Modified AXL peptides and their use in inhibition of AXL signaling in anti-metastatic therapy

Patent metadata

Field	Value
Publication number	US-11136563-B2
Application number	US-201715783850-A
Country	US
Kind code	B2
Filing date	Oct 13, 2017
Priority date	Dec 14, 2012
Publication date	Oct 5, 2021
Grant date	Oct 5, 2021

Abstract

Compositions and methods are provided for alleviating cancer in a mammal by administering a therapeutic dose of a pharmaceutical composition that inhibits activity of 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. An inhibitor of GAS6, wherein the inhibitor comprises a soluble AXL variant polypeptide wherein said soluble AXL variant polypeptide:
lacks the AXL transmembrane domain;
lacks both AXL fibronectin (FN) domains;
has an AXL Ig1 domain, and an AXL Ig2 domain;
has a set of amino acid substitutions relative to SEQ ID NO: 1, selected from the group consisting of: 1) Ala72Val; 2) Asp87Gly; 3) Val92Ala, Val92Gly or Val92Asp; 4) Ala19Thr; 5) Thr23Met; 6) Glu26Gly; 7) Glu27Gly or Glu27Lys; 8) Gly32Ser; 9) Asn33Ser; 10) Thr38Ile; 11) Thr44Ala; 12) His61Tyr; 13) Asp65Asn; 14) Ser74Asn; 15) GIn78Glu; 16) Val79Met; 17) GIn86Arg; 18) Asp88Asn; 19) Ile90Met or Ile90Val; 20) Ile97Arg; 21) Thr98Ala or Thr98Pro; 22) Thr105Met; 23) Gln109Arg; 24) Val112Ala; 25) Phe113Leu; 26) His116Arg; 27) Thr118Ala; 28) Gly127Arg or Gly127Glu; 29) Glu129Lys; 30) Glu26Gly, Val79Met, Val92Ala, and Gly127Glu; 31) Asp87Gly, Val92Ala,and Gly127Arg; 32) Gly32Ser, Val92Ala, and Glyl127Arg; 33) Gly32Ser, Asp87Gly, and Gly127Arg; 34) Gly32Ser, Asp87Gly, and Val92Ala; and 35) Asp87Gly and Val92Ala; and
wherein the inhibitor further comprises an Fc domain linked to the soluble AXL variant polypeptide by a linker comprising from 1 to 5 (GLY) 4 SER (SEQ ID NO: 10) units.

2. An inhibitor of GAS6, wherein the inhibitor comprises a soluble AXL variant polypeptide wherein said soluble AXL variant polypeptide:
lacks the AXL transmembrane domain;
lacks both AXL fibronectin (FN) domains;
has an AXL Ig1 domain, and an AXL Ig2 domain;
has a set of amino acid substitutions relative to SEQ ID NO: 1, selected from the group consisting of:
Glu26Gly, Val79Met, Val92Ala, and Gly127Glu;
Asp87Gly, Val92Ala, and Gly127Arg;
Gly32Ser, Val92Ala, and Gly127Arg;
Gly32Ser, Asp87Gly, and Gly127Arg;
Gly32Ser, Asp87Gly, and Val92Ala; and
Asp87Gly and Val92Ala; and
wherein the inhibitor further comprises an Fc domain linked to the soluble AXL variant polypeptide by a linker comprising from 1 to 5 (GLY) 4 SER (SEQ ID NO: 10) units.

3. A pharmaceutical formulation comprising an inhibitor of claim 1 and a pharmaceutically acceptable excipient.

4. A pharmaceutical formulation comprising an inhibitor of claim 2 and a pharmaceutically acceptable excipient.

5. A method of reducing growth or metastasis of a tumor that expresses GAS6, the method comprising administering to a patient with a tumor that expresses GAS6 an effective dose of the pharmaceutical formulation of claim 3 .

6. A method of reducing growth or metastasis of a tumor that expresses GAS6, the method comprising administering to a patient with a tumor that expresses GAS6 an effective dose of the pharmaceutical formulation of claim 4 .

Assignees

• Univ Leland Stanford Junior
• Aravive Biologics Inc

Inventors

• Giaccia Amato J
• Rankin Erinn Bruno
• Cochran Jennifer R
• Jones Douglas
• Kariolis Mihalis
• Fuh Katherine Cynthia
• Miao Yu
• Hershenson Susan

Classifications

• C07K2319/32

  fusions with soluble part of a cell surface receptor, "decoy receptors" · CPC title

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C12Y207/10001

  Receptor protein-tyrosine kinase (2.7.10.1) · CPC title