Inhibition of AXL/GAS6 signaling in the treatment of liver fibrosis

Patent metadata

Field	Value
Publication number	US-9879061-B2
Application number	US-201213714875-A
Country	US
Kind code	B2
Filing date	Dec 14, 2012
Priority date	Dec 15, 2011
Publication date	Jan 30, 2018
Grant date	Jan 30, 2018

Abstract

Compositions and methods are provided for alleviating endometriosis, kidney disease, inflammatory disease and/or transplant rejection in a mammal by administering a therapeutic dose of a pharmaceutical composition that inhibits AXL, MER or Tyro3 protein activity, for example by competitive or non-competitive inhibition of the binding interaction between AXL, MER or Tyro3 and its ligand GAS6.

First claim

What is claimed is:

1. A method of reducing liver fibrosis in a mammalian patient, the method comprising:
administering an effective dose of a soluble AXL variant polypeptide wherein said soluble AXL variant polypeptide:
lacks the AXL transmembrane domain,
lacks a functional fibronectin (FN) domain,
has an Ig1 domain, and an Ig2 domain,
has a set of amino acid substitutions at positions relative to SEQ ID NO:1: G32, A72, D87, V92 and G127; or at positions G32, D87, V92 and G127,
comprises an Fc domain linked to the AXL variant polypeptide by a linker comprising one or more (GLY) 4 SER (SEQ ID NO:10) units; and
wherein said AXL-variant polypeptide exhibits increased affinity of binding to GAS6 compared to wild-type AXL (SEQ ID NO:1).

2. The method of claim 1 , wherein said soluble AXL variant polypeptide comprises a set of amino acid substitutions where glycine 32 is replaced with a serine residue, aspartic acid 87 is replaced with a glycine residue, valine 92 is replaced with an alanine residue, and glycine 127 is replaced with an arginine residue, and optionally alanine 72 is replaced with a valine residue.

3. The method of claim 1 , wherein said soluble AXL variant polypeptide has an affinity of at least about 1×10 −8 M, 1×10 −9 M, 1×10 −10 M, 1×10 −11 M or 1×10 −12 M for GAS6.

4. The method of claim 1 , wherein said soluble AXL variant polypeptide exhibits an affinity to GAS6 that is at least about 5-fold stronger, at least about 10-fold stronger or at least about 20-fold stronger than the affinity of the wild-type AXL polypeptide.

Assignees

• Univ Leland Stanford Junior
• Aravive Biologics Inc

Inventors

• O'Connor Patrick
• Tabibiazar Raymond
• Giaccia Amato J
• Rankin Erinn Bruno
• Cochran Jennifer R
• Jones Douglas
• Kariolis Mihalis
• Fuh Katherine
• Miao Yu

Classifications

• G01N33/6893

  related to diseases not provided for elsewhere · CPC title

• G01N33/5023 Primary

  on expression patterns · CPC title

• C07K2317/34

  Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• C07K16/40

  against enzymes · CPC title