Fusion Polypeptides Capable Of Activating Receptors

Abstract

A fusion polypeptide comprising (A) x -M-A′) y , wherein A and A′ are each polypeptides capable of binding a target receptor. The fusion polypeptides of the invention form multimeric proteins which activate the target receptor. A and A′ may be each be an antibody or fragment derived from an antibody specific for a target receptor, such as the same or different scFv fragments, and/or a ligand or ligand fragment or derivative capable of binding the target protein, M is a multimerizing component, and X and Y are independently a number between 1-10.

1 .- 34 . (canceled) 
     
     
         35 . A method of activating a target receptor comprising:
 exposing a system comprising the target receptor to a dimer formed from two fusion polypeptides of the form (A)-M-(A′), wherein:   component A comprises an antibody fragment specific to a target receptor,   component A′ comprises either
 i) an antibody fragment specific to the target receptor; or 
 ii) a ligand or ligand fragment specific to the target receptor, and 
   component M is a multimerizing component comprising an Fc domain of IgG,   the dimer being characterized in that, when contacted with a system comprising the target receptor, it binds to and clusters four or more molecules of the target receptor, and wherein the target receptor is selected from the group consisting of an EGF receptor, Eph receptor, EPO receptor, FGF receptor, G-CSF receptor, GM-CSF receptor, a VEGF receptor, a PDGF receptor, TGFβ receptor, a Tie receptor and a Trk receptor.   
     
     
         36 . The method of  claim 35 , wherein A and A′ are different antibody fragments. 
     
     
         37 . The method of  claim 35 , wherein A and A′ are the same antibody fragment. 
     
     
         38 . The method of  claim 35 , wherein A′ is a ligand. 
     
     
         39 . The method of  claim 35 , wherein A′ is a ligand fragment. 
     
     
         40 . The method of  claim 35 , wherein M comprises an Fc domain of human IgG1. 
     
     
         41 . The method of  claim 35 , wherein the target receptor is EGF receptor, FGF receptor, Eph receptor, Trk receptor, or Tie receptor. 
     
     
         42 . The method of  claim 35 , wherein the target receptor is VEGF receptor, PDGF receptor, or TGFβ receptor. 
     
     
         43 . The method of  claim 35 , wherein the target receptor is EPO receptor or G-CSF receptor. 
     
     
         44 . The method of  claim 35 , wherein the target receptor is GM-C SF receptor. 
     
     
         45 . A method of treating a subject with a target receptor-related condition or disease comprising:
 administering to the subject a therapeutically effective amount of a composition comprising a dimer formed from two fusion polypeptides of the form (A)-M-(A′), wherein:   component A comprises an antibody fragment specific to a target receptor, component A′ comprises either
 i) an antibody fragment specific to the target receptor; or 
 ii) a ligand or ligand fragment specific to the target receptor, and 
   component M is a multimerizing component comprising an Fc domain of IgG,   the dimer being characterized in that, when contacted with a system comprising the target receptor, it binds to and clusters four or more molecules of the target receptor,   wherein the target receptor is selected from the group consisting of an EGF receptor, Eph receptor, EPO receptor, FGF receptor, G-CSF receptor, GM-C SF receptor, a VEGF receptor, a PDGF receptor, TGFβ receptor, a Tie receptor and a Trk receptor, and   wherein administering to the subject the composition activates the target receptor, and the target receptor-related condition or disease is ameliorated or inhibited.   
     
     
         46 . The method of  claim 45 , wherein A and A′ are different antibody fragments. 
     
     
         47 . The method of  claim 45 , wherein A and A′ are the same antibody fragment. 
     
     
         48 . The method of  claim 45 , wherein A′ is a ligand. 
     
     
         49 . The method of  claim 45 , wherein A′ is a ligand fragment. 
     
     
         50 . The method of  claim 45 , wherein M comprises an Fc domain of human IgG1. 
     
     
         51 . The method of  claim 45 , wherein the target receptor is EGF receptor, FGF receptor, Eph receptor, Trk receptor, or Tie receptor. 
     
     
         52 . The method of  claim 45 , wherein the target receptor is VEGF receptor, PDGF receptor, or TGFβ receptor. 
     
     
         53 . The method of  claim 45 , wherein the target receptor is EPO receptor or G-CSF receptor. 
     
     
         54 . The method of  claim 45 , wherein the target receptor is GM-CSF receptor.