Modified AXL Peptides and Their Use in Inhibition of AXL Signaling in Anti-Metastatic Therapy

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.

1 - 80 . (canceled) 
     
     
         81 . An inhibitor agent selected from the group consisting of (a) an inhibitor of AXL, MER or Tyro3-GAS6 interaction, (b) an inhibitor of AXL, MER and/or Tyro3 activity, and (c) an inhibitor of GAS6 activity, and wherein the inhibitor agent binds to GAS6 with increased affinity compared to wild-type AXL, MER or Tyro3. 
     
     
         82 . The inhibitor agent of  claim 81  wherein the inhibitor agent binds to two or more epitopes on a single GAS6, optionally where at least one of the epitopes is the major or minor AXL, MER or Tyro3 binding site of GAS6. 
     
     
         83 . The inhibitor agent of  claim 82 , 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 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) Thr38lle; 11) Thr44Ala; 12) His61Tyr; 13) Asp65Asn; 14) Ser74Asn; 15) Gln78Glu; 16) Val79Met; 17) Gln86Arg; 18) Asp88Asn; 19) lle90Met or lle90Val; 20) lle97Arg; 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 Gly127Arg; 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)4SER (SEQID NO: 10) units. 
 
     
     
         84 . A pharmaceutical formulation comprising an inhibitor of  claim 81  and a pharmaceutically acceptable excipient. 
     
     
         85 . 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 84 .