Factor XII inhibitors for the treatment of neurological inflammatory disorders

Patent metadata

Field	Value
Publication number	US-9957329-B2
Application number	US-201314374300-A
Country	US
Kind code	B2
Filing date	Jan 31, 2013
Priority date	Jan 31, 2012
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

This application relates to neurological inflammatory diseases, such as multiple sclerosis, and to methods of administering a Factor XII inhibitor to prevent, treat, or otherwise ameliorate the effects of a neurological inflammatory disease, such as multiple sclerosis. Agents and pharmaceutical compositions comprising agents which inhibit the activity of FXII are also provided.

First claim

The invention claimed is:

1. A method for treatment and/or amelioration of multiple sclerosis comprising administering to a subject in need thereof a therapeutically effective amount of a direct inhibitor of Factor XII (FXII), wherein the direct inhibitor of FXII contacts FXII to inhibit the activity and/or activation of FXII in the subject.

2. The method of claim 1 , wherein the direct inhibitor of FXII comprises the wild type infestin-4 polypeptide sequence (SEQ ID NO: 2), or a variant thereof, wherein the variant comprises:
(a) the N-terminal amino acids 2-13 of SEQ ID NO: 2 and at least one and up to five amino acid mutations outside said N-terminal amino acids that result in differences from the wild type infestin-4 sequence;
and/or
(b) the six conserved cysteine residues of the wild type Infestin-4 polypeptide sequence (SEQ ID NO: 2) and homology of at least 70% to the wild type Infestin-4 polypeptide sequence.

3. The method of claim 1 , wherein the direct inhibitor of FXII comprises wild-type SPINK-1 sequence (SEQ ID NO: 3), which is mutated to include the N-terminal amino acids 2-13 of SEQ ID NO: 2, or a variant of said mutated SPINK-1, wherein the variant comprises:
(a) the N-terminal amino acids 2-13 of SEQ ID NO: 2 and at least one and up to five amino acid mutations outside said N-terminal amino acids that result in differences from the wild type SPINK-1 sequence and which increase the homology of the variant to the wild type infestin-4 sequence; and/or
(b) the six conserved cysteine residues of the wild-type SPINK-1 sequence (SEQ ID NO: 3) and homology of at least 70% to the wild type SPINK-1 sequence.

4. The method of claim 3 , wherein the direct inhibitor of FXII comprises wild type SPINK-1 (SEQ ID NO: 3), SPINK-1 mutant K1 (SEQ ID NO: 4), SPINK-1 mutant K2 (SEQ ID NO: 5) or SPINK-1 mutant K3 (SEQ ID NO: 6).

5. The method of claim 1 , wherein the direct inhibitor of FXII comprises an anti-FXII antibody or antigen binding fragment.

6. The method of claim 5 , wherein the anti-FXII antibody or antigen binding fragment thereof comprises (a) a VH region comprising heavy chain CDR1 as set forth in SEQ ID NO: 9, heavy chain CDR2 as set forth in SEQ ID NO: 11, and heavy chain CDR3 as set forth in SEQ ID NO: 13; and/or (b) a VL region comprising light chain CDR1 as set forth in SEQ ID NO: 14, light chain CDR2 as set forth in SEQ ID NO: 15, and light chain CDR3 as set forth in SEQ ID NO: 17.

7. The method of claim 5 , wherein the anti-FXII antibody or antigen-binding fragment thereof comprises (a) a VH region comprising heavy chain CDR1 as set forth in SEQ ID NO: 9, heavy chain CDR2 as set forth in SEQ ID NO: 10, and heavy chain CDR3 as set forth in SEQ ID NO: 12; and/or (b) a VL region comprising light chain CDR1 as set forth in SEQ ID NO: 14, light chain CDR2 as set forth in SEQ ID NO: 15, and light chain CDR3 as set forth in SEQ ID NO: 16.

8. The method of claim 5 , wherein the anti-FXII antibody or antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 7 and a VL region comprising SEQ ID NO: 8.

9. The method of claim 5 , wherein the anti-FXII antibody is an IgG.

10. The method of claim 1 , wherein the direct inhibitor of FXII is linked to a half-life enhancing polypeptide that is albumin, afamin, alpha-fetoprotein, vitamin D binding protein, human albumin or a variant thereof, an immunoglobulin or a variant thereof, or an Fc of an IgG.

11. The method of claim 10 , wherein the half-life enhancing polypeptide is linked to the direct inhibitor of FXII via a linker.

12. The method of claim 11 , wherein the linker is
(a) cleavable;
(b) cleavable by a coagulation protease of the intrinsic, extrinsic, or common coagulation pathway;
and/or
(c) cleavable by Factor XIIa.

13. The method of claim 10 , wherein the half-life enhancing polypeptide is human albumin or a variant thereof.

14. The method of claim 1 , wherein the multiple sclerosis is relapsing remitting multiple sclerosis or primary progressing multiple sclerosis.

Assignees

• Csl Behring Gmbh
• Csl Ltd
• Univ Wuerzburg J Maximilians
• Univ Muenster Westfaelische Wilhelms

Inventors

• Meuth Sven
• Goebel Kerstin
• Kleinschnitz Christoph
• Mckenzie Brent
• Nolte Marc

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/92

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