Variants of TACE pro-domain as TNF-A inhibitor and their medical use

Patent metadata

Field	Value
Publication number	US-10933122-B2
Application number	US-201916521622-A
Country	US
Kind code	B2
Filing date	Jul 25, 2019
Priority date	May 9, 2012
Publication date	Mar 2, 2021
Grant date	Mar 2, 2021

Abstract

A method of treating an inflammatory disease is disclosed. The method comprises administering to the subject a therapeutically effective amount of a polypeptide comprising a pro-domain of TNF-alpha converting enzyme (TACE), said polypeptide being devoid of a catalytic domain of said TACE, said polypeptide comprising a modification at a site selected from the group consisting of R 58 , R 56 and K 57 which renders said polypeptide resistant to furin degradation said polypeptide being capable of downregulating an activity of TACE, thereby treating the inflammatory disease.

First claim

What is claimed is:

1. An isolated polypeptide comprising a pro-domain of TNF-.alpha. converting enzyme (TACE), the polypeptide being devoid of a catalytic domain of said TACE, said polypeptide comprising a modification at each of the sites R 58 , R 211 , R 214 and C 184 which renders said polypeptide resistant to furin degradation, the polypeptide being capable of downregulating an activity of TACE, wherein the numbering of the modifications corresponds to the full length human TACE enzyme.

2. The isolated polypeptide of claim 1 , wherein said TACE pro-domain comprises an amino acid sequence at least 90% homologous to the sequence as set forth in SEQ ID NO: 5 as determined by BlastP using default parameters.

3. The isolated polypeptide of claim 1 , wherein said modification at position 58 is a replacement of arginine to alanine.

4. The isolated polypeptide of claim 1 , wherein said modification at position 211 is a replacement of arginine to alanine.

5. The isolated polypeptide of claim 1 , wherein said modification at position 214 is a replacement of arginine to glycine.

6. The isolated polypeptide of claim 1 , wherein said modification at position 184 is a replacement of cysteine to alanine.

7. The isolated polypeptide of claim 1 , wherein said pro-domain of TACE is attached to a heterologous polypeptide.

8. The isolated polypeptide of claim 7 , wherein said heterologous polypeptide is selected from the group consisting of human serum albumin, immunoglobulin, and transferrin.

9. The isolated polypeptide of claim 8 , wherein said immunoglobulin comprises an Fc domain.

10. The isolated polypeptide of claim 1 , wherein said pro-domain of TACE is attached to a polymer.

11. The isolated polypeptide of claim 10 , wherein said polymer is selected from the group consisting of a polycationic polymer, a non-ionic water-soluble polymer, a polyether polymer and a biocompatible polymer.

Assignees

• Yeda Res & Dev

Inventors

• Sagi Irit
• Wong Eitan
• Afik Ran

Classifications

• A61K38/4886 Primary

  Metalloendopeptidases (3.4.24), e.g. collagenase · CPC title

• C12Y304/24086

  ADAM 17 endopeptidase (3.4.24.86), i.e. TNF-alpha converting enyzme · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• C12N9/6489

  Metalloendopeptidases (3.4.24) · CPC title