Methods of treating IgA nephropathy by administering an anti-APRIL (a proliferation-inducing ligand) antibody molecule
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. A method of treating IgA nephropathy, the method comprising administering to a subject in need thereof an effective amount of an anti-A PRoliferation Inducing Ligand (APRIL) antibody molecule,
wherein the antibody molecule comprises a heavy chain variable region (VH) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) and a light chain variable region (VL) comprising three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3),
wherein the VH comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 11; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 13; and the VL comprises an LCDR1 comprising the amino acid sequence of SEQ ID NO: 280; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 285, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or
wherein the VH comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 17; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 282, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 13; and the VL comprises an LCDR1 comprising the amino acid sequence of SEQ ID NO: 280; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 285, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16,
thereby treating IgA nephropathy.
2. The method of claim 1 , wherein the VH comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 11; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 13; and the VL comprises an LCDR1 comprising the amino acid sequence of SEQ ID NO: 280; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 285, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
3. The method of claim 1 , wherein the VH comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 17; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 282, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 13; and the VL comprises an LCDR1 comprising the amino acid sequence of SEQ ID NO: 280; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 285, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
4. The method of claim 1 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 296, or an amino acid sequence that is at least 85% identical thereto.
5. The method of claim 1 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 296.
6. The method of claim 1 , wherein the VL comprises the amino acid sequence of SEQ ID NO: 286, or an amino acid sequence that is at least 85% identical thereto.
7. The method of claim 1 , wherein the VL comprises the amino acid sequence of SEQ ID NO: 286.
8. The method of claim 1 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 296, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 286.
9. The method of claim 1 , wherein the VH comprises the amino acid sequence of any of SEQ ID NOs: 19, 283, 288, 289, 291, 292, 294, 296, or 317.
10. The method of claim 9 , wherein the VL comprises the amino acid sequence of SEQ ID NO: 286.
11. The method of claim 1 , wherein the antibody molecule is a synthetic antibody molecule, an isolated antibody molecule, or a humanized antibody molecule.
12. The method of claim 1 , wherein the antibody molecule comprises a heavy chain constant region of IgG1, IgG2, IgG3, or IgG4.
13. The method of claim 1 , wherein the antibody molecule comprises a heavy chain constant region of IgG2.
14. The method of claim 1 , wherein the antibody molecule comprises a light chain constant region of kappa or lambda light chain.
15. The method of claim 1 , wherein the antibody molecule comprises an Fc region.
16. The method of claim 1 , wherein the antibody molecule comprises:
(i) a Fab, F(ab′)2, Fv, or single chain Fv (scFv) fragment; or
(ii) two VHs and two VLs.
17. The method of claim 1 , wherein the VH is encoded by a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 313.
18. The method of claim 1 , wherein the VL is encoded by a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 306.
19. The method of claim 1 , wherein the antibody molecule is administered to the subject
(i) intravenously or subcutaneously;
(ii) at a dose between 0.1 mg/kg and 50 mg/kg; and/or
(iii) once a week, twice a week, once every two weeks, or once every four weeks.
20. The method of claim 1 , wherein administration of the antibody molecule reduces (a) the level of IgA in a peripheral tissue chosen from serum, mucosal tissue, or bone marrow; (b) the level of a variant of IgA chosen from IgA1, IgA1 in polymeric form (pIgA1), or IgA1 with an O-linked glycosylation variant; or (c) both (a) and (b).
21. The method of claim 1 , further comprising:
(i) determining the level of IgA in a peripheral tissue sample, wherein the peripheral tissue is serum, mucosal tissue, or bone marrow; and/or
(ii) administering to the subject a second therapy for IgA nephropathy.
22. The method of claim 21 , wherein the second therapy is chosen from an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), omega-3 fatty acids, an immunosuppressant, a statin, mycophenolate mofetil, or any combination thereof.
23. The method of claim 1 , wherein the antibody molecule is administered to the subject at a dose between 0.5 mg/kg and 10 mg/kg.
24. The method of claim 1 , wherein the antibody molecule is administered to the subject at a dose of 1 mg/kg, 2 mg/kg, 4 mg/kg, or 8 mg/kg.
25. The method of claim 1 , wherein the antibody molecule is administered to the subject once a month, once every two months, or once every three months.
26. The method of claim 1 , wherein the antibody molecule is administered to the subject intravenously.
27. The method of claim 1 , wherein the antibody molecule is administered to the subject subcutaneously.
28. The method of claim 1 , wherein the antibody molecule is administered to the subject at a dose between 0.5 mg/kg and 2 mg/kg.
29. The method of claim 1 , wherein the antibody molecule is administered to the subject at a dose between 1 mg/kg and 3 mg/kg.
30. The method of claim 1 , wherein the antibody molecule is administered to the subject at a dose between 1 mg/kg and 5 mg/kg.
31. The method of claim 1 , wherein the antibody molecule is administered to the subject at a dose between 1 mg/kg and 10 mg/kg.
32. 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,
wherein the antibody molecule comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 296, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 286.
33. The method of claim 32 , wherein the antibody molecule comprises a heavy chain constant region of IgG2.
34. The method of claim 32 , wherein the antibody molecule is administered intravenously or subcutaneously.
35. The method of claim 32 , wherein the antibody molecule is administered to the subject at a dose between 0.1 mg/kg and 50 mg/kg.
36. The method of claim 32 , wherein the antibody molecule is administered to the subject once a month, once every two months, or once every three months.
37. The method of claim 32 , wherein the antibody molecule is administered to the subject at a dose between 1 mg/kg and 10 mg/kg.
38. The method of claim 32 , wherein the antibody molecule is administered to the subject at a dose of 1 mg/kg, 2 mg/kg, 4 mg/kg, or 8 mg/kg.