Antibody molecules to a proliferation-inducing ligand (april)

Abstract

Antibody molecules that specifically bind to APRIL are disclosed. The antibody molecules can be used to treat, prevent, and/or diagnose disorders, such as IgA nephropathy.

1 . An anti-APRIL antibody molecule, which:
 (i) binds, or substantially binds, to human APRIL;   (ii) binds, or substantially binds, to mouse APRIL;   (iii) inhibits, or substantially inhibits, binding of APRIL to TACI; and   (iv) inhibits, or substantially inhibits, binding of APRIL to BCMA.   
     
     
         2 .- 7 . (canceled) 
     
     
         8 . The antibody molecule of  claim 1 , which comprises one or both of:
 (i) a heavy chain variable region (VH) comprising one, two, or all of the following:   an HCDR1 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 the HCDR1 of a monoclonal antibody chosen from antibodies 3525, 3530, 3833, 3631, 3732, 4540, 4540-063, or 4540-033;   an HCDR2 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 the HCDR2 of the monoclonal antibody; or   an 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 the HCDR3 of the monoclonal antibody, or   (ii) a light chain variable region (VL) comprising one, two, or all of the following:   an 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 with, the amino acid sequence of the LCDR1 of the monoclonal antibody;   an LCDR2 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 the LCDR2 of the monoclonal antibody; or   an LCDR3 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 the LCDR3 of the monoclonal antibody.   
     
     
         9 . (canceled) 
     
     
         10 . An anti-APRIL antibody molecule, which binds, or substantially binds, to 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, or more, residues within a region of human APRIL as defined in any of Tables 3-4 or 7-8. 
     
     
         11 .- 16 . (canceled) 
     
     
         17 . The anti-APRIL antibody molecule of  claim 10 , which:
 (i) binds, or substantially binds, to human APRIL;   (ii) inhibits, or substantially inhibits, binding of APRIL to TACI; and   (iii) inhibits, or substantially inhibits, binding of APRIL to BCMA.   
     
     
         18 .- 24 . (canceled) 
     
     
         25 . An anti-APRIL antibody molecule, comprising one or both of:
 (i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following:   an HCDR1 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 the HCDR1 of a monoclonal antibody chosen from 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, or 4237;   an HCDR2 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 the HCDR2 of the monoclonal antibody; or   an 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 the HCDR3 of the monoclonal antibody, or   (ii) a light chain variable region (VH), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following:   an 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 with, the amino acid sequence of the LCDR1 of the monoclonal antibody;   an LCDR2 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 the LCDR2 of the monoclonal antibody; or   an LCDR3 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 the LCDR3 of the monoclonal antibody.   
     
     
         26 . The antibody molecule of  claim 25 , which comprises one or both of:
 (i) 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 with, the amino acid sequence of the VH of the monoclonal antibody; 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 from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acid sequence of the VL of the monoclonal antibody.   
     
     
         27 . The antibody molecule of  claim 25 , which is a synthetic antibody molecule, an isolated antibody molecule, or a humanized antibody molecule. 
     
     
         28 . The antibody molecule of  claim 25 , which comprises: (a) a heavy chain constant region of IgG1, IgG2, IgG3, or IgG4; (b) a light chain constant region of kappa or lambda light chain; or (c) both (a) and (b). 
     
     
         29 . (canceled) 
     
     
         30 . The antibody molecule of  claim 25 , which comprises two heavy chain variable regions and two light chain variable regions, or is a Fab, F(ab′)2, Fv, Fd, or a single chain Fv fragment (scFv). 
     
     
         31 . An anti-APRIL antibody molecule, comprising:
 (a) one or both of:
 (i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: 
 an HCDR1 comprising an amino acid sequence of G-Y-T-F-T-D-Y (SEQ ID NO: 11); 
 an HCDR2 comprising an amino acid sequence of Y-P-L-R-G-S (SEQ ID NO: 12); or 
 an HCCDR3 comprising an amino acid sequence of H-G-A-Y-Y-S-N-A-F-D-Y (SEQ ID NO: 13), or 
 (ii) a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following: 
 an 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; 
 an LCDR2 comprising an 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 
 an LCDR3 comprising an amino acid sequence of Q-Q-S-N-K-D-P-Y-T (SEQ ID NO: 16), or 
   (b) one or both of:
 (i) a heavy chain variable region (VH), wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable region comprises one, two, or all of the following: 
 an HCDR1 comprising an amino acid sequence of D-Y-T-I-H (SEQ ID NO: 17); 
 an HCDR2 comprising an amino acid sequence of 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, X13 is E, P, or Q; X14 is K or S; X16 is K or Q; and X17 is D or G; or 
 an HCCDR3 comprising an amino acid sequence of H-G-A-Y-Y-S-N-A-F-D-Y (SEQ ID NO: 13), or 
 (ii) a light chain variable region (VL), wherein the light chain variable region comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the light chain variable region comprises one, two, or all of the following: 
 an 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; 
 an LCDR2 comprising an 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 
 an LCDR3 comprising an amino acid sequence of Q-Q-S-N-K-D-P-Y-T (SEQ ID NO: 16). 
   
     
     
         32 . An anti-APRIL antibody molecule, which competes for binding to APRIL with the antibody molecule of  claim 25 . 
     
     
         33 . An anti-APRIL antibody molecule, which binds, or substantially binds, to an epitope that completely or partially overlaps with the epitope of the antibody molecule of  claim 25 . 
     
     
         34 . A pharmaceutical composition comprising the antibody molecule of  claim 25  and a pharmaceutically acceptable carrier. 
     
     
         35 . A nucleic acid molecule encoding a heavy chain variable region (VH), a light chain variable region (VL), or both, of the antibody molecule of  claim 25 . 
     
     
         36 . A vector comprising the nucleic acid molecule of  claim 35 . 
     
     
         37 . A cell comprising the nucleic acid molecule of  claim 35 . 
     
     
         38 . A kit comprising the antibody molecule of  claim 25  and instructions to use of the antibody molecule. 
     
     
         39 . A container comprising the antibody molecule of  claim 25 . 
     
     
         40 . A method of producing an anti-APRIL antibody molecule, the method comprising culturing a cell of  claim 37  under conditions that allow production of an antibody molecule, thereby producing the antibody molecule. 
     
     
         41 . A method of treating IgA nephropathy, the method comprising administering to a subject in need thereof an effective amount of the antibody molecule of  claim 25 , thereby treating IgA nephropathy. 
     
     
         42 .- 48 . (canceled) 
     
     
         49 . A method of treating diabetic nephropathy, the method comprising administering to a subject in need thereof an effective amount of an antibody molecule of  claim 25 , thereby treating diabetic nephropathy. 
     
     
         50 . A method of treating cancer, the method comprising administering to a subject in need thereof an effective amount of the antibody molecule of  claim 25 , thereby treating cancer. 
     
     
         51 .- 52 . (canceled) 
     
     
         53 . A method of treating an immunoproliferative disorder, the method comprising administering to a subject in need thereof an effective amount of the antibody molecule of  claim 25 , thereby treating the immunoproliferative disorder. 
     
     
         54 . (canceled) 
     
     
         55 . A method of treating vasculitis, the method comprising administering to a subject in need thereof an effective amount of the antibody molecule of  claim 25 , thereby treating vasculitis. 
     
     
         56 . (canceled) 
     
     
         57 . A method of treating an autoimmune disorder, the method comprising administering to a subject in need thereof an effective amount of the antibody molecule of  claim 25 , thereby treating an autoimmune disorder. 
     
     
         58 . (canceled) 
     
     
         59 . A method of treating IgA pemphigus, the method comprising administering to a subject in need thereof an effective amount of the antibody molecule of  claim 25 , thereby treating IgA pemphigus. 
     
     
         60 . A method of treating celiac disease, the method comprising administering to a subject in need thereof an effective amount of the antibody molecule of  claim 25 , thereby treating celiac disease. 
     
     
         61 . A method of treating alcoholic cirrhosis, the method comprising administering to a subject in need thereof an effective amount of the antibody molecule of  claim 25 , thereby treating alcoholic cirrhosis. 
     
     
         62 . A method of reducing the level of IgA in a cell or subject, the method comprising contacting the cell or subject the antibody molecule of  claim 25 , thereby reducing the level of IgA. 
     
     
         63 . A method of detecting an APRIL molecule, the method comprising contacting a cell or a sample from a subject with the antibody molecule of  claim 25 , thereby detecting the APRIL molecule.