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

Patent metadata

Field	Value
Publication number	US-11345759-B2
Application number	US-201916674131-A
Country	US
Kind code	B2
Filing date	Nov 5, 2019
Priority date	Jul 22, 2011
Publication date	May 31, 2022
Grant date	May 31, 2022

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 interstitial lung disease in a subject in need thereof, 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 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 method of claim 1 , wherein the interstitial lung disease is fibroproliferative and/or idiopathic pulmonary fibrosis.

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

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

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. The method of claim 1 , wherein the vH region is selected from the sequences of SEQ ID NO: 4, 73, 74, 76, and 77, and wherein the vL region consists of the sequence of SEQ ID NO: 5.

11. 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.

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: 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.

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: 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.

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: 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.

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: 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.

16. 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.

17. 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.

18. 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 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 thereof for the polypeptide in (a) or (b) is lower than the affinity of the antibody or antigen-binding fragment thereof for a polypeptide comprising SEQ ID NO: 2 without the corresponding substitution.

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

20. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof competes with Infestin for binding to human Factor XIIa-beta.

21. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof is a human IgG or variant thereof.

22. The method of claim 21 , wherein the IgG is an IgG4.

Assignees

• Csl Behring Gmbh
• Csl Ltd

Inventors

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

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• C12Y304/21038

  Coagulation factor XIIa (3.4.21.38) · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• A61P1/18 Primary

  for pancreatic disorders, e.g. pancreatic enzymes · CPC title