapies, for example, due to less perturbation of B and T cell homeostasis in a murine model (Kim et al, PLoS one.2015;10 (9): e 0137044).

The antibody molecules described herein can be used to treat or prevent IgA nephropathy at different stages. In one embodiment, the antibody molecule is used to treat symptoms associated with IgA nephropathy, such as hematuria, proteinuria, albuminuria, hypertension, early kidney disease (e.g., in need of dialysis or transplantation), or a combination thereof. In one embodiment, the antibody molecule reduces aberrant glycosylated IgA1, autoantibody formation, deposition of nephrogenic immune complexes in the kidney, inflammation and loss of renal function, or a combination thereof. In one embodiment, the subject is at low risk, e.g., has a mild urinary tract abnormality (e.g., microauria), normal Glomerular Filtration Rate (GFR) and/or is free of hypertension. In another embodiment, the subject is at moderate to high risk, e.g., greater than 0.5-1g/d of proteinuria and/or reduced GFR (e.g., less than 30-50 ml/min) and/or hypertension. In another embodiment, the subject has acute or rapid GFR loss, e.g., suffers from nephrotic syndrome or Rapid Progressive Glomerulonephritis (RPGN), or Acute Kidney Injury (AKI) due to massive hematuria or other common causes. In one embodiment, the subject has greater than 0.5 g/day, e.g., between 0.5-1 g/day or greater than 1 g/day proteinuria. In one embodiment, a subject treated for IgA nephropathy has a Glomerular Filtration Rate (GFR) of less than 50ml/min, such as less than 30ml/min.

The antibody molecules described herein are useful for treating various forms of IgA nephropathy or diseases or disorders associated with IgA nephropathy. In one embodiment, the subject treated for IgA nephropathy has more advanced Chronic Kidney Disease (CKD), wherein the estimated GFR (eGFR) is 30 or 45. In one embodiment, the subject treated for IgA nephropathy has crescent Glomerulonephritis (GN). In one embodiment, the antibody molecule is used to treat pediatric IgA nephropathy. In one embodiment, the antibody molecule is used to treat post-transplant IgA nephropathy. In one embodiment, the antibody molecule is used to treat allergic purpura (HSP) or cutaneous vasculitis. In one embodiment, the antibody molecule does not significantly alter (e.g., is capable of preserving) immune cell homeostasis. In another embodiment, the antibody molecule results in a decrease in IgA rather than complete ablation of IgA.

Diabetic nephropathy

The antibody molecules described herein are useful for treating or preventing diabetic nephropathy. Diabetic nephropathy (or called diabetic kidney disease) is a progressive kidney disease caused by glomerular capillary damage. It is typically characterized by nephrotic syndrome and diffuse glomerular scar. This is often due to long-term diabetes mellitus, a major cause of dialysis. It is classified as a small vessel complication of diabetes.

Typical symptoms of diabetic nephropathy include, but are not limited to, severe fatigue, headache, general malaise, nausea, vomiting, frequent urination, loss of appetite, skin itching or leg swelling. Causes of diabetic nephropathy include hyperglycemia, end-stage glycosylation end-product formation, and the like. Cytokines may be involved in the development of diabetic nephropathy.

Diabetes causes a series of changes in the metabolism and blood circulation of the body that together may produce excess reactive oxygen species. These changes damage the glomeruli, resulting in the hallmark features of proteinuria (Cao and Cooper, J Diabetes invest.2011; 2 (4): 243-247). As diabetic nephropathy progresses, the Glomerular Filtration Barrier (GFB) consisting of open-pore endothelium, glomerular basement membrane and epithelial podocytes is increasingly compromised (Mora-Fernandez et al, J Physiol. (Lond.) 2014;592 (Pt 18): 3997-4012). Glomerular basement membrane injury can leak proteins in the blood, resulting in Bowman's interstitial accumulation as a distinct periodic acidic Schiff positive nodule (Kimmerstel-Wilson nodule).

The diagnosis of diabetic nephropathy can be based on a measurement of high albumin levels in urine or evidence of reduced renal function (Lewis and Maxwell practices.2014; 258 (1768): 13-7, 2). Albumin measurements can be defined as follows: normal proteinuria: urinary albumin excretion <30mg/24h; microalbuminuria: the urine albumin excretion amount is 30-299mg/24h; clinical (dominant) albuminuria: the excretion of urine albumin is more than or equal to 300mg/24h. To test kidney function, an estimated glomerular filtration rate (evfr) of a human is measured from a blood sample. Normal eGFR ranges from 90 to 120ml/min/1.73m ² 。

Other therapeutic methods that may be used in combination with the antibody molecules described herein for the treatment of diabetic nephropathy include, for example, angiotensin Converting Enzyme (ACE) inhibitors (such as captopril, enalapril, lisinopril, or ramipril), angiotensin II receptor blockers (ARB) (such as candesartan cilexetil, irbesartan, losartan, or telmisartan), calcium channel blockers (such as amlodipine, diltiazem, or verapamil), diuretics (such as chlorthalidone, hydrochlorothiazide, or spironolactone), 13-receptor blockers (e.g., atenolol, carvedilol, or metoprolol), and diabetes management (e.g., controlling hypertension or blood glucose levels, or reducing dietary salt intake).

Cancer of the human body

The antibody molecules described herein are useful for treating or preventing cancer. Exemplary cancers that may be treated or prevented by the antibody molecules described herein include, but are not limited to: acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), adrenocortical carcinoma, kaposi's sarcoma, AIDS-related lymphoma, primary Central Nervous System (CNS) lymphoma, anal carcinoma, appendicular carcinoma, astrocytoma, atypical malformations/human-like tumors, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, bone carcinoma (e.g., ewing's sarcoma or osteosarcoma and malignant fibrous histiocytoma), brain tumor (e.g., astrocytoma, brain stem glioma, central nervous system atypical malformations/rhabdoid tumor, central nervous system embryo tumor, central nervous system germ cell tumor, craniopharyngeal tumor or ependymoma), breast cancer, bronchial tumor, burkitt's lymphoma, carcinoid (e.g., gastrointestinal carcinoid), heart (heart) tumors, embryo tumors, germ cell tumors, lymphomas, cervical cancer, cholangiocarcinomas, chordoma, chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myeloproliferative tumors, colon cancer, colorectal cancer, craniopharyngeal tube tumors, cutaneous T-cell lymphomas, ductal Carcinoma In Situ (DCIS), endometrial cancer, ependymoma, esophageal cancer, nasal glioma, ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer (e.g., intraocular melanoma or retinoblastoma), fallopian tube cancer, bone fibroblastic cell tumors, osteosarcoma, gall bladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumors (e.g., central nervous system tumors, extracranial tumors, extragonadal tumors, ovarian or testicular cancers), gestational trophoblastic diseases, gliomas, hairy cell leukemia, head and neck cancers, hepatocellular (liver) cancers, hodgkin's lymphoma, hypopharyngeal cancers, intraocular melanoma, insulinoma, pancreatic neuroendocrine tumors, kaposi's sarcoma, renal cancers (e.g., renal cell carcinoma or Wilms tumor), langerhans cell histiocytosis (LCH), laryngeal carcinoma, leukemia (e.g., acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML) or hairy cell leukemia), lip and oral cancer, liver cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC) or small cell lung cancer), lymphoma (e.g., AIDS-related Burkitt lymphoma, cutaneous T-cell lymphoma, hodgkin's lymphoma, non-Hodgkin's lymphoma or primary Central Nervous System (CNS) lymphoma), waldenstone's lymphomaMacroglobulinemia, male breast cancer, bone malignant fibrous histiocytoma and osteosarcoma, melanoma (e.g., intraocular (ocular) melanoma), mercker cell carcinoma, mesothelioma, metastatic squamous carcinoma, midline carcinoma, oral cancer, multiple endocrine tumors, multiple myeloma/plasmacytomenoma, mycosis, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, chronic myelin proliferative neoplasm, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oral cancer, lip and oral cancer, oropharyngeal carcinoma, osteosarcoma and bone malignant fibrous histiocytoma, ovarian cancer (e.g., epithelial ovarian cancer or germ cell ovarian tumor), pancreatic cancer, pancreatic neuroendocrine tumor (islet cell tumor), papillomatosis, paragangliomas, paranasal sinus and nasal cavity cancers, parathyroid cancer, penile cancer, laryngeal pharyngeal cancer, pheochromocytomas, pituitary tumors, pleural pneumoblastomas, peritoneal cancers, prostate cancer, rectal cancer, retina, rhabdomyosarcoma, salivary gland cancers, sarcomas (e.g., ewing 'S sarcoma, kaposi' S sarcoma, osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma or uterine sarcoma), szechwan (szary) syndrome, skin cancers (e.g., melanoma, merck cell carcinoma or non-melanoma skin cancer), small intestine cancers, squamous cell carcinoma, testicular cancer, laryngeal cancer, thymoma and thymus cancer, thyroid cancers, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, endometrial uterine cancer, vaginal cancer, vulval cancer or metastatic lesions thereof.

In one embodiment, the cancer is a hematologic cancer, e.gSuch as lymphomas or leukemias, for example, selected from the group consisting of B-cell non-Hodgkin's lymphoma, chronic Lymphocytic Leukemia (CLL), hodgkin's lymphoma, multiple myeloma,Macroglobulinemia or lymphoplasmacytoid lymphoma. In one embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is a solid tumor, e.g., selected from colorectal cancer, breast cancer (e.g., breast cancer), esophageal cancer (e.g., esophageal adenocarcinoma), brain cancer (e.g., glioblastoma), or renal cancer (e.g., renal cell carcinoma).

In one embodiment, the antibody molecule is used to treat lymphoma. Other therapies that may be used in combination with the antibody molecules described herein for the treatment of lymphomas include, for example, chemotherapy, immunotherapy, targeted drug therapy, radiation therapy, and stem cell transplantation. Exemplary targeted drug therapies include CD20 inhibitors (e.g., rituximabOr Tilmizumab->。

In one embodiment, the antibody molecule is used to treat leukemia. Other therapies that may be used in combination with the antibody molecules described herein for the treatment of leukemia include, for example, chemotherapy, immunotherapy, targeted drug therapy, radiation therapy, and stem cell transplantation. Exemplary targeted drug therapies include tyrosine kinase inhibitors (e.g., imatinib

In one embodiment, the antibody molecule is used to treat multiple myeloma. Other therapies that may be used in combination with the antibody molecules described herein for the treatment of multiple myeloma include, for example, chemotherapy, corticosteroids, immunotherapy, targeted drug therapy, radiation therapy, and stem cell transplantation. Exemplary embodimentsTargeted drug therapies include, for example, thalidomide analogs (e.g., thalidomideLenalidomide->Or poise Ma Lidu amine->。

In one embodiment, the antibody molecule is for use in therapyMacroglobulinemia. Can be combined with the antibody molecules described herein for the treatment of +.>Other treatments for macroglobulinemia include, for example, plasma exchange, chemotherapy, immunotherapy, targeted drug therapy, and stem cell transplantation.

In one embodiment, the antibody molecule is for use in the treatment of colorectal cancer. Other therapies that may be used in combination with the antibody molecules described herein for the treatment of colorectal cancer include, for example, surgery, chemotherapy, radiation therapy, immunotherapy, and targeted drug therapies. Exemplary targeted drug therapies include, for example, VEGF inhibitors (e.g., bevacizumab) EGFR inhibitors (e.g., cetuximab +.>Panitumumab- >) And a dual VEGFR2-TIE2 tyrosine kinase inhibitor (e.g., agofenib->)。

In one embodiment, the antibody molecule is used to treat breast cancer, e.g., breast cancer. Other therapies that may be used in combination with the antibody molecules described herein for the treatment of breast cancer include, for example, surgery, chemotherapy, radiation therapy, hormonal therapy, immunotherapy and targeted drug therapy. Exemplary targeted drug therapies include, for example, HER2 inhibitors (e.g., trastuzumabPertuzumab ∈ ->Aldolizumab->Or Lapatinib->) Or VEGF inhibitors (e.g., bevacizumab ++>)。

In one embodiment, the antibody molecule is used to treat esophageal cancer, e.g., esophageal adenocarcinoma. Other therapies that may be used in combination with the antibody molecules 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, e.g., glioma. Other therapies that may be used in combination with the antibody molecules described herein for the treatment of brain cancer include, for example, surgery, chemotherapy, radiation therapy, radiosurgery, immunotherapy, and targeted drug therapies. Exemplary targeted drug therapies include, for example, VEGF inhibitors (e.g., bevacizumab )。

In one embodimentThe antibody molecules are useful for treating kidney cancer, e.g., renal cell carcinoma. Other therapies that may be used in combination with the antibody molecules described herein for the treatment of renal cancer include, for example, surgery, cryoablation, radiofrequency ablation, radiation therapy, immunotherapy, and targeted drug therapy. Exemplary targeted drug therapies include, for example, VEGF inhibitors (e.g., bevacizumab) Tyrosine kinase inhibitors (e.g., axitinib->PazopanibSorafenib->Or sunitinib->Or mTOR inhibitors (e.g., temsirolimus->Or everolimus->

Immunoproliferative diseases

The antibody molecules described herein are useful for the treatment or prevention of immunoproliferative diseases. An immunoproliferative disease (also known as an immunoproliferative disorder or immunoproliferative tumor) is a disorder of the immune system characterized by abnormal proliferation of primary cells of the immune system (such as B cells, T cells, and Natural Killer (NK) cells) or overproduction of immunoglobulins (such as antibodies).

Typical immunoproliferative diseases include, but are not limited to, lymphoproliferative diseases (LPD), hypergammaglobulinemia and paraproteinemia. Lymphoproliferative diseases include several conditions in which lymphocytes are overproduced. They typically occur in patients with compromised immune systems. Hypergammaglobulinemia is generally characterized by elevated immunoglobulin levels in serum. Paramynemia or monoclonal gammadisease refers to the presence of an excess of a single monoclonal gammaglobulin (e.g., a accessory protein) in the blood. In one embodiment, the antibody molecule is used to treat monoclonal IgA hypergammaglobulinemia.

Vasculitis (vasculitis)

The antibody molecules described herein are useful for treating or preventing vasculitis. Vasculitis is a group of diseases in which blood vessels are destroyed by inflammation. Vasculitis is mainly caused by leukocyte migration and damage caused thereby. Typical types of vasculitis include, but are not limited to, microscopic polyarteritis (polyarteritis), wegener's granulomatosis, allergic purpura and polyarteritis nodosa.

In one embodiment, the antibody molecule is used to treat IgA vasculitis. In one embodiment, the antibody molecule is used to treat allergic purpura (IgA-associated vasculitis).

Purpura (HSP, also known as allergic purpura, rheumatic purpura, or +.>Purpura) is a disease of the skin and other organs, most commonly affecting children. HSP is a systemic vasculitis (vascular inflammation) characterized by the deposition of immune complexes of IgA and complement component 3 (C3) on arterioles, capillaries and venules. On the skin, this disease causes accessible purpura (small bleeding); often with joint and abdominal pain. When the kidneys are affected, there may be a small loss of blood and protein in the urine; in a small fraction of cases, kidney involvement develops into chronic kidney disease and even irreversible kidney damage. HSPs often first develop infections, such as throat infections.

Symptoms of allergic purpura include, for example, rash (purpura), joint swelling or pain (arthritis), gastrointestinal symptoms (e.g., abdominal pain, nausea, vomiting, or bloody stool), and kidney involvement (e.g., protein or blood in the urine). Serum IgA levels were higher in HSP patients.

Criteria defining allergic purpura include, for example, the American society of rheumatology (ACR) classification (Mills et al, (1990) Arthritis and Rheumatism 33 (8): 1114-21), the Church mountain consensus conference (CHCC) 1994 (Jennette et al, (1994) Arthritis and Rheumatism (2): 187-92), the European anti-rheumatology alliance (EULAR) and the society of childhood rheumatology (PreS) classification in 2006, including touchable purpura as mandatory criteria, and at least one of the following findings: diffuse abdominal pain, primary IgA deposition (skin biopsies), acute arthritis of any joint and kidney involvement (evidenced by the presence of blood and/or proteins in urine) (Ozen et al, (2006) Annals of Rheumatic Diseases 65 (7): 936-41).

Other therapeutic methods that may be used in combination with the antibody molecules described herein for the treatment of allergic purpura include, for example, analgesics for abdominal and joint pain, steroids (e.g., oral steroids or intravenous injection of a combination of methylprednisolone (steroid), cyclophosphamide and dipyridamole, followed by prednisone). Other regimens also include, for example, steroid/azathioprine, and steroid/cyclophosphamide (with or without heparin and warfarin), or intravenous immunoglobulin (IVIG).

In another embodiment, the antibody molecule is used to treat acute proliferative glomerulonephritis, e.g., post streptococcal glomerulonephritis.

Acute proliferative glomerulonephritis is a disorder of glomeruli (glomerulonephritis) or small blood vessels of the kidney. It is a common complication of bacterial infection, usually skin infection by type 12, 4 and 1 streptococci (impetigo), but also occurs after streptococcal pharyngitis, so it is also known as post-infection or streptococcal glomerulonephritis. Such infection can cause inflammation of renal angiogenesis, thereby impeding the ability of the renal organs to filter urine.

The pathophysiology of this disease is consistent with immune complex mediated mechanisms. This disease produces proteins with different antigenic determinants which in turn have affinity for sites in the glomeruli. Once bound to the glomeruli, complement is activated by interaction with properti. Complement fixation can lead to the production of other inflammatory mediators.

Symptoms of acute proliferative glomerulonephritis include, for example, hematuria, oliguria, edema, hypertension, fever, headache, weakness, anorexia, and nausea.

Other therapeutic approaches that may be used in combination with the antibody molecules described herein to treat acute proliferative glomerulonephritis include, for example, controlling potassium content and controlling Blood Pressure (BP) in patients with acute oliguric kidney injury.

Autoimmune diseases

The antibody molecules described herein are useful for treating or preventing autoimmune diseases. Typical autoimmune diseases that can be treated or prevented by the antibody molecules described herein include, but are not limited to: acute Disseminated Encephalomyelitis (ADEM), acute necrotizing hemorrhagic encephalitis, addison's disease, gammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, anti-phospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomy abnormality, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune Inner Ear Disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune Thrombocytopenic Purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axons and neuronal neuropathy, balo disease, behcet's disease, bullous pemphigoid cardiomyopathy, giant lymph node hyperplasia (Castleman disease), celiac disease, chagas's disease, chronic fatigue syndrome, chronic Inflammatory Demyelinating Polyneuropathy (CIDP), chronic Recurrent Multifocal Osteomyelitis (CRMO), churg-Strauss syndrome, cicatricial pemphigoid/benign mucosal pemphigoid, crohn's disease, cogans syndrome, condenser-type disease, congenital heart obstruction, coxsackie myocarditis, CREST disease, primary mixed cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, dermatomyositis, devic disease (neuromyelitis optica), discoid lupus, drepler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, nodular erythema, experimental allergic encephalomyelitis, emmer syndrome, fibromyalgia, fibroalveolar inflammation, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, goodpasture syndrome, granulomatous Polyangiitis (GPA) (formerly known as Wegener's granulomatosis), graves' disease, grin-Bali syndrome, hashimoto encephalitis, hashimoto thyroiditis, hemolytic anemia, allergic purpura, pregnancy herpes, low gamma globulin, idiopathic Thrombocytopenic Purpura (ITP), igA nephropathy, igG 4-related sclerosing disease, immunoregulatory lipoproteins, inclusion myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes (type 1 diabetes), juvenile myositis, kawasaki syndrome, langery-Easter syndrome, white cell rupture vasculitis, lichen planus, lichen sclerosus, lignan conjunctivitis, igA disease (LAD), lupus (SLE), lyme disease, chronic, meyedosis, microscopic polyangiitis, mixed Connective Tissue Disease (MCTD), silkworm corneal ulcers (Monn's), tube's, lymphocytic leukemia, payne's, lymphocytic fulgorism, payne's, parvigor's, ocular neurosis, parvigator's, ocular neurosis, paroxysmal, ocular neurosis, peripheral-of the disease, ciliary body flattening (peripheral uveitis), pemphigus, peripheral neuropathy, peripheral encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, autoimmune polyadenopathy syndrome of type I, type II and type III, polymyositis, post myocardial infarction syndrome, post pericardiotomy syndrome, progestogenic dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red blood cell aplasia, raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophia, rate's syndrome, recurrent polychondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, schmitt syndrome, sclerostin, scleroderma, sjogren's syndrome, sperm and testis autoimmunity, stiff human syndrome, subacute Bacterial Endocarditis (SBE), susak's syndrome, sympathogenic ophthalmitis, high-life arteritis, temporal arteritis/giant cell arteritis, thrombocytopenic purpura (TTP), tolosao-Hunt syndrome, transverse myelitis, diabetes mellitus type 1, ulcerative colitis, undifferentiated Connective Tissue Disease (UCTD), uveitis, vasculitis, vesicular dermatopathy, vitiligo, wegener granulomatosis (also known as Granulomatosis Polyangiitis (GPA)).

In one embodiment, the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, linear IgA bullous disease (e.g., linear immunoglobulin a (IgA) skin disease), or IgA-mediated epidermolysis bullosa.

In one embodiment, the antibody molecule is for use in the treatment of rheumatoid arthritis. Other therapeutic methods that may be used in combination with the antibody molecules described herein for the treatment of rheumatoid arthritis include, for example, NSAIDs, steroids (e.g., corticosteroids), disease modifying antirheumatic drugs (DMARDs) (e.g., methotrexate)LeflunomideHydroxychloroquine->Or sulfasalazine->Biological response modifiers (e.g., abapyrite->Adalimumab->Arnapgold->CetuximabEtanercept->Golimumab->InfliximabRituximab->And Torpedo MAb->Or tofacitinib) Or surgery.

In one embodiment, the antibody molecule is used to treat Systemic Lupus Erythematosus (SLE). Other therapeutic methods that can be used in combination with the antibody molecules described herein for the treatment of SLE, such as non-steroidal anti-inflammatory drugs, antimalarial drugs (e.g., hydroxychloroquineCorticosteroids (e.g., prednisone), immunosuppressants (e.g., azathioprine) Mycophenolate->Leflunomide->Or methotrexate) Or BAFF inhibitor (such as belgium ++>

In one embodiment, the antibody molecule is used to treat a linear IgA bullous disease (e.g., linear immunoglobulin a (IgA) skin disease). Other therapeutic methods that may be used in combination with the antibody molecules described herein to treat linear IgA bullous diseases (e.g., linear immunoglobulin a (IgA) skin diseases) include, for example, corticosteroids (e.g., prednisone or prednisolone), antibiotics (e.g., tetracycline, erythromycin, sulfopyridine), colchicine, or mycophenolate esters.

In one embodiment, the antibody molecule is used to treat IgA-mediated epidermolysis bullosa. Other therapeutic approaches that may be used in combination with the antibody molecules described herein to treat IgA-mediated epidermolysis bullosa include, for example, antibiotics, anti-inflammatory drugs (e.g., corticosteroids) or surgery.

Linear IgA bullous skin disease

The antibody molecules described herein are useful for treating or preventing IgA dermatitis, such as linear IgA bullous/linear immunoglobulin a (IgA) skin diseases and IgA-mediated epidermolysis bullosa. Linear IgA bullous skin disease is an autoimmune disease of mucosal skin characterized by linear deposition of IgA and disruption of the dermal-epidermal junction. In one embodiment, the linear IgA bullous skin disorder is an autoimmune response to basement membrane proteins such as stratum hyaline and substratum compactum proteins. The basement membrane secures the epidermis to the dermis layer, helping to stabilize the skin. When IgA antibodies target these proteins, the basement membrane is unstable, leading to the formation of tonic vesicles. In one embodiment, the linear IgA bullous skin disorder is drug-induced (e.g., induced by antibiotics (e.g., vancomycin), antihypertensives, and nonsteroidal anti-inflammatory drugs), associated with another disease or disorder (e.g., lymphoproliferative disease, infection, ulcerative colitis, or Systemic Lupus (SLE)). In one embodiment, the linear IgA bullous skin disorder may be of idiopathic origin. In children, the lesions of linear IgA bullous skin disease are generally confined to the lower abdomen, perineal region and medial thigh. In adults, lesions are typically limited to the extensor face, torso, buttocks and face.

Typical symptoms of linear IgA bullous skin disorders include, but are not limited to, prodromal itching, burning of the eye, and secretions, formation of tension blisters at the bottom of red or normal skin, aggregation of blisters to form classical bead clusters or linear bead strings along the edges of blisters, and/or red bumps or plaques scattered at the site of inflammation.

Linear IgA bullous skin disorders can be diagnosed by clinical, immunological and histopathological examination. Blisters are typically biopsied for skin and immunofluorescence may also be performed to detect the presence of IgA deposits distributed linearly along the basal membrane strip, which is indicative of typical linear IgA bullous skin conditions.

Other therapeutic methods that may be used in combination with the antibody molecules described herein for the treatment of linear IgA bullous skin disorders include, for example, dapsone, sulfonamides, sulfopyridines, mycophenolates, corticosteroids (e.g., prednisone or prednisolone), colchicine, antibiotics (e.g., tetracycline, erythromycin, sulfopyridines), nicotinamide, or surgery.

IgM mediated neuropathy

The antibody molecules described herein are useful for treating or preventing IgM-mediated neuropathy, such as anti-myelin-associated glycoprotein (MAG) peripheral neuropathy or anti-GM 1 antibody-associated IgM-mediated neuropathy. In one embodiment, the antibody molecules described herein are useful for the treatment or prevention of anti-MAG. anti-MAG neuropathy is characterized by the development of autoantibodies against myelin-associated glycoprotein (MAG), which is found in myelin and schwann cells. These autoantibodies can disrupt MAG function and neuronal signals, leading to loss of nerve function and sensory and motor function problems. In one embodiment, the anti-MAG neuropathy is derived from a monoclonal gamma disease, e.g., igM monoclonal gamma disease.

Typical symptoms of anti-MAG neuropathy include, but are not limited to, sensory loss, e.g., sensory loss of toes and fingers, loss of vibrant feel, gait instability, tremor of hands and feet, or weakness.

anti-MAG neuropathy can be diagnosed by clinical characterization, electrical diagnostic studies, and measurement of serum IgM protein levels.

Other therapeutic approaches that may be used in combination with the antibody molecules described herein to treat anti-MAG neuropathy include cyclophosphamide, rituximabPlasma exchange or intravenous immunoglobulin (IvIg).

In one embodiment, the antibody molecules described herein can be used to treat or prevent IgM-mediated neuropathy, e.g., multifocal Motor Neuropathy (MMN), associated with anti-GM 1 ganglioside antibodies. MMN is characterized by progressive asymptomatic muscle weakness and atrophy. In one embodiment, the subject receiving MMN treatment has IgM anti-GMI 1 ganglioside antibodies. Typical symptoms include, but are not limited to: functional motor deficits, ganglioside accumulation, increased cerebrospinal fluid proteins, muscle spasms, reduced tendon reflex, progressive muscle weakness, weakness of the hands and lower arms, cramps, involuntary contractions or twitches, wrist or foot drop, or affected muscle atrophy. In one embodiment, MMN is produced by an aberrant immune response. MMN can be diagnosed by clinical features, electrical diagnostic studies, and measurement of serum IgM protein levels. Other therapeutic approaches that may be used in combination with the antibody molecules described herein for the treatment of MMN include intravenous immunoglobulin (IvIg), rituximab Cyclophosphamide or physical therapy.

Waldenstrom macroglobulinemia

The antibody molecules described herein are useful for the treatment or prevention of Waldenstrom macroglobulinemia. Waldenstrom macroglobulinemia is a hematologic cancer that is typically characterized by lymphoplasmacytoid in the bone marrow. In one embodiment, waldenstrom macroglobulinemia is classified as lymphoplasmacytic lymphoma. These abnormal cells are generally characterized by lymphocytes and B cells and are characterized by abnormal expression of IgM, i.e., production of excessive IgM. In one embodiment, excess IgM can accumulate in various organs, such as the heart and/or kidneys, resulting in amyloidosis. In one embodiment, accumulation of lymphoplasmacytes in different tissues can result in hepatomegaly, splenomegaly, or enlarged lymph nodes.

Waldenstrom macroglobulinemia may be a slow growing lymphoma. In one embodiment, waldenstrom macroglobulinemia may be clinically insignificant and painless. In one embodiment, waldenstrom macroglobulinemia may be clinically significant. In one embodiment, waldenstrom macroglobulinemia is caused by a combination of gene mutations, such as MYD88 gene and/or CXCR4 gene mutations.

Typical symptoms of Waldenstrom macroglobulinemia include, but are not limited to: is prone to bruise, nasal bleeding, gingival bleeding, fatigue, weight loss, peripheral neuropathy (numbness of hands and feet), anemia, fever, headache, shortness of breath, vision changes (e.g., blurred or lost vision), dizziness, ataxia, cryoglobulinemia, confusion of thinking, or night sweats.

Waldenstrom macroglobulinemia can be diagnosed by blood tests, such as blood count, igM protein levels in the blood and/or measuring organ functions, such as kidney and/or liver functions. Waldenstrom macroglobulinemia can also be diagnosed and/or predicted by bone marrow biopsy and/or imaging (e.g., CT scan or PET scan).

Can be combined with the antibody molecules described herein for use in therapyOther treatments for macroglobulinemia include, for example, plasma exchange, chemotherapy, immunotherapy, targeted drug therapy, and stem cell transplantation.

Lupus nephritis

The antibody molecules described herein are useful for treating or preventing lupus nephritis. Lupus nephritis is an autoimmune disease, a form of glomerulonephritis, and can constitute the most severe organ manifestation of Systemic Lupus Erythematosus (SLE). Lupus nephritis causes the kidneys to produce autoantibodies, thereby causing inflammation, such as nephron inflammation, and compromising kidney function, such as waste removal and filtration. It can lead to permanent scarring and kidney damage, and can lead to End Stage Renal Disease (ESRD). Lupus nephritis typically develops in subjects within five years of lupus.

Exemplary symptoms of lupus nephritis include, but are not limited to, blood (hematuria) in urine, proteinuria, foamy urine (e.g., foamy urine due to too much protein in urine), increased urination, edema, joint pain, hypertension, swelling of the hands, ankles and feet, excessive creatinine levels in the blood, muscle pain, weight gain, fever of unknown origin, erythema that is typically located on the face (e.g., across the nose and face).

Diagnosis of lupus nephritis can be based on urine analysis and measurement of protein levels in blood, cell types (e.g., cellular debris often found in the blood and/or tubules), and urine. The diagnosis may also be based on a blood test that evaluates kidney function, e.g., a creatinine blood test with or without a Blood Urea Nitrogen (BUN) test. In addition, to test kidney function, an estimated glomerular filtration rate (evfr) of a human can be measured from a blood sample. Renal biopsies can also be performed, which can be used for staged lupus nephritis. In one embodiment, lupus nephritis is classified as one of six stages under the international society of renal disease/the society of renal pathology (ISN/RPS) classification system, including minimal membranous lupus nephritis (class I), membranous proliferative lupus nephritis (class II)), focal lupus nephritis (< 50% of glomeruli) (class III), diffuse segmental or global lupus nephritis (> 50% of glomeruli) (class IV), membranous lupus nephritis (class V) or late-stage sclerotic lupus nephritis (class VI).

Other therapeutic methods that may be used in combination with the antibody molecules described herein for the treatment of lupus nephritis include, but are not limited to, cyclophosphamide, mycophenolate mofetil, calcineurin inhibitors (e.g., azathioprine or tacrolimus), cyclosporine A,Hydroxychloroquine, rituximabBelimumab, dialysis, kidney transplantation, corticosteroid Angiotensin Converting Enzyme (ACE) inhibitors with Angiotensin Receptor Blockers (ARBs), diuretics, beta blockers, and/or calcium channel blockers.

Other diseases

The antibody molecules described herein are useful for the treatment or prophylaxis of other diseases such as IgA pemphigus, celiac disease or alcoholic cirrhosis.

In one embodiment, the antibody molecule is for use in the treatment or prevention of IgA pemphigus. Other therapeutic approaches that may be used in combination with the antibody molecules described herein for the treatment of IgA pemphigus include, for example, corticosteroids, immunosuppressants (e.g., azathioprineMethotrexate>Or mycophenolate->) CD-20 inhibitors (e.g. rituximab +)>Antibiotics, antiviral drugs or antifungal drugs.

In one embodiment, the antibody molecule is for use in the treatment or prevention of celiac disease. Other therapeutic methods that may be used in combination with the antibody molecules described herein include, for example, gluten-free diets, vitamin or mineral supplements, or steroids.

In one embodiment, the antibody molecule is used to treat or prevent alcoholic cirrhosis. Other therapeutic methods that may be used in combination with the antibody molecules described herein to treat alcoholic cirrhosis include, for example, immunosuppressants (e.g., azathioprine, prednisone, azathioprine, cyclosporin, or methotrexate) or liver transplantation.

Combination therapy

The antibody molecules described herein may be used in combination with other therapies. For example, combination therapy may include co-formulation and/or co-administration of an antibody molecule with one or more other therapeutic agents (e.g., one or more other therapeutic agents described herein). In other embodiments, the antibody molecule is administered in combination with other therapeutic treatment modalities (e.g., other therapeutic treatment modalities described herein). Such combination therapies may advantageously utilize lower doses of the given therapeutic agents, thereby avoiding the potential toxicity or complications associated with each individual therapy.

As used herein, "co-administration" refers to the delivery of two (or more) different treatments/therapies to a subject prior to or during the subject's suffering from a disorder. In one embodiment, the two or more treatments are delivered prophylactically, e.g., before the subject suffers from a disorder or is diagnosed with the disorder. In another embodiment, two or more treatments are performed after the subject has developed or diagnosed with the disease. In some embodiments, delivery of the first treatment is still sustained at the beginning of delivery of the second treatment, whereby there is overlap. Sometimes referred to as "simultaneous" or "co-delivery". In other embodiments, delivery of the other process is resumed after delivery of the first process is terminated. In either embodiment, the treatment is more effective due to the combined administration. For example, the second treatment is more effective than would be observed if the second treatment alone was administered without the first treatment (e.g., the same effect was observed with fewer second treatments, or the second treatment reduces or reduces symptoms to a greater extent), or vice versa for the first treatment. In some embodiments, the delivery of one treatment reduces or reduces other parameters associated with the symptom or condition to a greater extent than would be observed if the other treatment were delivered. The effect of the two treatments may be partially additive, fully additive or greater than additive. The delivery may be such that the effect of delivering the first treatment may still be detected while delivering the second treatment.

In certain embodiments, the additional agent is a second antibody molecule, e.g., a second antibody molecule that is different from the first antibody molecule. Exemplary antibody molecules that may be used in combination include, but are not limited to, any combination of the antibody molecules listed in tables 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 a second therapy to treat or prevent IgA nephropathy accompanied by crescentic Glomerulonephritis (GN).

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 an Fc decoy receptor (e.g., a soluble Fc receptor). In one embodiment, the soluble Fc receptor is soluble Fc-gamma receptor IIB. In one embodiment, the soluble Fc receptor is SM101/BAX1810 (Baxalta). In one embodiment, the soluble Fc receptor is administered at a dose of between 1mg/kg and 50mg/kg, for example, between 5mg/kg and 15mg/kg, between 12mg/kg and 24mg/kg, or between 20mg/kg and 30 mg/kg.

In one embodiment, the antibody molecule is conjugated to a library of corticotropins Combination administration. Kuh-adrenocorticotropic hormone (ACTH) is an adrenocorticotropic hormone (ACTH) analog. In one embodiment, the kuh-adrenocorticotropic hormone is administered at a dose of between 50U and 150U, for example, between 80U and 120U, by subcutaneous injection, twice or three times per week. In one embodiment, the kuh-adrenocorticotropic hormone is administered at a dose of 120U by subcutaneous injection, e.g., once, twice or three times per week.

In one embodiment, the antibody molecule is administered in combination with Mycophenolate Mofetil (MMF). Mycophenolate mofetil (Mycophenolate mofetil) is 2-morpholinoethyl mycophenolic acid (MPA), an immunosuppressant and an inosine monophosphate dehydrogenase (IMPDH) inhibitor. In one embodiment, the mycophenolate mofetil is administered orally or intravenously in a dose of between 0.5g to 2g, e.g., between 1g to 1.5g or between 1.5g to 2g, e.g., 1, 2, or 3 times per day.

In one embodiment, the antibody molecule is conjugated to bortezomibCombination administration. Bortezomib, also known as [ (1R) -3-methyl-1- ({ (2S) -3-phenyl-2- [ (pyrazin-2-ylcarbonyl) amino]Propionyl } amino) butyl]Boric acid, a proteasome inhibitor. In one embodiment, bortezomib is at 0.5mg/m ² To 2.5mg/m ² In between, e.g. 1mg/m every three days or weekly ² To 1.5mg/m ² The dosage in between.

In one embodiment, the antibody molecule is conjugated to allopurinolCombination administration. Allopurinol, also known as 1H-pyrazolo [3,4-d ]]Pyrimidin-4 (2H) -ones are purine analogues. In one embodiment, allopurinol is administered at a dose of between about 50mg and 1000mg, for example, between 100mg and 600mg or between 200 and 300mg, orally, for example, once a day or once two days.

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 between 0.2mg/kg and 2mg/kg, e.g., between 0.5mg/kg and 1mg/kg, e.g., once daily. In one embodiment, cyclophosphamide is administered at a dose of between 0.2g and 2g, e.g., between 0.5g and 1g, e.g., once daily.

In one embodiment, the antibody molecule is in combination with rituximabCombination administration. Rituximab is a chimeric anti-CD 20 monoclonal antibody. In one embodiment, rituximab is at 100mg/m ² To 500mg/m ² Between, for example, 200mg/m ² To 450mg/m ² Between or 300mg/m ² To 400 ofmg/m ² The dosage in between is administered intravenously, for example, once every 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 brimod. Cloth Li Mode, also known as A-623 or AMG 623, is a selective antagonist of B cell activating factor (BAFF, also known as B lymphocyte stimulator or BLyS).

In one embodiment, the antibody molecule is administered in combination with budesonide. In one embodiment, budesonide isAn oral formulation for the release of budesonide.

In one embodiment, the antibody molecule is administered in combination with valsartan and/or probucol. In one embodiment, valsartan is administered at a dose between 50 mg/day and 200 mg/day, for example, between 80 mg/day and 160 mg/day. In one embodiment, probucol is administered at a dose between 500 mg/day and 1000 mg/day, for example, between 700 mg/day and 800 mg/day.

In one embodiment, the antibody molecule is administered in combination with OPL-CCL 2-LPM. OPL-CCL2-LPM is a recombinant fusion protein consisting of a shortened version of the human CCL2 (monocyte chemotactic protein-1) chemokine fused to the A1 domain of shigella dysenteriae holotoxin (SA 1) enzyme activity. In one embodiment, the OPL-CCL2-LPM is administered at a dose of between 0.001mg/kg and 1mg/kg, e.g., between 0.01mg/kg and 0.5mg/kg or between 0.05mg/kg and 0.1mg/kg, e.g., by intravenous injection.

In one embodiment, the antibody molecule is administered in combination with methylprednisolone. In one embodiment, methylprednisolone is administered, e.g., orally, at a dose of 0.1mg/kg to 2 mg/kg/day, e.g., 0.2 mg/kg/day to 1.5 mg/kg/day or 0.5 mg/kg/day to 1 mg/kg/day.

In one embodiment, the antibody molecule is administered in combination with sirolimus. Sirolimus, also known as rapamycin, blocks activation of T cells and B cells by acting on mTOR to inhibit cytokine receptor-dependent signaling mechanisms such as IL-2. In one embodiment, sirolimus is administered at a dose of between 0.2 mg/day and 2 mg/day, for example, between 0.5 mg/day and 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). Typical ACE inhibitors that may be used in combination with the antibody molecules described herein include, for example, benazeprilCaptopril, enalapril +.>Fosinopril, lisinopril +.>Moexipril->Perindopril>Quinolone pride->Ramipril->Or spring dopril->Typical AT1 receptor blockers that can be used in combination with the antibody molecules described herein include, for example, candesartan Eprosartan->EbenshaTam->LosartanOlmesartan->Telmisartan->Or valsartan->

In one embodiment, the antibody molecule is administered in combination with fostantinib. Futamtinib is a prodrug of the active compound tamatinib (R-406), which is an inhibitor of the enzyme spleen tyrosine kinase (Syk). In one embodiment, the fostering agent is administered at a dose of 50mg to 200mg, e.g., 100mg to 150mg, e.g., orally, e.g., daily.

In one embodiment, the antibody molecule is administered in combination with paricalcitol. In one embodiment, paricalcitol is administered in a dose of 0.2mg to 2mg, e.g. 0.5mg to 1mg, e.g. daily.

In one embodiment, the antibody molecule is administered in combination with ramipril. In one embodiment, ramipril is administered at a dose of between about 0.5mg to 5mg, for example, between 1mg to 4mg or between 2mg to 3mg, for example, daily.

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

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 Tacrolimus, 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 CCX 168. CCX168 is an orally administered C5aR inhibitor.

Exemplary treatments/therapies that may be used in combination with the antibody molecules or compositions described herein to treat or prevent other disorders are also described in the "methods of treating or preventing disorders" section herein.

Diagnostic method

In some aspects, the present disclosure provides diagnostic methods for detecting the presence of APRIL in vitro (e.g., in a biological sample, such as a biopsy or blood sample) or in vivo (e.g., imaged in a subject). The method comprises the following steps: (i) Contacting a sample with, or administering to a subject, an antibody molecule described herein; (optionally) (ii) contacting a reference sample, e.g., a control sample (e.g., a control biological sample, e.g., a biopsy or blood sample) or a control subject, with an antibody molecule described herein; and (iii) detecting complex formation between the antibody molecule and APRIL in the sample or subject or the control sample or subject, wherein a change (e.g., a statistically significant change) in complex formation in the sample or subject relative to the control sample or subject is indicative of the presence of APRIL in the sample. The antibody molecule may be directly or indirectly labeled with a detectable substance to facilitate detection of bound or unbound antibody. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, and radioactive materials as described above and in more detail below.

The term "sample" refers to a sample for detecting a polypeptide (e.g., APRIL) or a nucleic acid encoding the polypeptide, including, but not limited to, a cell lysate, a protein or cell membrane extract, a bodily fluid such as blood, or a tissue sample (e.g., a biopsy).

Complex formation between an antibody molecule and APRIL can be detected by measuring or observing the antibody molecule that binds to APRIL or the antibody molecule that does not bind. Any suitable detection method may be used, conventional detection methods including enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA) or tissue immunohistochemistry. In addition to labeling antibody molecules, the presence of APRIL may be determined by competitive immunoassays, using standards labeled with a detectable substance and unlabeled antibody molecules. In this test, a biological sample, a labeled standard and an antibody molecule are combined and the amount of labeled standard bound to the 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 are useful for diagnosing diseases treatable or preventable by the antibody molecules described herein. The detection or diagnostic methods described herein may be combined with other methods described herein to treat or prevent the disorders described herein.

Other aspects and embodiments

In one aspect, the disclosure features a composition (e.g., a pharmaceutical composition) comprising an antibody molecule as described herein. In one embodiment, the composition further comprises a pharmaceutically acceptable carrier.

In one aspect, the disclosure features nucleic acid molecules encoding the heavy chain variable region (VH), the light chain variable region (VL), or both of the antibody molecules described herein. In one embodiment, the nucleic acid molecule encodes the Heavy Chain (HC), the Light Chain (LC), or both of the antibody molecules described herein. In one aspect, the disclosure features, among other things, a vector comprising a nucleic acid molecule described herein. In one aspect, the disclosure features a cell (e.g., an isolated cell) comprising a nucleic acid molecule described herein or a vector described herein.

In one aspect, the disclosure features a kit comprising an antibody molecule described herein and instructions for use of the antibody molecule.

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

In one aspect, the disclosure features a method of producing an anti-APRIL antibody molecule, the method comprising culturing a cell described herein under conditions that allow 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 features a method of treating IgA nephropathy, the method comprising administering to a subject 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 to the subject intravenously.

In one embodiment, the antibody molecule is administered to a subject at the following doses: 0.1mg/kg to 50mg/kg, for example, 0.2mg/kg to 25mg/kg, 0.5mg/kg to 10mg/kg, 0.5mg/kg to 5mg/kg, 0.5mg/kg to 3mg/kg, 0.5mg/kg to 2.5mg/kg, 0.5mg/kg to 2mg/kg, 0.5mg/kg to 1.5mg/kg, 0.5mg/kg to 1mg/kg, 1mg/kg to 1.5mg/kg, 1mg/kg to 2mg/kg, 1mg/kg to 2.5mg/kg, 1mg/kg to 3mg/kg, 1mg/kg to 2.5mg/kg, or 1mg/kg to 5mg/kg.

In one embodiment, the antibody molecule is administered to the subject at the following fixed doses: 10mg to 1000mg, for example, 10mg to 500mg, 10mg to 250mg, 10mg to 150mg, 10mg to 100mg, 10mg to 50mg, 250mg to 500mg, 150mg to 500mg, 100mg to 500mg, 50mg to 500mg, 25mg to 250mg, 50mg to 150mg, 50mg to 100mg, 100mg to 150mg, 100mg to 200mg, or 150mg to 250mg.

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 or once every three months.

In one embodiment, administration of the antibody molecule reduces the level of IgA in peripheral tissue, e.g., in serum, mucosal tissue, bone marrow, or any combination thereof.

In one embodiment, administration of the antibody molecule reduces the level of IgA 1. In one embodiment, administration of the antibody molecule reduces IgA1 levels in polymerized form (pIgA 1). In one embodiment, administration of the antibody molecule reduces IgA1 levels with O-linked glycosylation variations (e.g., aberrant or reduced galactose composition in the CH1 hinge region).

In one embodiment, the method further comprises determining the level of IgA in a peripheral tissue sample from the subject, e.g., selected from serum, mucosal tissue, or bone marrow.

In one embodiment, the method further comprises administering to the subject a second therapy for IgA nephropathy. In one embodiment, the second therapy is selected from an Angiotensin Converting Enzyme (ACE) inhibitor, an Angiotensin Receptor Blocker (ARB), omega-3 fatty acids, immunosuppressives (e.g., corticosteroids, e.g., prednisone), statins, mycophenolate esters, or any combination thereof.

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

In one embodiment, the cancer is a hematologic cancer. In one embodiment, the hematological cancer is selected from the group consisting of B-cell non-Hodgkin's lymphoma, chronic Lymphocytic Leukemia (CLL), hodgkin's lymphoma, multiple myeloma,Macroglobulinemia or lymphoplasmacytoid lymphoma. In one embodiment, the cancer is multiple myeloma.

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

In one embodiment, the vasculitis is renal vasculitis. In one embodiment, the vasculitis is IgA-related vasculitis (e.g., allergic purpura) or post-streptococcal glomerulonephritis.

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

In one embodiment, the autoimmune disease is selected from rheumatoid arthritis, systemic lupus erythematosus, linear IgA bullous disease (e.g., linear immunoglobulin a (IgA) skin disease), or IgA-mediated acquired bullous Epidermolysis (EBA).

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

In one aspect, the disclosure features a method of treating celiac disease, the method comprising administering to a subject 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 features a method of treating alcoholic cirrhosis, the method comprising administering to a subject 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 invention features a method of reducing IgA levels in a cell or a subject, the method comprising contacting the cell or subject, or administering to a subject in need thereof, an effective amount of an antibody molecule described herein or a composition described herein, thereby reducing IgA levels.

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 every three months.

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

In another aspect, the disclosure features an antibody molecule described herein or a composition described herein for use in treating a disorder described herein.

In one aspect, the disclosure features a method of detecting an APRIL molecule, the method comprising contacting a cell or a subject from the subject with an antibody molecule described herein, thereby detecting the APRIL molecule.

In one embodiment, the antibody molecule is conjugated 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.

Examples

Example 1: effect of anti-APRIL antibody molecules on serum aberrant glycosylated IgA levels

In this study, a dose-dependent decrease in serum aberrant glycosylated IgA (a-g IgA) levels from baseline levels was observed following administration of exemplary anti-APRIL antibody molecules mAb 2419-1406, and a timely dose response at nadir was generally observed.

Results

Following antibody administration, a dose-dependent decrease in serum a-g IgA at the time point level over baseline was observed. The maximum average (median) percentage of serum a-g IgA ranged from-24.35% (-28.13%) for the 0.5mg/kg group (corresponding to 3.554[2.730] μg/mL) to-71.61% (-68.94%) for the 12.0mg/kg group (corresponding to 1.920[1.750] μg/mL) observed), and the dose response generally occurred at the nadir in time, which occurred at week 4 for the 0.5mg/kg group and at week 12 for the 12.0mg/kg group (Table 10).

Inhibition of serum a-g IgA levels was reversible with timely dose response during follow-up to recovery: the mean (median) percent change at 16 weeks post-dose for the 0.5, 2.0, 6.0 and 12.0mg/kg groups were-18.16% (-21.43%), -15.41% (-8.25%), -9.93% (-21.21%) and-50.05% (-45.65%) (table 10). In general, the trends of japanese and non-japanese subjects are generally similar to those of the whole subject (fig. 1).

Table 10. Aberrant glycosylated immunoglobulin a: summary by treatment-any race (pharmacodynamic population)

Max = Max; med = median; min = minimum; n=the number of objects in the PD group; n=the number of objects evaluated; PD = pharmacodynamics; SD = standard deviation

[1] All subjects receiving placebo were received in groups 1-4.

[2] All subjects receiving placebo were received in group 5.

[3] % change: percent change from baseline.

Analysis

In data from a single, increasing dose study of exemplary antibody molecules of healthy participants, the antibody molecules reduced serum levels of IgA and abnormally glycosylated IgA1 (a-g IgA 1). During the course of the study KM55[ rat anti (a-g IgA 1) was used]A coated plate with a bound standard and subsequently a sample detected with anti-human IgA, the aberrant glycosylated IgA being measured by a validated ELISA method ₁ 。

At baseline, the a-g IgA levels of each group ranged from 5.4-7.0 μg/mL (Table 11). In contrast, baseline total IgA levels were 2076-2866 μg/mL. Thus, serum a-g IgA in healthy individuals is about 0.19-0.27% of total serum IgA at baseline.

Following antibody dosing in the study, a dose-dependent decrease in serum a-g IgA1 at the time point level over baseline was observed. At the peak a-g IgA nadir, the ratio of serum a-g IgA to total IgA at the corresponding time point ranges from 0.17% to 0.23%.

These data indicate that a-g IgA represents approximately 0.19% to 0.27% of total IgA at baseline, and that the ratio of a-g IgA to total IgA ranges from 0.17% to 0.23% at the nadir of a-g IgA, with 2149-1406 significantly decreasing the ratio of total IgA and a-g IgA in healthy volunteers, but without significantly altering the ratio of abnormally glycosylated IgA to total IgA.

TABLE 11 serum IgA, a-g IgA, and a-g IgA to Total IgA ratio changes with respect to time

Example 2: study to evaluate pharmacokinetics, pharmacodynamics, safety and tolerability of subcutaneous anti-APRIL antibodies

This period of time, a non-blind single increment single dose (SAD) study assessed the Pharmacokinetics (PK), safety and tolerability, and Pharmacokinetics (PD) of exemplary anti-APRIL antibody molecule mAb 2419-1406 following Subcutaneous (SC) administration in healthy non-Japanese humans 18-55 years old and Japanese male and female participants. These results can provide information for the design and dose selection of other studies and provide data related to IgAN treatment.

Inclusion criteria:

healthy participants in this study were selected from 18-55 year old men and women based on pre-study medical evaluations (medical history, physical examination, vital signs, 12-lead Electrocardiogram (ECG) and clinical laboratory evaluations). The participants had to meet the following criteria at the time of the initial screening: white blood cells (3000-12000/mm) ³ ) Platelet [ ], platelet ]>150000/mm ³ ) Hemoglobin (Male)>13gm/dL, female>11 gm/dL) and the glomerular filtration rate was estimated>80mL/min/1.73m ² ) Serum creatinine<1.25×upper limit of normal (ULN)), glucose (after 8 hours of fasting)<115 mg/dL), serum IgG (18-year-old participants ² Between them.

Dosage is as follows:

in group 1, exemplary antibody molecules were subcutaneously injected (SC) at a starting dose of 200 mg. The doses for groups 2 and 3 may be given as one or two SC injections. The dose of group 2 can be adjusted according to the data of group 1, the dose of group 3 can be adjusted according to the data of groups 1 and 2, and the total dose does not exceed 800mg. The highest potential single dose was 800mg SC (in alternative group 3), approximately equivalent to 9.1mg/kg based on 70kg body weight and 80% bioavailability.

The initial dose was chosen taking into account antibody targets and mechanisms of action, in vitro/in vivo toxicology data, no observed adverse reaction levels (NOAEL) observed in cynomolgus toxicology studies, and data from previous first use of exemplary antibody molecules in human studies.

Table 12 summarizes the exemplary dose levels for each group.

Table 12 exemplary dose levels for each group

Group of	Treatment of
		Group 1	200mg mAb (1 mL injection)
Group 2	400mg mAb (2 mL injection)
		Group 3	No more than 800mg mAb

The doses of groups 2 and 3 can be administered as 1 or 2 SC injections with a total dose of no more than 800mg mAb. The potential dose of 400mg mAb 2419-1406 given for the SC of group 2 may be further adjusted according to the data of group 1, while the decision of group 3 may be made according to the data of groups 1 and 2. The dosage may be selected so that it does not exceed the maximum allowable dose of 800mg. The doses of groups 2 and 3 can be administered by 1 or 2 SC injections.

Study design:

the study was performed in 3 sequential dosing groups. On day 1, a single dose of an exemplary antibody molecule was given SC in the morning about 30 minutes after a light meal. For the participants of groups 1, 2, the participants were initially dosed and monitored for potential unexpected Adverse Events (AEs) for 24 hours. After a successful observation period, the remaining participants of group I were then dosed. The dose level of group 2 participants can be modified based on the data of the group 1 study. Group 3 is the best group from which other dose levels can be assessed. The dose level for group 3 may be determined based on the data obtained for groups 1 and 2. Study intervention for each group in this study is shown in table 13.

Table 13: research intervention identification

Pharmacokinetic sampling starts on day 1 until the last follow-up on day 112 to collect the sample. Pharmacodynamic samples (total IgA, igG and IgM), APRIL, a-gIgA, anti-drug antibodies (ADA), secretory immunoglobulin A (sIgA) and saliva IgA were also collected during the study.

During the course of the study, participants were monitored to detect AE and SAE, and appropriate tracking was performed to ensure resolution of AE. The following conditions may lead to study intervention disruption and participant disruption/exit: AE of any severe intensity and related causality or SAE of any related causality; symptomatic hypotension (systolic blood pressure)<85mmHg and/or 20mmHg reduction in systolic pressure, based on 3 systolic pressure measurements), tachycardia (heart rate>120 times/min for more than 30 minutes or impaired consciousness), ALT not less than 3 XULN, AST not less than 3 XULN, serum creatinine>1.5 XULN, hemoglobin concentration decreases from baseline>3g/dL, white blood cell count<1500/mm ³ And/or platelets<50000/mm ³ 。

Sample collection:

about 5ml of whole blood samples were collected at each time point (last follow-up from day 1 to day 112), and serum concentrations of exemplary antibody molecules were measured for pharmacokinetic studies. Pharmacodynamic samples (total immunoglobulin IgA, igG and IgM), APRIL, abnormally glycosylated immunoglobulin A (a-g IgA), anti-drug antibodies (ADA), secretory immunoglobulin A (sIgA) and saliva IgA were also collected during the course of the study. Saliva IgG was collected at each time point and saliva IgG levels were determined. In particular, about 3.5mL of whole blood samples were collected for Ig levels and about 5mL of whole blood samples were collected for APRIL, a-g IgA, and sIgA at different time points. To assess the effect of exemplary antibody molecules on PD parameters, serum Ig levels (total IgA, igG and IgM) were assessed. Serum was also evaluated for APRIL, a-g IgA and sIgA. Saliva IgA was also evaluated in saliva samples taken at different time points.

Endpoint parameters measured:

for Pharmacokinetics (PK), the following parameters were measured: c (C) _max (major) AUC _0-in f (primary), AUC _0-last (mainly), C _Finally (minor), t _max (minor), T _Finally (minor), t ₁ / ₂ (minor) AUC ₀ - _28d (minor) AUC ₀ - _112d (minor),% AUC _ex (minor), V _d/F (minor), and CL/F (minor).

For safety, the following parameters were measured: physical examination, vital signs (blood pressure, pulse, respiratory rate, and oral temperature), clinical laboratory examinations (hematology, clinical chemistry, urinalysis, and anti-drug antibody response), injection site evaluations, pain visual analog scales, and Adverse Events (AEs).

For Pharmacodynamics (PD), the following parameters were measured: changes in total serum IgG, igA, and IgM concentrations from baseline and recovery time; serum a-g IgA level changes; plasma or serum APRIL level changes; serum sIgA level changes; saliva IgA level changes; PK and PD/exploratory endpoint.

The following additional parameters were also measured: ADA level characterization; the effect of ADA status on mAb 2419-1406PK parameters was evaluated.

% AUCex = extrapolated AUC _0-inf Is a percentage of (2); AUC = area under concentration-time curve; AUC (AUC) _0-28d Concentration-area under curve from time 0 to day 28; AUC (AUC) _0-112d AUC from time 0 to day 112; AUC (AUC) _{0 inf} AUC extrapolated from time 0 to infinite time; AUC (AUC) _0-last AUC from time 0 to last quantifiable concentration; CL/F = apparent clearance; c (C) _Finally Time of last serum concentration; t is t _1/2 Apparent terminal elimination half-life; sIgA = secretory immunoglobulin a; t is t _Finally Time of last quantifiable observed concentration; t is t _max Time of maximum serum concentration; VAS = visual analog scale; and Vd/f=apparent distribution volume.

Analysis:

serum Ig levels (total IgA, igG and IgM) were assessed to assess the effect of exemplary antibody molecules on PD parameters. Serum was also evaluated for APRIL, a-g IgA and sIgA. Statistical analysis was performed on the data collected from the study. Descriptive statistics of continuous variables are summarized by treatment group, including number of participants, arithmetic mean, standard deviation, median, minimum and maximum; descriptive statistics of the classification data are summarized by treatment group frequency of use counts and percentages. Descriptive statistics of PK parameters include observations, arithmetic mean, standard deviation, arithmetic variation in percent (% CV), geometric mean, median, geometric% CV, minimum and maximum. The data grouped by group and overall (all groups) are analyzed separately as deemed appropriate. All security analyses were performed using the security population.

Pharmacokinetic analysis was performed using data assigned to all participants of the PK population. The serum antibody concentrations for each participant are listed. Pooled statistics of serum concentrations of both groups of antibodies were given at dose level; the first group incorporates ethnicity and the second group is stratified by ethnicity for each dose level. Individual and average antibody concentration-time profiles for each dose level were plotted on a linear and logarithmic scale. The PK parameters described in the parameter measurement section were applied to non-Japanese, japanese and all participants at dose level using descriptive statistical methodsSummary. Non-compartmental PK parameters using PhoenixVersion 8.0 or higher. pharmacokinetic/PD modeling can be used to further characterize the data and reported separately.

Pharmacodynamics of total IgA, igG, and IgM, as well as other relevant PD-applicable markers in serum or appropriate matrices (using raw data, baseline data variance, and baseline percentage of variance, as the case may be), are summarized using descriptive statistical methods and plotted as a function of time. Baseline data was used as the last measurement prior to dosing, and if not, screening values were used. Exploratory PK/PD analysis can be performed between study intervention serum concentration and PD assessment if deemed appropriate.

Serum samples were screened for antibody binding to exemplary antibody molecules (ADA) and positive sample titers confirmed were reported. Summary tables of positive or negative for ADA are given, based on treatment (antibody molecule dose) and study days based on safety population. In addition, ADA titers are summarized by treatment and study day. The effect of ADA response on PK parameters was also analyzed.

Clinical laboratory testing

The tests detailed in table 14 were performed.

TABLE 14 clinical laboratory test

Results

The three groups of study designs described in the above schemes were expanded as follows:

the study recruited and dosed 4 consecutive groups of 12 participants (48 total, including 9 japanese blood families). The subject received subcutaneous injections (SC) of mAb 2419-1406 (200 mg/mL liquid). The doses for groups 1 to 4 were 200mg (1 m1 SC injection), 400mg (2 1ml SC injection), 400mg (1 2ml SC injection) and 600mg (1 2ml SC injection+1 1m1 SC injection), respectively. Participants received SC administration of study medication on day 1, discharged on day 2, and followed up on outpatient to day 112. Standard safety assessments and blood sampling of PK and PD were performed periodically.

48 participants were enrolled and given study medication. Groups 1 and 2 have completed study access. Group 3 and queue 4 had completed dosing and are currently being followed. mAb 2419-1406 was well tolerated by SC injection, without serious Adverse Events (AEs) or AEs leading to study discontinuation, nor injection site reactions. Emergency AE (TEAE) occurred in the treatment were mild and all alleviated. The treatment had no clinically relevant effect on laboratory tests, vital signs, electrocardiographic parameters or physical examination. Preliminary PK results showed about 75% bioavailability compared to the data for intravenous mAb 2419-1406. Single SC doses (400 mg or 600 mg) can reduce total IgA by up to about 60% from baseline. This suggests that similar levels and trajectories of IgA inhibition were obtained by intravenous administration of mAb 2419-1406 formulations in the first human study in healthy volunteers (FIG. 5).

In summary, this ongoing Ph1 study shows that, to date, single dose mAb2419-1406 administered by the SC route is safe in healthy adults, well tolerated, shows acceptable bioavailability, and inhibits total IgA by about 60% relative to baseline at doses of 400mg and 600 mg. The final study data might support further clinical development of SC-administered mAb2419-1406 as a candidate treatment drug for IgAN.

Example 3: safety, tolerability, pharmacokinetics and pharmacodynamics of anti-APRIL antibody molecules in healthy volunteers

This example describes a human study to evaluate the safety and tolerability of an exemplary anti-APRIL antibody molecule, mAb2419-1406, in healthy volunteers and to characterize the Pharmacokinetics (PK) and Pharmacodynamics (PD) of the antibody molecule.

Briefly, a phase 1 randomized, double-blind, placebo-controlled, single-escalated dose study of mAb2419-1406 (in the form of humanized IgG 2) was performed in healthy adult male and female volunteers. The study was performed in sequential dosing groups. The first four groups (0.5, 2.0, 6.0 and 12.0mg/kg, respectively) recruited 9 participants (4 Japanese and 5 non-Japanese) who were randomly assigned to mAb2419-1406 or placebo at a ratio of 7:2. In addition, the fifth group included 15 adults who received either 6.0mg/kg mAb2419-1406 or placebo (10:5) at random, followed by a tetanus/diphtheria vaccine challenge after 28 days Sanofebard Co Ltd; the effect of APRIL inhibition on vaccine response is described in the companion abstract). Participants received 2419-1406 intravenous injections on day 1, discharged on day 2, and followed up on the clinic for 16 weeks. Standard safety assessments and blood sampling of PK and PD were performed periodically.

Overall, 51 participants were recruited, randomized and dosed with mAb 2419-1406, of which 47 (92.2%) completed the study. 2419-1406 are well tolerated, without death, without serious Adverse Events (AEs) or AEs resulting in discontinuation of the study. Most treatment-induced AEs (TEAE) were mild; the incidence and severity of TEAE was dose independent. One participant in the 2.0mg/kg group had severe TEAE syncope after blood sampling, and the investigator considered unlikely to be related to study drug. The treatment had no clinically relevant effect on laboratory tests, vital signs, electrocardiographic parameters or physical examination. The PK of mAb 2419-1406 is nonlinear: half-life (t 1/2) increases with increasing dose, whereas drug exposure (AUC) increases more than the dose ratio. Upon administration of mAb 2419-1406, serum immunoglobulins (IgA, a-g IgA1, igG and IgM) were reversibly inhibited in a dose-dependent manner. The average comparison results of immunoglobulin treatments are shown in figure 2. The maximum average percent decrease in the 12.0mg/kg dose compared to baseline occurred at week 12: igA, -57.2% (fig. 2, right panel); a-g IgA1, -71.6% (FIG. 2, left panel); igG, -33.6%; and IgM, -67.2%. These reductions were reversible with timely dose responses to recovery. At week 1, the average free (non-mAb 2419-1406 binding) serum APRIL levels at all mAb 2419-1406 doses dropped to the lower limit of quantitation (50 pg/mL) and also showed timely dose response to recovery. No depletion of the circulating lymphocyte population was observed. There were no significant differences in PK or PD between japanese and non-japanese participants.

In summary, up to 12.0mg/kg of mAb2419-1406 single dose was safe for healthy adults and well tolerated. Single doses of mAb2419-1406 can inhibit serum free APRIL to lower quantitative levels. Serum a-g IgA1 was reduced in parallel with total serum IgA and recovered in a dose-dependent manner after detection of free APRIL in serum.

Example 4: effect of anti-APRIL antibody molecules on immune responses elicited by tetanus and diphtheria toxoid vaccines in healthy volunteers

As shown in example 3, exemplary anti-APRIL antibody molecules mAb2419-1406 were associated with dose-dependent reduction of serum immunoglobulins (IgA, igG, and IgM), which was reversible and had timely dose response to recovery. This example describes a study examining whether mAb2419-1406 inhibits APRIL affecting the response of T cell dependent antibodies to tetanus and diphtheria toxoid vaccination.

Briefly, a phase 1 randomized, double-blind, placebo-controlled, single-escalated dose study of mAb2419-1406 (in the form of humanized IgG 2) was performed in healthy adult male and female volunteers. In one group of the study, participants received 6.0mg/kg mAb2419-1406 or placebo intravenously at a 2:1 ratio and then received a vaccine consisting of tetanus and diphtheria toxoid Sanofebard Inc.) to evaluate the effect of mAb2419-1406 on the ability of the recipient to produce a vaccine-enhancing response. Participants received mAb2419-1406 intravenous on day 1, discharge on day 2, single intramuscular vaccine on day 28, followed by 16 weeks of follow-up on the clinic. Periodic blood sampling and anti-tetanus toxoid and anti-diphtheria toxoid are carried outQuantitative determination of plain IgG, igM and IgA ELISA. Tetanus and diphtheria anti-toxoid IgG titres ≡0.1IU/mL are generally considered protective.

In the vaccinated group, 15 participants were recruited, randomly assigned and dosed with mAb2419-1406, with 14 completed the study and 1 participant receiving mAb2419-1406 was lost prior to vaccination. Both groups (placebo and mAb 2419-1406) showed an increase in tetanus anti-toxoid IgG titer following immunization, with an average 7.9-fold increase in placebo recipient IU/mL and an average 6.4-fold increase in mAb2419-1406 recipient IU/mL on day 42 (fig. 3). Tetanus anti-toxoid IgG titers greater than or equal to 0.1IU/mL are considered protective. In the follow-up after 42 days, tetanus anti-toxoid IgG titers in the mAb2419-1406 groups decreased more rapidly than in the placebo group (consistent with the total IgG decrease associated with mAb2419-1406 dosing), but the tetanus anti-toxoid IgG titers were still above the protection threshold of 0.1IU/mL for all participants throughout the study (fig. 3). Similar trends were observed for diphtheria anti-toxoid IgG titers, with an average 5.5-fold increase in IU/mL for placebo recipients and an average 5.1-fold increase in IU/mL for mAb2419-1406 recipients at day 42 visit (fig. 4). Diphtheria anti-toxoid IgG titers greater than or equal to 0.1IU/mL are considered protective. In the placebo or mAb2419-1406 groups, there was no evidence that tetanus or diphtheria toxoid caused IgM reactions, consistent with the recall nature of vaccination. In one post hoc analysis, existing serum anti-Td IgA titers decreased between day 1 and day 28, consistent with overall inhibition of serum total IgA, and after vaccination, the serum anti-Td IgA titers of both groups of patients increased to similar levels, followed by a faster decrease in mAb2419-1406 recipients.

In conclusion, mAb 2419-1406 treatment did not interfere with the ability of the recipient to produce antigen-specific serum IgG or IgA-enhanced responses to tetanus and diphtheria toxoid vaccination. There was no evidence of tetanus or diphtheria-specific IgM reactions in either placebo or mAb 2419-1406 groups, consistent with recalled vaccination exposure. These data indicate that qualitative T cell dependent antibody responses are retained during the inhibition of APRIL.

Incorporated by reference

All publications, patents, and accession numbers mentioned herein are incorporated herein by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

Equivalent forms

While specific embodiments of the invention have been discussed, the above specification is illustrative only and not limiting. Many variations of the invention will become apparent to those skilled in the art upon review of the specification and appended claims. The full scope of the invention should be determined by reference to the appended claims, along with their full scope of equivalents, and the specification, along with such variations.

Sequence listing

<110> Witerla (VISTERRA, INC.)

<120> antibody molecule against APRIL and use thereof

<130> P2029-7037WO

<140>

<141>

<150> 63/195,527

<151> 2021-06-01

<150> 63/136,950

<151> 2021-01-13

<150> 63/091,002

<151> 2020-10-13

<150> 63/043,558

<151> 2020-06-24

<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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Peptide'

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Tyr Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val

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<212> PRT

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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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<210> 7

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

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Peptide'

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Ser Gly Tyr Tyr Trp Asn

1 5

<210> 8

<211> 16

<212> PRT

<213> artificial sequence

<220>

<221> Source

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Peptide'

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Tyr Ile Ser Tyr Asp Gly Tyr Asn Asn Tyr Asn Pro Ser Leu Lys Asn

1 5 10 15

<210> 9

<211> 120

<212> PRT

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<221> Source

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Polypeptide'

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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

<210> 10

<211> 111

<212> PRT

<213> artificial sequence

<220>

<221> Source

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Polypeptide'

<400> 10

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

85 90 95

Lys Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 11

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 11

Gly Tyr Thr Phe Thr Asp Tyr

1 5

<210> 12

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 12

Tyr Pro Leu Arg Gly Ser

1 5

<210> 13

<211> 11

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 13

His Gly Ala Tyr Tyr Ser Asn Ala Phe Asp Tyr

1 5 10

<210> 14

<211> 15

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 14

Arg Ala Ser Glu Ser Val Asp Asn Asp Gly Ile Arg Phe Met His

1 5 10 15

<210> 15

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 15

Arg Ala Ser Asn Leu Glu Ser

1 5

<210> 16

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 16

Gln Gln Ser Asn Lys Asp Pro Tyr Thr

1 5

<210> 17

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 17

Asp Tyr Thr Ile His

1 5

<210> 18

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Polypeptide'

<400> 19

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

85 90 95

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

<211> 111

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Polypeptide'

<400> 20

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

<210> 21

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 21

Gly Tyr Thr Phe Thr Ser Tyr

1 5

<210> 22

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 22

Tyr Ile Gly Asn Gly Tyr

1 5

<210> 23

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 23

Tyr Tyr Pro Trp Phe Thr Tyr

1 5

<210> 24

<211> 11

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 24

Arg Ala Ser Glu Asn Ile Tyr Ser Tyr Leu Ala

1 5 10

<210> 25

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 25

Asn Ala Lys Thr Leu Ala Glu

1 5

<210> 26

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 26

Gln His His Tyr Asp Thr Pro Phe Thr

1 5

<210> 27

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 27

Ser Tyr Gly Ile Asn

1 5

<210> 28

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 28

Tyr Ile Tyr Ile Gly Asn Gly Tyr Ala Glu Tyr Asn Glu Arg Phe Lys

1 5 10 15

Gly

<210> 29

<211> 116

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Polypeptide'

<400> 29

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

<210> 30

<211> 107

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Polypeptide'

<400> 30

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

<400> 31

000

<210> 32

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 32

Tyr Pro Arg Asp Ser Ser

1 5

<210> 33

<211> 12

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 33

Glu Gly Tyr Asp Tyr Asp Lys Arg Gly Phe Asp Tyr

1 5 10

<210> 34

<211> 15

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 34

Lys Ala Ser Gln Ser Val Ser Phe Ala Gly Thr Asn Leu Met His

1 5 10 15

<210> 35

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 35

Arg Ala Ser Asn Leu Glu Pro

1 5

<210> 36

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 36

Gln Gln Ser Arg Glu Tyr Pro Trp Thr

1 5

<210> 37

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 37

Ser Tyr Asp Val Phe

1 5

<210> 38

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 38

Trp Ile Tyr Pro Arg Asp Ser Ser Thr Lys Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 39

<211> 121

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Polypeptide'

<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

<211> 111

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Polypeptide'

<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

<210> 42

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 42

Asp Pro Glu Thr Gly Gly

1 5

<210> 43

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 43

Trp Asn Asp Gly Asp Tyr

1 5

<210> 44

<211> 16

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 44

Lys Ser Ser Gln Ser Leu Leu Tyr Ser Asn Gly Lys Thr Tyr Leu Asn

1 5 10 15

<210> 45

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 45

Gln Val Ser Lys Leu Asp Pro

1 5

<210> 46

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 46

Leu Gln Gly Thr Tyr Tyr Pro Tyr Thr

1 5

<210> 47

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 47

Asp Tyr Glu Met His

1 5

<210> 48

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 48

Ala Ile Asp Pro Glu Thr Gly Gly Thr Ala Tyr Asn Gln Arg Phe Lys

1 5 10 15

Gly

<210> 49

<211> 115

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Polypeptide'

<400> 49

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

<210> 50

<211> 112

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Polypeptide'

<400> 50

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

<210> 51

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 51

Gly Tyr Ser Phe Thr Gly Tyr

1 5

<210> 52

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 52

Asn Pro Tyr Asn Gly Asp

1 5

<210> 53

<211> 11

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 53

Glu Gly Asp Gly Tyr Tyr Trp Tyr Phe Asp Val

1 5 10

<210> 54

<211> 15

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 54

Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Ile Ser Phe Met Asn

1 5 10 15

<210> 55

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 55

Ala Ala Ser Asn Gln Gly Ser

1 5

<210> 56

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 56

Gln Gln Ser Lys Glu Val Pro Arg Thr

1 5

<210> 57

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 57

Gly Tyr Phe Met Asn

1 5

<210> 58

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 58

Arg Ile Asn Pro Tyr Asn Gly Asp Thr Phe Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 59

<211> 120

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Polypeptide'

<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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 61

Gly Tyr Thr Phe Thr Asp His

1 5

<210> 62

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 62

Asp Pro Asp Thr Gly Asp

1 5

<210> 63

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 63

Trp Thr Gly Gly Asp Tyr

1 5

<210> 64

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 64

Asp His Glu Met His

1 5

<210> 65

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 71

gatgtacagc ttcaggagtc aggacctggc ctcgtgaaac cttctcagtc tctgtctctc 60

acctgctctg tcactggcta ctccatcacc agtggttatt actggaactg gatccggcag 120

tttccaggaa 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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 75

gaggtccagc ttcagcagtc tggagctgag ctggtgaggc ctgggtcctc agtgaagatg 60

tcctgcaaga cttctggata tactttcaca agctacggta taaactgggt gaagcagagg 120

cctggacagg gcctggaatg gattggatat atttatattg 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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 80

gatgttgtga tgacccagac tccactgtct ttgtcggtta ccattggaca accagcctcc 60

atttcttgca agtcaagtca gagcctctta tacagtaatg gaaagacata tttgaattgg 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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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> PRT

<213> Homo sapiens (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> PRT

<213> Homo sapiens (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> PRT

<213> Homo sapiens (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> PRT

<213> Homo sapiens (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> PRT

<213> Homo sapiens (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> PRT

<213> Homo sapiens (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> PRT

<213> mice (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> PRT

<213> mice (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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 93

Gly Phe Ser Leu Thr Ile Tyr

1 5

<210> 94

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 94

Trp Ser Asp Gly Ser

1 5

<210> 95

<211> 10

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 95

Asn Trp Val Asp Gln Ala Trp Phe Ala Tyr

1 5 10

<210> 96

<211> 11

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 96

Arg Ala Ser Lys Asn Ile Tyr Ser Tyr Leu Ala

1 5 10

<210> 97

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 97

Asn Ala Lys Thr Leu Pro Glu

1 5

<210> 98

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 98

Gln His His Tyr Gly Thr Pro Leu Thr

1 5

<210> 99

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 99

Ile Tyr Asp Val His

1 5

<210> 100

<211> 16

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 103

Gly Tyr Ile Phe Thr Asp Tyr

1 5

<210> 104

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 104

Tyr Pro Gly Ser Gly Asn

1 5

<210> 105

<211> 12

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 105

Glu Ser Asn Tyr Val Gly Tyr Tyr Ala Met Asp Tyr

1 5 10

<210> 106

<211> 16

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 107

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 108

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 108

Phe Gln Gly Ser His Val Pro Trp Thr

1 5

<210> 109

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 109

Asp Tyr Thr Ile Asn

1 5

<210> 110

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 113

Gly Tyr Thr Phe Thr Asn Tyr

1 5

<210> 114

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 114

Tyr Pro Gly Gly Ile Gly Gly Gly Tyr

1 5

<210> 115

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 115

Ser Glu Thr Gly Arg Ala Met Asp Tyr

1 5

<210> 116

<211> 11

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 116

Lys Ala Ser Gln Asp Ile Asn Lys Tyr Ile Ala

1 5 10

<210> 117

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 117

Tyr Thr Ser Thr Leu Lys Pro

1 5

<210> 118

<211> 8

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 118

Leu Gln Tyr Asp Asn Leu Asn Thr

1 5

<210> 119

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 119

Asn Tyr Trp Ile Gly

1 5

<210> 120

<211> 20

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 123

Gly Tyr Ser Phe Thr Asp Tyr

1 5

<210> 124

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 124

Asp Pro Ser Asn Gly Gly

1 5

<210> 125

<211> 11

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 125

Arg Asp Asn Tyr Gly Ser Gly Thr Met Asp Tyr

1 5 10

<210> 126

<211> 11

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 126

Lys Ala Ser Gln Asn Val Gly Thr Asp Val Ser

1 5 10

<210> 127

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 127

Trp Ala Ser Asn Arg Phe Thr

1 5

<210> 128

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 128

Glu Gln Tyr Ser Ile Tyr Pro Leu Thr

1 5

<210> 129

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 129

Asp Tyr Asn Ile Tyr

1 5

<210> 130

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 133

Gly Tyr Ser Phe Thr Asp Asp

1 5

<210> 134

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 134

Asp Pro Leu Asn Gly Gly

1 5

<210> 135

<211> 11

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 135

Arg Asp Asn Tyr Ala Thr Gly Thr Met Asp Tyr

1 5 10

<210> 136

<211> 11

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 136

Lys Ala Ser Lys Asn Val Gly Thr Asp Val Ser

1 5 10

<210> 137

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 137

Glu Gln Tyr Ser Ser Tyr Pro Leu Thr

1 5

<210> 138

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 138

Asp Asp Asn Met Tyr

1 5

<210> 139

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 142

Tyr Pro Ile Asn Gly Tyr

1 5

<210> 143

<211> 11

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 143

Asp Ser Asn Tyr Val Gly Trp Tyr Phe Asp Val

1 5 10

<210> 144

<211> 16

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 145

Ser Gln Ser Thr His Val Pro Arg Thr

1 5

<210> 146

<211> 15

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 147

Phe Thr Ser Asp Leu Glu Pro

1 5

<210> 148

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 148

Gln His Ser Arg Glu Leu Pro Tyr Pro

1 5

<210> 149

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 149

Asp Tyr Asn Met Asp

1 5

<210> 150

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 154

Gly Tyr Thr Phe Ala Asp Tyr

1 5

<210> 155

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 155

Phe Pro Gly Ser Gly Ser

1 5

<210> 156

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 156

Gly Asp Ser Gly Arg Ala Met Asp Tyr

1 5

<210> 157

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 157

Tyr Thr Ser Thr Leu Gln Ser

1 5

<210> 158

<211> 8

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 158

Leu Gln Tyr Asp Asn Leu Leu Thr

1 5

<210> 159

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 159

Asp Tyr Tyr Ile Asn

1 5

<210> 160

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 163

Gly Phe Ser Leu Thr Asp Tyr

1 5

<210> 164

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 164

Trp Asn Asp Gly Ser

1 5

<210> 165

<211> 10

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 165

Asn Trp Tyr Gly Gly Tyr Trp Phe Ala Tyr

1 5 10

<210> 166

<211> 11

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 166

Arg Ser Ser Glu Asn Ile Tyr Ser Tyr Leu Ala

1 5 10

<210> 167

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 167

Asn Ala Asn Ala Leu Ala Glu

1 5

<210> 168

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 168

Gln His His Tyr Gly Thr Pro Phe Thr

1 5

<210> 169

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 169

Asp Tyr Asp Val His

1 5

<210> 170

<211> 16

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 173

caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagag cctgtccatc 60

acctgcacag tctctggttt ctcattaacc atctatgatg tacactgggt tcgccagtct 120

ccaggaaagg 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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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 ggatcgggga 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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 177

caggtccagc tgcagcagtc tggagctgag ctggtaaggc ctgggacttc agtgaagatg 60

tcctgcaagg ctgctggata caccttcaca aactactgga taggttgggt 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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 178

gacatccaga tgacacagtc tccatcctca ctgtctgcat ctctgggagg caaagtcacc 60

atcacttgca aggcaagcca agacattaat aagtatatag cttggtacca acacaagcct 120

ggaaaaggtc ctaggctgct 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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 181

gagatccagc tgcagcagtc tggacctgag ctggtgaagc ctggggcgtc agtgaaggta 60

tcctgcaagg cttctggtta ctcattcact gacgacaaca tgtactgggt 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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 188

caggcgcacc tgaaggagtc aggacctggc ctggtggcgc cctcacagag cctgtccatc 60

acctgcacag tctctggttt ctcattaacc gactatgatg tacactgggt tcgccagtct 120

ccaggaaagg 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= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 266

Asp Tyr Ser Phe Thr Gly Tyr

1 5

<210> 267

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 267

His Pro Tyr Tyr Gly Gly

1 5

<210> 268

<211> 10

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 268

Glu Arg Ser Asn Phe His Ala Leu Asp Tyr

1 5 10

<210> 269

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 269

Gly Tyr Asn Met Asn

1 5

<210> 270

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 274

Gln Ala Ser Gln Asp Ile Asn Lys Tyr Leu Ala

1 5 10

<210> 275

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 275

Tyr Thr Ser Thr Leu Glu Thr

1 5

<210> 276

<211> 5

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 276

Asp Tyr Tyr Met Asn

1 5

<210> 277

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 281

Arg Ala Ser Asn Arg Glu Thr

1 5

<210> 282

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 285

Arg Ala Ser Thr Arg Ala Thr

1 5

<210> 286

<211> 111

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 293

Arg Ala Ser Thr Leu Glu Thr

1 5

<210> 294

<211> 120

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 299

caggtacaac tccaggaatc cgggcctggg ctcgtcaaac caagcgaaac actctctctc 60

acctgcaccg tttctgggtt ttctcttact atctatgacg tacattgggt aaggcaacca 120

cccgggaagg ggctggagtg gatcggtgta atctggtcag atggatctac agactacaac 180

ccatccctta aaagcagggt gaccatttct 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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 304

caagttcagt tggtgcaaag cggggcagaa gtgaagaaac ctggtgcttc tgtgaaagtt 60

tcctgcaagg ccagcggcta cacctttact gattacacaa tacactgggt acggcaggca 120

actgggcaag gattggaatg gatggggtgg atatacccat tgcgagggtc tataaactac 180

gcacagaaat ttcaaggtcg agtaacaatg acagccaaca aatcaataag caccgtttat 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= "description of artificial sequence: synthesis

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 tccggaaccg 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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 306

gagatagtta tgactcagtc tcccgccaca ctttcagtaa gtcccggtga acgcgccacc 60

ctgtcctgcc gtgcttccga atcagtggat aatgacggca ttaggttttt gcactggtac 120

caacaaaagc ccggacaggc cccccgcctg ctgatatatc gtgcatcaac acgagcaaca 180

gggatccccg ctcgatttag tggatccgga agcaggaccg aatttacact taccatttcc 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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 307

gaggtccagt tggtccagtc aggagccgaa gtcaagaagc ctggggaaag cctgaaaata 60

agttgcaaag ctagtggata tacatttaca gattatacca ttcattgggt ccggcaaatg 120

ccaggaaaag gcttggagtg gatggggtgg atttatcccc tccgaggctc aataaattat 180

agtcctagtt ttcaggggca ggtaactatt agcgctgata aaagtatttc tacagtttat 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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 308

caggtgcaac ttgttcagtc aggggctgaa gtaaagaagc caggctcatc agtcaaggta 60

tcatgcaaag catctggcta tacatttaca gattacacca ttcactgggt 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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 309

caagttcaac ttgtccaaag tggggctgaa gttaaaaaac ctggatcatc agtcaaggtt 60

tcatgcaaag ccagcggtta cacatttaca gactatacaa tacattgggt tcgacaggct 120

cccgggcaag 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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 310

caagtgcagt tggtccagag tggagcagag gtgaagaagc ctggtgcttc cgtcaaggtg 60

agttgcaagg catctggtta tactttcact gactacacaa ttcattgggt 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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

Polynucleotide'

<400> 313

caagttcagt tggtgcaaag cggggcagaa gtgaagaaac ctggtgcttc tgtgaaagtt 60

tcctgcaagg ccagcggcta cacctttact gattacacaa tacactgggt acggcaggca 120

actgggcaag gattggaatg gatggggtgg atatacccat tgcgagggtc tataaactac 180

gcacagaaat ttcaaggtcg agtaacaatg acagccgaca aatcaataag caccgtttat 240

atggaactct catctctcag gagtgaggat accgccgtgt atttctgcgc acgacacggt 300

gcatattact caaacgcttt cgactattgg ggccagggca cccttgtgac tgttagtagc 360

<210> 314

<211> 15

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 315

Arg Ala Ser Thr Arg Glu Ser

1 5

<210> 316

<211> 111

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

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 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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (1)..(1)

<223 >/substitution= "Lys"

<220>

<221> variant

<222> (2)..(2)

<223 >/substitution= "Ser"

<220>

<221> variant

<222> (4)..(4)

<223 >/substitution= "Gln"

<220>

<221> variant

<222> (14)..(14)

<223 >/substitution= "Leu"

<220>

<221> site

<222> (1)..(15)

<223 >/note = "variant residues given in sequence have no preference" over those in the variant position note "

<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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (4)..(4)

<223 >/substitution= "Thr"

<220>

<221> variant

<222> (5)..(5)

<223 >/substitution= "Arg"

<220>

<221> variant

<222> (6)..(6)

<223 >/substitution= "Ala"

<220>

<221> variant

<222> (7)..(7)

<223 >/substitution= "Thr"

<220>

<221> site

<222> (1)..(7)

<400> 328

Arg Ala Ser Asn Leu Glu Ser

1 5

<210> 329

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (12)..(12)

<223 >/substitution= "Ser" or "Ala"

<220>

<221> variant

<222> (13)..(13)

<223 >/substitution= "Pro" or "Gln"

<220>

<221> variant

<222> (14)..(14)

<223 >/substitution= "Ser"

<220>

<221> variant

<222> (16)..(16)

<223 >/substitution= "Gln"

<220>

<221> variant

<222> (17)..(17)

<223 >/substitution= "Gly"

<220>

<221> site

<222> (1)..(17)

<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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (3)..(3)

<223 >/substitution= "Thr"

<220>

<221> variant

<222> (4)..(4)

<223 >/substitution= "Phe"

<220>

<221> variant

<222> (6)..(6)

<223 >/substitution= ""

<220>

<221> variant

<222> (7)..(7)

<223 >/substitution= "Asp" or "Ser"

<220>

<221> site

<222> (1)..(8)

<400> 330

Gly Tyr Ser Ile Thr Ser Gly Tyr

1 5

<210> 331

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (1)..(1)

<223 >/substitution= "Tyr" or "":

<220>

<221> variant

<222> (2)..(2)

<223 >/substitution= "Pro"

<220>

<221> variant

<222> (3)..(3)

<223 >/substitution= "Leu" or "Arg"

<220>

<221> variant

<222> (4)..(4)

<223 >/substitution= "Asn" or "Arg"

<220>

<221> variant

<222> (5)..(5)

<223 >/substitution= "Ser"

<220>

<221> variant

<222> (6)..(6)

<223 >/substitution= "Asp" or "Ser"

<220>

<221> site

<222> (1)..(6)

<400> 331

Asn Ser Tyr Asp Gly Tyr

1 5

<210> 332

<211> 12

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (1)..(1)

<223 >/substitution= "Glu" or "His"

<220>

<221> variant

<222> (2)..(2)

<223 >/substitution= ""

<220>

<221> variant

<222> (3)..(3)

<223 >/substitution= "Asp" or "Ala"

<220>

<221> variant

<222> (4)..(4)

<223 >/substitution= "Gly" or "Tyr"

<220>

<221> variant

<222> (6)..(6)

<223 >/substitution= "Asp" or "";

<220>

<221> variant

<222> (7)..(7)

<223 >/substitution= "Tyr" or "Ser" or "Lys"

<220>

<221> variant

<222> (8)..(8)

<223 >/substitution= "Asn" or "Arg"

<220>

<221> variant

<222> (9)..(9)

<223 >/substitution= "Ala" or "Gly"

<220>

<221> variant

<222> (11)..(11)

<223 >/substitution= "Asp"

<220>

<221> variant

<222> (12)..(12)

<223 >/substitution= "Tyr"

<220>

<221> site

<222> (1)..(12)

<400> 332

Tyr Gly Tyr Asp Tyr Glu Asp Trp Tyr Phe Gly Val

1 5 10

<210> 333

<211> 15

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (1)..(1)

<223 >/substitution= "Lys"

<220>

<221> variant

<222> (4)..(4)

<223 >/substitution= "Gln"

<220>

<221> variant

<222> (7)..(7)

<223 >/substitution= "Ser"

<220>

<221> variant

<222> (8)..(8)

<223 >/substitution= "Phe" or "Ile"

<220>

<221> variant

<222> (9)..(9)

<223 >/substitution= "Ala" or "Ile" or "Asp"

<220>

<221> variant

<222> (11)..(11)

<223 >/substitution= "Thr"

<220>

<221> variant

<222> (12)..(12)

<223 >/substitution= "Asn" or "Arg"

<220>

<221> variant

<222> (13)..(13)

<223 >/substitution= "Leu" or "Ser"

<220>

<221> variant

<222> (14)..(14)

<223 >/substitution= "Ile"

<220>

<221> variant

<222> (15)..(15)

<223 >/substitution= "His"

<220>

<221> site

<222> (1)..(15)

<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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (1)..(1)

<223 >/substitution= "Arg" or "His"

<220>

<221> variant

<222> (5)..(5)

<223 >/substitution= "Leu"

<220>

<221> variant

<222> (6)..(6)

<223 >/substitution= "Glu"

<220>

<221> variant

<222> (7)..(7)

<223 >/substitution= "Pro" or "Thr"

<220>

<221> site

<222> (1)..(7)

<400> 334

Ala Ala Ser Asn Gln Gly Ser

1 5

<210> 335

<211> 9

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (1)..(1)

<223 >/substitution= "Leu"

<220>

<221> variant

<222> (4)..(4)

<223 >/substitution= "Arg" or "Asn"

<220>

<221> variant

<222> (5)..(5)

<223 >/substitution= "Lys"

<220>

<221> variant

<222> (6)..(6)

<223 >/substitution= "Tyr" or "Ile" or "Asp"

<220>

<221> variant

<222> (8)..(8)

<223 >/substitution= "Trp" or "Tyr"

<220>

<221> site

<222> (1)..(9)

<400> 335

Gln Gln Ser Lys Glu Val Pro Arg Thr

1 5

<210> 336

<211> 6

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (1)..(1)

<223 >/substitution= ""

<220>

<221> variant

<222> (2)..(2)

<223 >/substitution= "Asp" or "Ser"

<220>

<221> variant

<222> (4)..(4)

<223 >/substitution= "Phe" or "Thr" or "Asp"

<220>

<221> variant

<222> (5)..(5)

<223 >/substitution= "Met" or "Ile" or "Val"

<220>

<221> variant

<222> (6)..(6)

<223 >/substitution= "His" or "Phe"

<220>

<221> site

<222> (1)..(6)

<400> 336

Ser Gly Tyr Tyr Trp Asn

1 5

<210> 337

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (1)..(1)

<223 >/substitution= "Arg" or "Trp"

<220>

<221> variant

<222> (3)..(3)

<223 >/substitution= "Tyr" or "":

<220>

<221> variant

<222> (4)..(4)

<223 >/substitution= "Pro"

<220>

<221> variant

<222> (5)..(5)

<223 >/substitution= "Leu" or "Arg"

<220>

<221> variant

<222> (6)..(6)

<223 >/substitution= "Asn" or "Arg"

<220>

<221> variant

<222> (7)..(7)

<223 >/substitution= "Ser"

<220>

<221> variant

<222> (8)..(8)

<223 >/substitution= "Asp" or "Ser"

<220>

<221> variant

<222> (9)..(9)

<223 >/substitution= "Thr" or "Ile"

<220>

<221> variant

<222> (10)..(10)

<223 >/substitution= "Phe" or "Lys"

<220>

<221> variant

<222> (13)..(13)

<223 >/substitution= "Gln" or "Glu"

<220>

<221> variant

<222> (14)..(14)

<223 >/substitution= "Lys"

<220>

<221> variant

<222> (15)..(15)

<223 >/substitution= "Phe"

<220>

<221> variant

<222> (17)..(17)

<223 >/substitution= "Gly" or "Asp"

<220>

<221> site

<222> (1)..(17)

<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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 338

Asp Asp Ser Asp

1

<210> 339

<211> 8

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 339

Val Thr Phe Thr Met Gly Gln Val

1 5

<210> 340

<211> 4

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 340

Met Pro Ser His

1

<210> 341

<211> 4

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<400> 341

Pro Arg Ala Arg

1

<210> 342

<211> 16

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (12)..(12)

<223 >/substitution= "Pro"

<220>

<221> variant

<222> (13)..(13)

<223 >/substitution= "Ser"

<220>

<221> variant

<222> (14)..(14)

<223 >/substitution= "Leu"

<220>

<221> variant

<222> (15)..(15)

<223 >/substitution= "Lys"

<220>

<221> site

<222> (1)..(16)

<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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (4)..(4)

<223 >/substitution= "Met"

<220>

<221> site

<222> (1)..(5)

<400> 343

Asp Tyr Tyr Ile Asn

1 5

<210> 344

<211> 17

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (12)..(12)

<223 >/substitution= "Ala"

<220>

<221> variant

<222> (13)..(13)

<223 >/substitution= "Gln"

<220>

<221> variant

<222> (15)..(15)

<223 >/substitution= "Leu"

<220>

<221> variant

<222> (16)..(16)

<223 >/substitution= "Gln"

<220>

<221> site

<222> (1)..(17)

<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> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (1)..(1)

<223 >/substitution= "Gln"

<220>

<221> site

<222> (1)..(11)

<400> 345

Lys Ala Ser Gln Asp Ile Asn Lys Tyr Ile Ala

1 5 10

<210> 346

<211> 7

<212> PRT

<213> artificial sequence

<220>

<221> Source

<223 >/note= "description of artificial sequence: synthesis

Peptide'

<220>

<221> variant

<222> (6)..(6)

<223 >/substitution= "Glu"

<220>

<221> variant

<222> (7)..(7)

<223 >/substitution= "Thr"

<220>

<221> site

<222> (1)..(7)

<400> 346

Tyr Thr Ser Thr Leu Gln Ser

1 5

Claims

1. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of treating a condition in a human subject,

optionally, wherein the condition is IgA nephropathy.

2. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of reducing the level of a-g IgA in a human subject,

3. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of treating a condition in a human subject,

Optionally, wherein the condition is IgA nephropathy.

4. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of treating a condition in a human subject,

optionally, wherein the condition is IgA nephropathy.

5. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of treating a condition in a human subject,

Optionally wherein the condition is IgA nephropathy,

6. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of treating a condition in a human subject,

Optionally, wherein the antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises three heavy chain complementarity determining regions (HCDRl, HCDR2 and HCDR 3) and VL comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3),

optionally, wherein the condition is IgA nephropathy.

7. An anti-APRIL antibody molecule, or a pharmaceutical composition comprising said anti-APRIL antibody molecule, for use in a method of treating a condition in a human subject,

Optionally wherein the condition is IgA nephropathy,

8. A method of treating a condition, comprising:

optionally wherein the condition is IgA nephropathy,

thereby treating the condition.

9. A method of reducing the level of a-g IgA comprising:

thereby reducing the level of a-g IgA.

10. A method of treating a condition, comprising:

selecting an agent or dose of an anti-APRIL antibody molecule;

Optionally wherein the subject has or is at risk of developing IgA nephropathy,

thereby treating the condition.

11. A method of treating a condition, comprising:

optionally wherein the condition is IgA nephropathy,

thereby treating the condition.

12. A method of treating a condition, comprising:

optionally wherein the condition is IgA nephropathy,

thereby treating the condition.

13. A method of treating a condition, comprising:

optionally wherein the condition is IgA nephropathy,

thereby treating the condition.

14. A method of treating a condition, comprising:

Optionally wherein the condition is IgA nephropathy,

thereby treating the condition.

15. A method of selecting an anti-APRIL antibody molecule for use in treating a disorder, comprising:

optionally wherein the condition is IgA nephropathy,

thereby selecting the antibody molecule.

16. A method of selecting an agent or dose of an anti-APRIL antibody molecule to treat a disorder, comprising:

optionally wherein the condition is IgA nephropathy,

thereby selecting the agent or dose.

17. A method of selecting a human subject to treat a disorder, comprising:

optionally wherein the condition is IgA nephropathy,

thereby selecting an object.

18. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7, or the method of any one of claims 8-17, wherein a-g IgA comprises or is a-g IgA1.

19. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18, or the method of any one of claims 8-18, wherein the level of a-g IgA is reduced by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, for a predetermined period of time, for example, at least 1, 2, 3 or 4 weeks, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months.

20. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-19, or the method of any one of claims 8-19, wherein the level of a-g IgA is reduced by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% about 4 weeks after administration of the antibody molecule.

21. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-20, or the method of any one of claims 8-20, wherein the level of a-g IgA is reduced by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% about 8 weeks after administration of the antibody molecule.

22. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-21, or the method of any one of claims 8-21, wherein the level of a-g IgA is reduced by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% about 12 weeks after administration of the antibody molecule.

23. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-22, or the method of any one of claims 8-22, wherein the level of a-g IgA is reduced by at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% about 16 weeks after administration of the antibody molecule.

24. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-23, or the method of any one of claims 8-23, wherein the level of a-g IgA is reduced by at least 50%.

25. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-24, or the method of any one of claims 8-24, wherein the level of a-g IgA is reduced by at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.

26. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-25, or the method according to any one of claims 8-25, for example, over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 months.

27. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-26, or the method of any one of claims 8-26, wherein the antibody molecule is administered as a repeat agent, e.g., over a period of at least 3, 6, 9, 12, 15, 18, 24, 30, or 36 months, optionally wherein the subject is administered one or more additional doses of the anti-APRIL antibody molecule (e.g., 24 hours, 48 hours, 72 hours, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after the first administration).

28. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-27, or the method according to any one of claims 8-27, wherein the antibody molecule is administered subcutaneously.

29. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-27, or the method according to any one of claims 8-27, wherein the antibody molecule is administered intravenously.

30. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-29, or the method according to any one of claims 8-29, wherein the disorder is an APRIL-related disorder.

31. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-30, or the method of any one of claims 8-30, wherein the disorder is associated with abnormal levels of total IgA.

32. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-31, or the method according to any one of claims 8-31, wherein the disorder is a disorder associated with a-g IgA.

33. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-32, or the method according to any one of claims 8-32, wherein the disorder is IgA nephropathy (IgAN).

34. The antibody molecule or pharmaceutical composition for use of claim 33, or the method of claim 33, wherein the IgAN is familial IgAN.

35. The antibody molecule or pharmaceutical composition for use of claim 33, or the method of claim 33, wherein the IgAN is adult IgAN.

36. The antibody molecule or pharmaceutical composition for use according to claim 33, or the method according to claim 33, wherein IgAN is post-transplant IgAN, pediatric IgAN or crescent IgAN.

37. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-32, or the method according to any one of claims 8-32, wherein the disorder is Chronic Kidney Disease (CKD) or a disorder associated with CKD.

38. The antibody molecule or pharmaceutical composition for use of claim 37, or the method of claim 37, wherein CKD is advanced CKD, e.g., which estimates glomerular filtration rate (eGFR) equal to or greater than about 30 or about 45.

39. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-32, or the method according to any one of claims 8-32, wherein the disorder is allergic purpura (HSP).

40. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-32, or the method according to any one of claims 8-32, wherein the disorder is cutaneous vasculitis or IgA vasculitis.

41. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-32, or the method according to any one of claims 8-32, wherein the disorder is IgA dermatitis, e.g. IgA bullous skin disease.

42. An antibody molecule or pharmaceutical composition for use according to any one of claims 1 to 7 or 18 to 32, or a method according to any one of claims 8 to 32, wherein the disorder isMacroglobulinemia (WM).

43. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-32, or the method according to any one of claims 8-32, wherein the disorder is lupus nephritis.

44. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-43, or the method according to any one of claims 8-43, wherein the subject is a human patient.

45. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-44, or the method of any one of claims 8-44, wherein the subject has or is determined to have a-g IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the a-g IgA level in a reference subject (e.g., a subject not suffering from the disorder, e.g., a healthy or normal subject).

46. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-45, or the method of any one of claims 8-45, wherein the subject has or is determined to have a total IgA level that is at least 1, 1.5, 2, 2.5, 3.5, 4, 4.5, or 5 times higher than the total IgA level in a reference subject (e.g., a subject not suffering from the disorder, e.g., a healthy or normal subject).

47. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-46, or the method according to any one of claims 8-46, wherein the subject has received or is receiving a different therapeutic agent or regimen for treating the disorder.

48. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-46, or the method of any one of claims 8-46, wherein the subject has not received or is not receiving a different therapeutic agent or regimen for treating the disorder.

49. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-6 or 18-43, or the method according to any one of claims 8-13 or 15-43, wherein the subject has received, is receiving or is about to receive a vaccine, e.g. within 1, 2, 3, 4, 5 or 6 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks of administration of the antibody molecule.

50. The antibody molecule or pharmaceutical composition for use of any one of claims 1-6, 18-43 or 49, or the method of any one of claims 8-13, 15-43 or 49, wherein the subject is in need of or is determined to be in need of receiving a vaccine, e.g., within 1, 2, 3, 4, 5 or 6 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks of administration of the antibody molecule.

51. The antibody molecule or pharmaceutical composition for use according to claim 49 or 50, or the method according to claim 49 or 50, wherein the subject receives a vaccine prior to, simultaneously with or after administration of the antibody molecule.

52. The antibody molecule or pharmaceutical composition for use of any one of claims 1-6, 18-43 or 49-51, or the method of any one of claims 8-13, 15-43 or 49-51, wherein administration of the antibody molecule reduces the ability of a subject to produce an effective antigen-specific serum IgG and/or IgA response to a vaccine by no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%.

53. The antibody molecule or pharmaceutical composition for use of any one of claims 1-6, 18-43 or 49-52, or the method of any one of claims 8-13, 15-43 or 49-52, wherein administration of the antibody molecule does not reduce or not significantly reduce the ability of the subject to produce an effective antigen-specific serum IgG and/or IgA response to the vaccine.

54. The antibody molecule or pharmaceutical composition for use of any one of claims 1-6, 18-43 or 49-53, or the method of any one of claims 8-13, 15-43 or 49-53, wherein the subject has or maintains an effective (e.g., protective) antigen-specific serum IgG and/or IgA response to the vaccine following administration of the antibody molecule.

55. The antibody molecule or pharmaceutical composition for use of any one of claims 1-6, 18-43, or 49-54, or the method of any one of claims 8-13, 15-43, or 49-54, wherein the vaccine comprises tetanus toxoid, diphtheria toxoid, or both (e.g.,)。

56. the antibody molecule or pharmaceutical composition for use of claim 55, or the method of claim 55, wherein the subject has or remains effective (e.g., protective) levels of tetanus and/or diphtheria anti-toxoid IgG (e.g., equal to or higher than 0.1IU/mL in blood) after administration of the antibody molecule, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks or longer after administration.

57. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-56, or the method of any one of claims 8-56, wherein the subject has or is determined to have a genomic predisposition locus for the disease (e.g., igA nephropathy).

58. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-57, or the method of any one of claims 8-57, further comprising determining whether the subject has a genomic predisposition locus for the disease (e.g., igA nephropathy).

59. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-58, or the method of any one of claims 8-58, wherein the antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises three heavy chain complementarity determining regions (HCDR 1, HCDR2 and HCDR 3), and VL comprises three light chain complementarity determining regions (LCDR 1, LCDR2 and LCDR 3),

60. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-59, or the method of any one of claims 8-59, wherein the antibody molecule comprises VH and VL, wherein the VH comprises the amino acid sequence of SEQ ID NO:296, and the VL comprises the amino acid sequence SEQ ID NO:286,

Optionally, wherein the antibody molecule is IgG2.

61. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-60, or the method of any one of claims 8-60, wherein the level of a-g IgA is determined in a sample from the subject.

62. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-61, or the method of any one of claims 8-61, further comprising determining the level of a-g IgA in a sample from a subject.

63. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-62, or the method of any one of claims 8-62, further comprising determining the level of total IgA in the sample.

64. The antibody molecule or pharmaceutical composition for use according to any one of claims 1-7 or 18-63, or the method according to any one of claims 8-63, further comprising determining the level of IgM and/or IgG in the sample.

65. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-64, or the method of any one of claims 8-64, further comprising obtaining a sample from a subject.

66. The antibody molecule or pharmaceutical composition for use according to claim 65, or the method according to claim 65, wherein the sample is a blood or serum sample.

67. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-66, or the method of any one of claims 8-66, further comprising administering a second therapeutic agent or mode of treatment to the subject.

68. The antibody molecule or pharmaceutical composition for use of claim 67, or the method of claim 67, wherein the second therapeutic agent or therapeutic modality is a small molecule.

69. The antibody molecule or pharmaceutical composition for use of claim 67, or the method of claim 67, wherein the second therapeutic agent or mode of treatment is an antibody molecule.

70. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-69, or the method of any one of claims 8-69, wherein the anti-APRIL antibody molecule is administered to the subject at a concentration of about 100, 150, 175, 180, 190, 200, 210, 220, 225, 230, 240, 250, or 300 mg/mL.

71. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-70, or the method of any one of claims 8-70, wherein the anti-APRIL antibody molecule is administered to the subject at a concentration of about 200 mg/mL.

72. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-71, or the method of any one of claims 8-71, wherein the anti-APRIL antibody molecule is administered to the subject at about 200, 250, 300, 450, 400, 450, 500, 550, 600, 650, 700, 750, or 800mg of the fixative.

73. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-72, or the method of any one of claims 8-72, wherein the anti-APRIL antibody molecule is administered to the subject in about 200mg of the fixative (e.g., a volume of about 1 mL).

74. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-72, or the method of any one of claims 8-72, wherein the anti-APRIL antibody molecule is administered to the subject in a total volume of about 400mg of the fixing agent (e.g., about 2mL, e.g., 2 administrations in 1mL volume or 1 administration in 2mL volume).

75. The antibody molecule or pharmaceutical composition for use of any one of claims 1-7 or 18-72, or the method of any one of claims 8-72, wherein the anti-APRIL antibody molecule is administered to the subject in a total volume of about 600mg of the fixing agent (e.g., about 3mL, e.g., 1 administration in a volume of 2mL and 1 administration in a volume of 1 mL).