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