Inhibitory anti-factor XII/XIIA monoclonal antibodies and their uses

Patent metadata

Field	Value
Publication number	US-9518127-B2
Application number	US-201214234021-A
Country	US
Kind code	B2
Filing date	Jul 20, 2012
Priority date	Jul 22, 2011
Publication date	Dec 13, 2016
Grant date	Dec 13, 2016

Abstract

The invention relates to inhibitory anti-factor XII/FXIIa antibodies and methods of their use.

First claim

The invention claimed is:

1. An anti-Factor XII/XIIa monoclonal antibody or antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable (vH) region and an immunoglobulin light chain variable (vL) region,
wherein the vH region comprises:
a heavy chain CDR1 consisting of the sequence of SEQ ID NO: 6;
a heavy chain CDR2 consisting of the sequence of GIX 1 X 2 X 3 X 4 X 5 X 6 TVYADSVKG (SEQ ID NO: 8), wherein X 1 is R, N, or D; X 2 is P, V, I, or M; X 3 is S, P, or A; X 4 is G, L, V, or T; X 5 can be any amino acid; and X 6 is T, G, or S; and
a heavy chain CDR3 consisting of the sequence of ALPRSGYLX 1 X 2 X 3 X 4 YYYYALDV (SEQ ID NO: 10), wherein X 1 is I, M, or V; X 2 is S or K; X 3 is P, K, T, or H; and X 4 is H, N, G, or Q; and
wherein the vL region comprises:
a light chain CDR1 consisting of the sequence set forth in any one of SEQ ID NOs: 11 and 44-51;
a light chain CDR2 consisting of the sequence of SEQ ID NO: 12; and
a light chain CDR3 consisting of the sequence of AX 1 WX 2 X 3 X 4 X 5 RX 6 X 7 (SEQ ID NO: 14), wherein X 1 is A or S; X 5 is L or V; X 6 is G, L, or K; and X 2 , X 3 , X 4 and X 7 can be any amino acid.

2. The antibody or antigen-binding fragment according to claim 1 , wherein the vH region comprises an amino acid sequence more than 85% identical to the sequence of SEQ ID NO: 4.

3. The antibody or antigen-binding fragment according to claim 1 , wherein the vL region comprises an amino acid sequence more than 85% identical to the sequence of SEQ ID NO: 5.

4. The antibody or antigen-binding fragment according to claim 1 , wherein the heavy chain CDR2 consists of the sequence set forth in any one of SEQ ID NOs: 7 and 29-38.

5. The antibody or antigen-binding fragment according to claim 1 , wherein the heavy chain CDR3 consists of the sequence set forth in any one of SEQ ID NOs: 9 and 39-43.

6. The antibody or antigen-binding fragment according to claim 1 , wherein
X 5 is G, Y, Q, K, R, N, or M in the heavy chain CDR2;
X 2 is D, Y, E, T, W, E, or S in the light chain CDR3;
X 3 is A, N, I, L, V, P, Q, or E in the light chain CDR3;
X 4 is S, D, P, E, Q, or R in the light chain CDR3; and/or
X 7 is V, A, D, T, M, or G in the light chain CDR3.

7. The antibody or antigen-binding fragment according to claim 1 , wherein the light chain CDR3 consists of the sequence set forth in any one of SEQ ID NOs: 13 and 52-63.

8. The antibody or antigen-binding fragment according to claim 1 , wherein the vH region comprises a heavy chain CDR1 consisting of the sequence of SEQ ID NO: 6, a heavy chain CDR2 consisting of the sequence of SEQ ID NO: 7, a heavy chain CDR3 consisting of the sequence of SEQ ID NO: 9, and wherein the vL region comprises a light chain CDR1 consisting of the sequence of SEQ ID NO: 11, a light chain CDR2 consisting of the sequence of SEQ ID NO: 12, and a light chain CDR3 consisting of the sequence of SEQ ID NO: 13.

9. The antibody or antigen-binding fragment according to claim 1 , wherein the vH region consists of the sequence of SEQ ID NO: 4, and wherein the vL region consists of the sequence of SEQ ID NO: 5.

10. The antibody or antigen-binding fragment according to claim 1 , wherein the vH region comprises a heavy chain CDR1 consisting of the sequence of SEQ ID NO: 6, a heavy chain CDR2 consisting of the sequence of SEQ ID NO: 29, a heavy chain CDR3 consisting of the sequence of SEQ ID NO: 9, and wherein the vL region comprises a light chain CDR1 consisting of the sequence of SEQ ID NO: 11, a light chain CDR2 consisting of the sequence of SEQ ID NO: 12, and a light chain CDR3 consisting of the sequence of SEQ ID NO: 13.

11. The antibody or antigen-binding fragment according to claim 1 , wherein the vH region comprises a heavy chain CDR1 consisting of the sequence of SEQ ID NO: 6, a heavy chain CDR2 consisting of the sequence of SEQ ID NO: 30, a heavy chain CDR3 consisting of the sequence of SEQ ID NO: 9, and wherein the vL region comprises a light chain CDR1 consisting of the sequence of SEQ ID NO: 11, a light chain CDR2 consisting of the sequence of SEQ ID NO: 12, and a light chain CDR3 consisting of the sequence of SEQ ID NO: 13.

12. The antibody or antigen-binding fragment according to claim 1 , wherein the vH region comprises a heavy chain CDR1 consisting of the sequence of SEQ ID NO: 6, a heavy chain CDR2 consisting of the sequence of SEQ ID NO: 31, a heavy chain CDR3 consisting of the sequence of SEQ ID NO: 9, and wherein the vL region comprises a light chain CDR1 consisting of the sequence of SEQ ID NO: 11, a light chain CDR2 consisting of the sequence of SEQ ID NO: 12, and a light chain CDR3 consisting of the sequence of SEQ ID NO: 13.

13. The antibody or antigen-binding fragment according to claim 1 , wherein the vH region comprises a heavy chain CDR1 consisting of the sequence of SEQ ID NO: 6, a heavy chain CDR2 consisting of the sequence of SEQ ID NO: 32, a heavy chain CDR3 consisting of the sequence of SEQ ID NO: 9, and wherein the vL region comprises a light chain CDR1 consisting of the sequence of SEQ ID NO: 11, a light chain CDR2 consisting of the sequence of SEQ ID NO: 12, and a light chain CDR3 consisting of the sequence of SEQ ID NO: 13.

14. The antibody or antigen-binding fragment according to claim 1 , wherein the vH region comprises a heavy chain CDR1 consisting of the sequence of SEQ ID NO: 6, a heavy chain CDR2 consisting of the sequence of SEQ ID NO: 7, a heavy chain CDR3 consisting of the sequence of SEQ ID NO: 9, and wherein the vL region comprises a light chain CDR1 consisting of the sequence of SEQ ID NO: 44, a light chain CDR2 consisting of the sequence of SEQ ID NO: 12, and a light chain CDR3 consisting of the sequence of SEQ ID NO: 13.

15. The antibody or antigen-binding fragment according to claim 1 , wherein the antibody or antigen-binding fragment has a more than 2 fold higher binding affinity to human Factor XIIa-beta than to human Factor XII and is capable of inhibiting the amidolytic activity of human Factor XIIa at a concentration of 100 nM or lower in an in vitro amidolytic activity assay by 80% or more.

16. The antibody or antigen-binding fragment according to claim 1 , wherein the antibody or antigen-binding fragment inhibits the amidolytic activity of Factor XIIa-alpha by more than 50% in an in vitro amidolytic activity assay when used at a molar ratio of FXIIa-alpha to antibody of 1:0.2.

17. The antibody or antigen-binding fragment according to claim 1 , wherein the antibody or antigen-binding fragment binds murine FXII/FXIIa; and wherein the antibody or antigen-binding fragment binds to a polypeptide comprising the sequence of SEQ ID NO: 2 in which (a) the asparagine residue at position 398 of SEQ ID NO: 2 is substituted for lysine; or (b) the isoleucine residue at position 438 of SEQ ID NO: 2 is substituted for alanine, and wherein the affinity of the antibody or antigen-binding fragment for the polypeptide in (a) or (b) is lower than the affinity of the antibody or antigen-binding fragment for a polypeptide comprising SEQ ID NO: 2 without the corresponding substitution.

18. The antibody or antigen-binding fragment according to claim 1 , wherein the antibody or antigen-binding fragment binds human Factor XIIa-beta with a K D of better than 10 −7 M.

19. The antibody or antigen-binding fragment according to claim 1 , wherein the antibody or antigen-binding fragment competes with Infestin for binding to human Factor XIIa-beta.

20. The antibody or antigen-binding fragment according to claim 1 , wherein the antibod

Assignees

• Panousis Con
• Rayzman Veronika
• Nash Andrew
• Wilson Michael
• Schmidbauer Stefan
• Nolte Marc
• Csl Behring Gmbh
• Csl Ltd

Inventors

• Panousis Con
• Rayzman Veronika
• Nash Andrew
• Wilson Michael
• Schmidbauer Stefan
• Nolte Marc

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title