Anti-TNF-α antibodies and their uses
View Patent ↗The present disclosure relates to antibodies directed to the tumor necrosis factor alpha (“TNF-α”) and uses of such antibodies, for example, to treat diseases associated with the activity and/or overproduction of TNF-α.
1. A monoclonal antibody or a binding fragment thereof which:
(a) specifically binds to human TNF-α;
(b) competes for binding to human TNF-α with an antibody comprising a V H sequence of SEQ ID NO:2 and a V L sequence of SEQ ID NO:4; and
(c) comprises six CDRs that have one or more amino acid substitutions or combinations of amino acid substitutions as compared to the CDRs of SEQ ID NO:5 (CDR-H1), SEQ ID NO:6 (CDR-H2), SEQ ID NO:7 (CDR-H3), SEQ ID NO:8 (CDR-L1), SEQ ID NO:9 (CDR-L2) and SEQ ID NO:10 (CDR-L3), wherein said one or more amino acid substitutions or combinations of substitutions are selected from:
(1) the CDR-L1 substitutions R7Q; A11S; R7Q+A11S; N8T; N8T+A11S; I6T; A11G; I6T+A11G; Q4G; Q4G+A11S; Q4G+A11G; Q4H; Q4H+A11S; Q4R; Q4R+A11S; G5S+A11S; N8S+A11S; I6T+A11S; and N8T+A11G;
(2) the CDR-L2 substitutions S3K or S3R; T4H, T4Q, T4F, T4W or T4Y; L5R or L5K; and Q6R;
(3) the CDR-H1 substitutions: Y2H and A3G; and
(4) the CDR-H2 substitution: T3N.
2. The monoclonal antibody or binding fragment of claim 1 , which comprises at least one amino acid substitution selected from S3K or S3R in CDR-L2; T4H, T4Q, T4F, T4W or T4Y in CDR-L2; L5R or L5K in CDR-L2; Q6R in CDR-L2; Y2H in CDR-H1; A3G in CDR-H1 and T3N in CDR-H2.
3. The monoclonal antibody or binding fragment of claim 2 , which comprises at least one amino acid substitution selected from T4F, T4W or T4Y in CDR-L2; L5R or L5K in CDR-L2; Q6R in CDR-L2; Y2H in CDR-H1; A3G in CDR-H1 and T3N in CDR-H2.
4. The monoclonal antibody or binding fragment of claim 1 , which comprises at least one amino acid substitution selected from R7Q in CDR-L1; A11S in CDR-L1; R7Q+A11S in CDR-L1; N8T in CDR-L1; N8T+A11S in CDR-L1; I6T in CDR-L1; A11G in CDR-L1; I6T+A11G in CDR-L1; Q4G in CDR-L1; Q4G+A11S in CDR-L1; Q4G+A11G in CDR-L1; Q4H in CDR-L1; Q4H+A11S in CDR-L1; Q4R in CDR-L1; Q4R+A11S in CDR-L1; G5S+A11S in CDR-L1; N8S+A11S in CDR-L1; I6T+A11S in CDR-L1; and N8T+A11G in CDR-L1.
5. The monoclonal antibody or binding fragment of claim 1 which is a human or humanized antibody, or binding fragment of a human or humanized antibody, respectively.
6. The monoclonal antibody or binding fragment of claim 1 which is an IgG.
7. The monoclonal antibody or binding fragment of claim 6 which is an IgG 1 .
8. The monoclonal antibody or binding fragment of claim 1 which has the heavy chain framework sequences of the V H sequence of SEQ ID NO:2 and the light chain framework sequences of the V L sequence of SEQ ID NO:4.
9. The monoclonal antibody or binding fragment of claim 1 which is a bispecific antibody or a TNF-α binding fragment of a bispecific antibody.
10. The monoclonal antibody or binding fragment of claim 9 , wherein said bispecific antibody is specific to TNF-α and another pro-inflammatory cytokine.
11. The monoclonal antibody or binding fragment of claim 10 , wherein said pro-inflammatory cytokine is lymphotoxin, interferon-γ, or interleukin-1.
12. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L1 has the substitutions Q4R+A11S.
13. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L1 has the substitutions Q4G+A11G.
14. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L1 has the substitutions Q4H+A11S.
15. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L1 has the substitutions G5S+A11S.
16. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L2 has the substitution S3K.
17. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L2 has the substitution S3R.
18. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L2 has the substitution T4H.
19. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L2 has the substitution T4Q.
20. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L2 has the substitution T4F.
21. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L2 has the substitution T4W.
22. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L2 has the substitution T4Y.
23. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L2 has the substitution L5R.
24. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L2 has the substitution L5K.
25. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L2 has the substitution Q6R.
26. The monoclonal antibody or binding fragment of claim 1 , in which CDR-H1 has the substitution Y2H.
27. The monoclonal antibody or binding fragment of claim 1 , in which CDR-H1 has the substitution A3G.
28. The monoclonal antibody or binding fragment of claim 1 , in which CDR-H2 has the substitution T3N.
29. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L2 further comprises the substitution S3N.
30. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L2 further comprises the substitution T4V.
31. The monoclonal antibody or binding fragment of claim 1 , in which CDR-L2 further comprises the substitution Q6K.
32. The monoclonal antibody or binding fragment of claim 1 , in which CDR-H1 further comprises the substitution D1G.
33. The monoclonal antibody or binding fragment of claim 1 or claim 3 , which has a K D towards human TNF-α that is 1.1-fold to 4-fold the K D of an antibody having a V H sequence of SEQ ID NO:2 and a V L sequence of SEQ ID NO:4 as analyzed by BIAcore.
34. The monoclonal antibody or binding fragment of claim 33 , which has a K D towards TNF-α that is 1.5-fold to 3-fold the K D of an antibody having a V H sequence of SEQ ID NO:2 and a V L sequence of SEQ ID NO:4 as analyzed by BIAcore.
35. An antibody-drug conjugate comprising the monoclonal antibody or binding fragment of claim 1 .
36. A pharmaceutical composition comprising an anti-TNF-α antibody or anti-TNF-α binding fragment according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.