HUMANIZED ANTI-C1S ANTIBODIES AND METHODS OF USE THEREOF

• US 20180092974A1
• Filed: 04/05/2016
• Published: 04/05/2018
• Est. Priority Date: 04/06/2015
• Status: Active Grant

• Current Assignee: Bioverativ USA Inc.
• Original Assignee: Bioverativ USA Inc.
• Inventors: PANICKER, Sandip, PARRY, Graham
• Granted Patent: US 10,729,767 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/90 characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The present disclosure provides humanized anti-C1s antibodies. The present disclosure provides nucleic acids comprising nucleotide sequences encoding the humanized anti-C1s antibodies; and host cells comprising the nucleic acids. The present disclosure provides compositions comprising the humanized anti-C1s antibodies. The present disclosure provides methods of use of the humanized anti-C1s antibodies.

Claims

1. A humanized antibody that specifically binds complement component C1s, wherein the antibody comprises:

a) a VH region comprising the amino acid sequence;

(Q/E)VQL(V/Q)QSGAE(V/L)KKPGASVK(L/V)SC(T/A)ASGFNIKDDYIHWV(K/R)QAPGQGLEWI GRIDPADGHTKYAPKFQVK(V/A)TITADTST(S/N)TAY(L/M)(E/Q)LSSL(R/T)SEDTAVYYCARY GYGREVFDYWGQGTTVTVSS (SEQ ID NO;

26); and

b) a VL region comprising the amino acid sequence;

2. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

10; and

b) a VL region comprising SEQ ID NO;

20.

3. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

10; and

b) a VL region comprising SEQ ID NO;

22.

4. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

10; and

b) a VL region comprising SEQ ID NO;

24.

5. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

12; and

b) a VL region comprising SEQ ID NO;

20.

6. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

12; and

b) a VL region comprising SEQ ID NO;

22.

7. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

12; and

b) a VL region comprising SEQ ID NO;

24.

8. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

14; and

b) a VL region comprising SEQ ID NO;

20.

9. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

14; and

b) a VL region comprising SEQ ID NO;

22.

10. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

14; and

b) a VL region comprising SEQ ID NO;

24.

11. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

16; and

b) a VL region comprising SEQ ID NO;

20.

12. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

16; and

b) a VL region comprising SEQ ID NO;

22.

13. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

16; and

b) a VL region comprising SEQ ID NO;

24.

14. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

18; and

b) a VL region comprising SEQ ID NO;

20.

15. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

18; and

b) a VL region comprising SEQ ID NO;

22.

16. The humanized antibody of claim 1, comprising:

a) a VH region comprising SEQ ID NO;

18; and

b) a VL region comprising SEQ ID NO;

24.

17. The humanized antibody of any one of claims 1-16, wherein the humanized antibody is selected from the group consisting of a Fab fragment, a F(ab′

)₂ fragment, a scFv, and a Fv.

18. The humanized antibody of any one of claims 1-16, wherein the humanized antibody comprises a heavy chain constant region of the isotype IgG1, IgG2, IgG3, or IgG4.

19. A composition comprising:

a) the humanized antibody of any one of claims 1-18; and

b) a pharmaceutically acceptable excipient.

20. The composition of claim 19, wherein the composition comprises one or more of a tonicity agent, a suspending agent, an emulsifying agent, a stabilizer, a preservative, a lyoprotectant, a surfactant, and a sugar.

21. A container comprising the composition of claim 19 or claim 20.

22. The container of claim 21, wherein the container is sterile.

23. The container of claim 21 or claim 22, wherein the container is a vial, a bottle, or a syringe.

24. A method of reducing the level of a complement component cleavage product in an individual, the method comprising administering to the individual the antibody of any one of claims 1-18, or the composition of claim 19 or 20, in an amount effective to inhibit C1s and to reduce the level of the cleavage product.

25. The method of claim 24, wherein the complement component cleavage product is a C4 cleavage product.

26. The method of claim 25, wherein the complement component cleavage product is a C2 cleavage product.

27. The method of claim 25, wherein the complement component cleavage product is a C3 cleavage product.

28. The method of any one of claims 24-27, wherein the individual is a human.

29. The method of any one of claims 24-28, wherein the administering is intravenous.

30. The method of any one of claims 24-28, wherein the administering is intramuscular.

31. The method of any one of claims 24-28, wherein the administering is intrathecal.

32. The method of any one of claims 24-28, wherein the administering is subcutaneous.

33. The method of any one of claims 24-28, wherein said reducing is effective to treat a complement-mediated disorder.

34. The method of claim 33, wherein the complement-mediated disorder is an alloimmune disorder.

35. The method of claim 33, wherein the complement-mediated disorder is an autoimmune disorder.

36. A method of inhibiting C1s-mediated cleavage of a complement component in an individual, the method comprising administering to the individual the antibody of any one of claims 1-18, or the composition of claim 19 or 20, in an amount effective to inhibit C1s-mediated cleavage of a complement component.

37. A method of treating a complement-mediated disease or disorder in an individual, the method comprising administering to the individual the antibody of any one of claims 1-18, or the composition of claim 19 or 20, in an amount effective to treat the complement-mediated disease or disorder.