Anti-complement C1s antibodies and methods of inhibiting complement C1s activity

• US 9,512,233 B2
• Filed: 05/11/2015
• Issued: 12/06/2016
• Est. Priority Date: 10/25/2012
• Status: Active Grant

• Current Assignee: Bioverativ USA Inc. (Sanofi )
• Original Assignee: True North Therapeutics, Inc. (Sanofi )
• Inventors: Van Vlasselaer, Peter, Parry, Graham, Stagliano, Nancy E., Panicker, Sandip
• Primary Examiner(s): Gambel, Phillip
• Application Number:
  US14/709,275
• Publication Number:
  US 20150259437A1
• Time in Patent Office: 575 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/14 Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/30 characterized by aspects of specificity or valency
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/64 : comprising a combination of variable region and constant region components
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C12Y 304/21042 : Complement subcomponent C1s (3.4.21.42)

Abstract

The present disclosure provides antibodies that bind complement C1s protein; and nucleic acid molecules that encode such antibodies. In some embodiments, such anti-complement C1s antibodies inhibit proteolytic activity of C1s. The present disclosure also provides compositions comprising such antibodies, and methods to produce and use such antibodies, nucleic acid molecules, and compositions.

Claims

1. A method of inhibiting complement C1s activity in an individual, the method comprising administering to the individual an effective amount of an antibody that:

i) selectively binds active form of complement component C1s compared to inactive C1s; and

ii) inhibits complement C1s activity by at least 60% in a protease assay.

2. The method of claim 1, wherein the individual is a human.

3. The method of claim 1, wherein the antibody is administered subcutaneously.

4. The method of claim 1, wherein the antibody is administered intravenously.

5. The method of claim 1, wherein the antibody is administered intramuscularly.

6. The method of claim 1, wherein the antibody is administered once a month.

7. The method of claim 1, wherein the antibody comprises VH complementarity-determining regions (CDRs) present in SEQ ID NO:

8, SEQ ID NO;

16, SEQ ID NO;

32, SEQ ID NO;

40, or SEQ ID NO;

88.

8. The method of claim 1, wherein the antibody comprises VH and VL complementarity-determining regions (CDRs) present in:

a) VL complementarity-determining regions (CDRs) present in SEQ ID NO;

7 and VH CDRs present in SEQ ID NO;

8;

b) VL CDRs present in SEQ ID NO;

15 and VH CDRs present in SEQ ID NO;

16;

e) VL CDRs present in SEQ ID NO;

31 and VH CDRs present in SEQ ID NO;

32;

f) VL CDRs present in SEQ ID NO;

39 and VH CDRs present in SEQ ID NO;

40;

or

j) VL CDRs present in SEQ ID NO;

87 and VH CDRs present in SEQ ID NO;

88.

9. The method of claim 1, wherein the antibody binds active form of C1s with a K_D of no more than 2 nM.

10. The method of claim 1, wherein the antibody is selected from the group consisting of a Fab fragment, a F(ab′

)₂ fragment, a scFv, and an Fv.

11. The method of claim 1, wherein the antibody comprises a heavy chain constant region of the isotype IgG1, IgG2, IgG3, or IgG4.

12. The method of claim 1, wherein the antibody is humanized.

13. The method of claim 12, wherein the antibody comprises a humanized VH framework.

14. The method of claim 12, wherein the antibody comprises a humanized VL framework.

26. The method of claim 1, wherein the antibody comprises VL complementarity-determining regions (CDRs) present in SEQ ID NO:

7 and VH CDRs present in SEQ ID NO;

8.

27. The method of claim 1, wherein the antibody comprises VL CDRs present in SEQ ID NO:

15 and VH CDRs present in SEQ ID NO;

16.

28. The method of claim 1, wherein the antibody comprises VL CDRs present in SEQ ID NO:

31 and VH CDRs present in SEQ ID NO;

32.

29. The method of claim 1, wherein the antibody comprises VL CDRs present in SEQ ID NO:

39 and VH CDRs present in SEQ ID NO;

40.

30. The method of claim 1, wherein the antibody comprises VL CDRs present in SEQ ID NO:

87 and VH CDRs present in SEQ ID NO;

88.

31. The method of claim 1, wherein the antibody inhibits complement C1s activity by at least 75% in a protease assay.

32. The method of claim 1, wherein the antibody inhibits complement C1s activity by at least 85% in a protease assay.

33. The method of claim 1, wherein the antibody inhibits complement C1s activity by at least 95% in a protease assay.

15. A humanized antibody that inhibits complement C1s activity, wherein the humanized antibody selectively binds active form of complement component C1s compared to inactive C1s and wherein the humanized antibody inhibits complement C1s activity by at least 60% in a protease assay.

16. The humanized antibody of claim 15, wherein the antibody comprises VH complementarity-determining regions (CDRs) present in SEQ ID NO:

8, SEQ ID NO;

16, SEQ ID NO;

32, SEQ ID NO;

40, or SEQ ID NO;

88.

17. The humanized antibody of claim 15, wherein the antibody comprises:

a) VL complementarity-determining regions (CDRs) present in SEQ ID NO;

7 and VH CDRs present in SEQ ID NO;

8;

b) VL CDRs present in SEQ ID NO;

15 and VH CDRs present in SEQ ID NO;

16;

e) VL CDRs present in SEQ ID NO;

31 and VH CDRs present in SEQ ID NO;

32;

f) VL CDRs present in SEQ ID NO;

39 and VH CDRs present in SEQ ID NO;

40;

or

j) VL CDRs present in SEQ ID NO;

87 and VH CDRs present in SEQ ID NO;

88.

18. The humanized antibody of claim 15, wherein the antibody binds active form of C1s with a K_D of no more than 2 nM.

19. The humanized antibody of claim 15, wherein the humanized antibody is selected from the group consisting of a Fab fragment, a F(ab′

)₂ fragment, a scFv, and an Fv.

20. The humanized antibody of claim 15, wherein the humanized antibody comprises a heavy chain constant region of the isotype IgG1, IgG2, IgG3, or IgG4.

21. The humanized antibody of claim 15, wherein the humanized antibody inhibits complement C1s activity by at least 65% in a protease assay.

22. The humanized antibody of claim 15, wherein the antibody comprises a humanized VH framework.

23. The humanized antibody of claim 15, wherein the antibody comprises a humanized VL framework.

24. A composition comprising:

a) the humanized antibody of claim 15; and

b) a pharmaceutically acceptable excipient.

25. The composition of claim 24, 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.

34. The humanized antibody of claim 15, wherein the antibody comprises VL complementarity-determining regions (CDRs) present in SEQ ID NO:

7 and VH CDRs present in SEQ ID NO;

8.

35. The humanized antibody of claim 15, wherein the antibody comprises VL CDRs present in SEQ ID NO:

15 and VH CDRs present in SEQ ID NO;

16.

36. The humanized antibody of claim 15, wherein the antibody comprises VL CDRs present in SEQ ID NO:

31 and VH CDRs present in SEQ ID NO;

32.

37. The humanized antibody of claim 15, wherein the antibody comprises VL CDRs present in SEQ ID NO:

39 and VH CDRs present in SEQ ID NO;

40.

38. The humanized antibody of claim 15, wherein the antibody comprises VL CDRs present in SEQ ID NO:

87 and VH CDRs present in SEQ ID NO;

88.

39. The humanized antibody of claim 15, wherein the antibody inhibits complement C1s activity by at least 75% in a protease assay.

40. The humanized antibody of claim 15, wherein the antibody inhibits complement C1s activity by at least 85% in a protease assay.

41. The humanized antibody of claim 15, wherein the antibody inhibits complement C1s activity by at least 95% in a protease assay.