Methods of administering inhibitory anti-factor XII/XIIA monoclonal antibodies

Patent metadata

Field	Value
Publication number	US-9856326-B2
Application number	US-201615343447-A
Country	US
Kind code	B2
Filing date	Nov 4, 2016
Priority date	Jul 22, 2011
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

Abstract

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

First claim

The invention claimed is:

1. A method of treating venous, arterial, or capillary thrombus formation; thrombus formation in the heart; thromboembolism; thrombus formation during and/or after contacting blood with artificial surfaces; or intraluminal thrombi in a subject in need thereof, the method comprising administering to the subject an effective amount of 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 5, 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 method of claim 1 , wherein the subject suffers from venous or arterial thrombus formation selected from stroke, myocardial infarction, deep vein thrombosis, portal vein thrombosis, thromboembolism, renal vein thrombosis, jugular vein thrombosis, cerebral venous sinus thrombosis, Budd-Chiari syndrome, and Paget-Schroetter disease.

3. The method of claim 1 , wherein the subject suffers from thrombus formation during and/or after contacting blood of the subject with one or more artificial surfaces during and/or after a medical procedure performed on said subject, wherein the anti-Factor XII/XIIa monoclonal antibody or antigen-binding fragment thereof is administered before and/or during and/or after said medical procedure, and wherein
(i) the artificial surface is exposed to at least 80% of the blood volume of the subject and the artificial surface is at least 0.2 m 2 ,
(ii) the artificial surface is a container for collection of blood outside the body of the subject, or
(iii) the artificial surface is a stent, valve, intraluminal catheter, or a system for internal assisted pumping of blood.

4. The method of claim 1 , wherein the vH region comprises an amino acid sequence more than 85% identical to the sequence of SEQ ID NO: 4.

5. The method of claim 1 , wherein the vL region comprises an amino acid sequence more than 85% identical to the sequence of SEQ ID NO: 5.

6. The method of claim 1 , wherein the heavy chain CDR2 consists of the sequence set forth in any one of SEQ ID NOs: 7 and 29-38.

7. The method of claim 1 , wherein the heavy chain CDR3 consists of the sequence set forth in any one of SEQ ID NOs: 9 and 39-43.

8. The method of 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.

9. The method of claim 1 , wherein the light chain CDR3 consists of the sequence set forth in any one of SEQ ID NOs: 13 and 52-63.

10. The method of 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.

11. The method of 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.

12. The method of 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.

13. The method of 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.

14. The method of 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.

15. The method of 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.

16. The method of 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.

17. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof 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.

18. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof 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.

19. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof binds murine FXII/FXIIa; and wherein the antibody or antigen-binding fragment thereof binds to a polypeptide comprising the sequence of SEQ ID NO: 2 in which (a) the asparagine res

Assignees

• Csl Behring Gmbh
• Csl Ltd

Inventors

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

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• 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

• A61P7/10

  Antioedematous agents; Diuretics · CPC title