Thrombospondin-1 polypeptides and methods of using same

Abstract

The invention features thrombospondin-1 (TSP-1) polypeptides (e.g., 3TSR-Fc fusion proteins), nucleic acid molecules encoding the TSP-1 polypeptides, and compositions thereof. The invention also features methods of making and using the TSP-1 polypeptides of the invention (e.g., using 3TSR-Fc fusion proteins to treat a subject having a disorder associated with pathological angiogenesis, e.g., cancer, e.g., epithelial ovarian cancer (EOC)).

What is claimed is: 
     
         1 . A polypeptide comprising a thrombospondin-1 (TSP-1) domain, or portion thereof, and a fragment crystallizable (Fc) region. 
     
     
         2 . The polypeptide of  claim 1 , wherein said TSP-1 domain, or portion thereof, is a type 1 repeat (TSR) domain, or portion thereof. 
     
     
         3 . The polypeptide of  claim 2 , wherein said TSR domain, or portion thereof, is a TSR domain, or portion thereof, of human TSP-1. 
     
     
         4 . The polypeptide of  claim 3 , wherein the amino acid sequence of said TSR domain, or portion thereof, of human TSP-1 comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 1-7. 
     
     
         5 . The polypeptide of  claim 1 , wherein said Fc region comprises a CH2 domain and a CH3 domain. 
     
     
         6 . The polypeptide of  claim 5 , wherein said CH2 domain and said CH3 domain are heavy chain constant domains of an immunoglobulin selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. 
     
     
         7 . The polypeptide of  claim 1 , wherein said TSP-1 domain, or portion thereof, and said Fc region are positioned relative to each other in an N-terminal to C-terminal direction as follows: X-TSP-1 domain-Y-Fc region-Z,
 wherein each of X, Y, and Z is absent or is an amino acid sequence of at least one amino acid.   
     
     
         8 . The polypeptide of  claim 1 , wherein said TSP-1 domain, or portion thereof, and said Fc region are positioned relative to each other in an N-terminal to C-terminal direction as follows: X-Fc region-Y-TSP-1 domain-Z,
 wherein each of X, Y, and Z is absent or is an amino acid sequence of at least one amino acid.   
     
     
         9 . The polypeptide of  claim 1 , wherein said Fc region is conjugated to a functional moiety. 
     
     
         10 . A polynucleotide encoding a polypeptide of  claim 1 . 
     
     
         11 . A vector comprising the polynucleotide of  claim 10 . 
     
     
         12 . A host cell comprising the vector of  claim 11 . 
     
     
         13 . A method of producing a polypeptide of  claim 1 , said method comprising culturing said host cell of  claim 12  in a culture medium. 
     
     
         14 . A composition comprising the polypeptide of  claim 1 . 
     
     
         15 . A method of treating a subject having a disorder associated with pathological angiogenesis comprising administering a therapeutically effective amount of the composition of  claim 14  to said subject, thereby treating said subject. 
     
     
         16 . A method of treating a subject having a disorder associated with pathological angiogenesis comprising administering a therapeutically effective amount of a composition, wherein said composition comprises a polypeptide comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 1-7 or a polynucleotide encoding said polypeptide. 
     
     
         17 . The method of  claim 15  or  16 , wherein said disorder is cancer. 
     
     
         18 . The method of  claim 17 , wherein said cancer is epithelial ovarian cancer (EOC). 
     
     
         19 . The method of  claim 15  or  16 , wherein said composition is administered intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctivally, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions. 
     
     
         20 . A kit comprising:
 (a) the composition of  claim 14 ; and   (b) instructions for administering said composition to a subject to treat a disorder associated with pathological angiogenesis.