Targeted therapeutics based on engineered proteins for tyrosine kinases receptors, including igf-ir

Abstract

The present invention provides innovative proteins that bind to insulin-like growth factor-I receptor (IGF-IR), as well as other important proteins. The invention also provides innovative proteins in pharmaceutical preparations and derivatives of such proteins and the uses of same in diagnostic, research and therapeutic applications. The invention further provides cells comprising such proteins, polynucleotide encoding such proteins or fragments thereof, and vectors comprising the polynucleotides encoding the innovative proteins.

1 - 21 . (canceled) 
     
     
         22 . A nucleic acid encoding a tenth fibronectin type III ( 10 Fn3) domain comprising an amino acid sequence that is at least 85% identical to any one of SEQ ID NOs: 184-203, wherein the  10 Fn3 domain binds human insulin-like growth factor-I receptor (IGF-IR) with a dissociation constant of about 1 μM or less. 
     
     
         23 . The nucleic acid of  claim 22 , wherein the  10 Fn3 domain comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 184-203. 
     
     
         24 . The nucleic acid of  claim 22 , wherein the  10 Fn3 domain comprises an amino acid sequence that is at least 95% identical to any one of SEQ ID NOs: 184-203. 
     
     
         25 . A nucleic acid encoding a tenth fibronectin type III ( 10 Fn3) domain comprising the amino acid sequence of any one of SEQ ID NOs: 184-203. 
     
     
         26 . A nucleic acid encoding a encoding a tenth fibronectin type III ( 10 Fn3) domain consisting of an amino acid sequence that is at least 85% identical to any one of SEQ ID NOs: 184-203, wherein the  10 Fn3 domain binds human insulin-like growth factor-I receptor (IGF-IR) with a dissociation constant of about 1 μM or less. 
     
     
         27 . The nucleic acid of  claim 26 , wherein the amino acid sequence of the  10 Fn3 domain is at least 90% identical to any one of SEQ ID NOs: 184-203. 
     
     
         28 . The nucleic acid of  claim 26 , wherein the amino acid sequence of the  10 Fn3 domain is at least 95% identical to any one of SEQ ID NOs: 184-203. 
     
     
         29 . The nucleic acid of  claim 26 , wherein the amino acid sequence of the  10 Fn3 domain is at least 95% identical to any one of SEQ ID NOs: 184-203. 
     
     
         30 . The nucleic acid of  claim 26 , wherein the amino acid sequence of the  10 Fn3 domain is identical to any one of SEQ ID NOs: 184-203. 
     
     
         31 . A vector comprising the nucleic acid of  claim 22 . 
     
     
         32 . A vector comprising the nucleic acid of  claim 26 . 
     
     
         33 . A host cell expressing the nucleic acid of  claim 22 . 
     
     
         34 . A host cell expressing the nucleic acid of  claim 26 . 
     
     
         35 . A method of treating a subject have cancer associated with increased insulin-like growth factor activity, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a polypeptide comprising an altered tenth fibronectin type III ( 10 Fn3) domain comprising an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 184-203, and wherein the  10 Fn3 domain binds human insulin-like growth factor-I receptor (IGF-IR) with a dissociation constant of about 1 μM or less. 
     
     
         36 . The method of  claim 35 , wherein the altered  10 Fn3 domain binds human IGF-IR with a disassociation constant of about 10 nM or less. 
     
     
         37 . The method of  claim 35 , wherein the altered  10 Fn3 domain comprises an amino acid sequence that is at least 85% identical to any one of SEQ ID NOs: 184-203. 
     
     
         38 . The method of  claim 35 , wherein the altered  10 Fn3 domain comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 184-203. 
     
     
         39 . The method of  claim 35 , wherein the altered  10 Fn3 domain comprises an amino acid sequence that is at least 95% identical to any one of SEQ ID NOs: 184-203. 
     
     
         40 . The method of  claim 35 , wherein the altered  10 Fn3 domain comprises an amino acid sequence that is identical to any one of SEQ ID NOs: 184-203. 
     
     
         41 . The method of  claim 35 , wherein the altered  10 Fn3 domain comprises an amino acid sequence of SEQ ID NO: 184. 
     
     
         42 . The method of  claim 35 , wherein the polypeptide further comprises one or more pharmacokinetic (PK) moieties selected from: a polyoxyalkylene moiety, a human serum albumin binding protein, sialic acid, human serum albumin, transferrin, and an Fc fragment. 
     
     
         43 . The method of  claim 42 , wherein the PK moiety is the polyoxyalkylene moiety and said polyoxyalkylene moiety is polyethylene glycol. 
     
     
         44 . The method of  claim 35 , wherein the polypeptide inhibits the binding of insulin-like growth factor-I (IGF-I) or insulin-like growth factor-II (IGF-II) to IGF-IR and does not activate human IGF-IR at sub IC50 concentrations in a cell-based assay. 
     
     
         45 . The method of  claim 35 , wherein the cancer is selected from the group consisting of breast cancer, colon cancer, ovarian carcinoma, osteosarcoma, cervical cancer, prostate cancer lung cancer, synovial carcinoma, pancreatic cancer, plasmacytoma, rhabdomyosarcoma and multiple myeloma.