Method of using anti-APRIL (a proliferation-inducing ligand) antibodies to reduce IGA
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 reducing the level of IgA in a cell or subject, the method comprising contacting the cell or subject with 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 reducing the level of IgA.
2. The method of claim 1 , wherein:
(a) the VH comprises the amino acid sequence of SEQ ID NO: 296, 283, 288, 289, 291, 292, 294, or 317, or an amino acid sequence that is at least 85% identical thereto;
(b) the VL comprises the amino acid sequence of SEQ ID NO: 286, or an amino acid sequence that is at least 85% identical thereto; or
(c) both (a) and (b).
3. The method of claim 1 , wherein:
(a) the VH comprises the amino acid sequence of SEQ ID NO: 296;
(b) the VL comprises the amino acid sequence of SEQ ID NO: 286; or
(c) both (a) and (b).
4. The method of claim 1 , wherein the antibody molecule is a synthetic antibody molecule, an isolated antibody molecule, or a humanized antibody molecule.
5. The method of claim 1 , wherein the antibody molecule 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).
6. The method of claim 1 , wherein the antibody molecule comprises a heavy chain constant region of IgG2.
7. The method of claim 1 , wherein the antibody molecule comprises an Fc region.
8. The method of claim 1 , which comprises two VHs and two VLs, or comprises a Fab, F(ab′)2, Fv, or single chain Fv (scFv) fragment.
9. The method of claim 1 , wherein the level of IgA comprises:
(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).
10. The method of claim 1 , wherein the level of IgA comprises the level of aberrantly glycosylated IgA1.
11. The method of claim 1 , wherein the contacting the antibody molecule is contacted with the cell or subject in vivo.
12. 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.
13. 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.
14. The method of claim 1 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 296; and the VL comprises the amino acid sequence of SEQ ID NO: 286.
15. A method of reducing the level of aberrantly glycosylated IgA1 in a subject, the method comprising administering to a subject in need thereof amount of an anti-APRIL antibody molecule,
wherein the antibody molecule comprises a VH comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) and a 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 reducing the level of aberrantly glycosylated IgA1.
16. The method of claim 15 , wherein:
(a) the VH comprises the amino acid sequence of SEQ ID NO: 296, 283, 288, 289, 291, 292, 294, or 317, or an amino acid sequence that is at least 85% identical thereto;
(b) the VL comprises the amino acid sequence of SEQ ID NO: 286, or an amino acid sequence that is at least 85% identical thereto; or
(c) both (a) and (b).
17. The method of claim 15 , wherein:
(a) the VH comprises the amino acid sequence of SEQ ID NO: 296;
(b) the VL comprises the amino acid sequence of SEQ ID NO: 286; or
(c) both (a) and (b).
18. The method of claim 15 , wherein the antibody molecule is a synthetic antibody molecule, an isolated antibody molecule, or a humanized antibody molecule.
19. The method of claim 15 , wherein the antibody molecule 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).
20. The method of claim 15 , wherein the antibody molecule comprises a heavy chain constant region of IgG2.
21. The method of claim 15 , wherein the antibody molecule comprises an Fc region.
22. The method of claim 15 , which comprises two VHs and two VLs, or comprises a Fab, F(ab′)2, Fv, or single chain Fv (scFv) fragment.
23. The method of claim 15 , wherein the antibody molecule is administered to the subject intravenously or subcutaneously.
24. The method of claim 15 , wherein the antibody molecule is administered to the subject at a dose between 0.1 mg/kg and 50 mg/kg.
25. The method of claim 15 , wherein the antibody molecule is administered once a week, twice a week, once every two weeks, or once every four weeks, or once a month, once every two months, or once every three months.
26. The method of claim 15 , further comprising determining the level of aberrant glycosylated IgA1 in the subject.
27. The method of claim 15 , 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.
28. The method of claim 15 , 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.
29. The method of claim 15 , wherein the antibody molecule is administered to the subject at a dose between 0.5 mg/kg and 10 mg/kg.
30. The method of claim 15 , wherein the antibody molecule is administered to the subject at a dose between 0.5 mg/kg and 2 mg/kg.
31. The method of claim 15 , wherein the antibody molecule is administered to the subject at a dose between 1 mg/kg and 3 mg/kg.
32. The method of claim 15 , wherein the antibody molecule is administered to the subject at a dose between 1 mg/kg and 5 mg/kg.
33. The method of claim 15 , wherein the antibody molecule is administered to the subject at a dose between 1 mg/kg and 10 mg/kg.
34. The method of claim 15 , 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.
35. The method of claim 15 , wherein the antibody molecule is administered to the subject intravenously.
36. The method of claim 15 , wherein the antibody molecule is administered to the subject subcutaneously.
37. A method of reducing the level of IgA in a cell or subject, the method comprising contacting the cell or subject with 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,
thereby reducing the level of IgA.
38. The method of claim 37 , wherein the antibody molecule is contacted with the cell or subject in vivo.
39. A method of reducing the level of aberrantly glycosylated IgA1 in a subject, the method comprising administering to a subject in need thereof 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,
thereby reducing the level of aberrantly glycosylated IgA1.
40. The method of claim 39 , wherein the antibody molecule comprises a heavy chain constant region of IgG2.
41. The method of claim 39 , wherein the antibody molecule is administered to the subject intravenously or subcutaneously.
42. The method of claim 39 , wherein the antibody molecule is administered to the subject at a dose between 0.1 mg/kg and 50 mg/kg.
43. The method of claim 39 , wherein the antibody molecule is administered once a week, twice a week, once every two weeks, or once every four weeks, or once a month, once every two months, or once every three months.
44. The method of claim 39 , wherein the antibody molecule is administered to the subject at a dose between 0.5 mg/kg and 10 mg/kg.
45. The method of claim 39 , wherein the antibody molecule is administered to the subject at a dose between 0.5 mg/kg and 2 mg/kg.
46. The method of claim 39 , wherein the antibody molecule is administered to the subject at a dose between 1 mg/kg and 3 mg/kg.
47. The method of claim 39 , wherein the antibody molecule is administered to the subject at a dose between 1 mg/kg and 5 mg/kg.
48. The method of claim 39 , wherein the antibody molecule is administered to the subject at a dose between 1 mg/kg and 10 mg/kg.
49. The method of claim 39 , 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.
50. The method of claim 39 , wherein the antibody molecule is administered to the subject intravenously.
51. The method of claim 39 , wherein the antibody molecule is administered to the subject subcutaneously.