US2006008844A1PendingUtilityA1

c-Met kinase binding proteins

53
Assignee: AVIDIA RES INSTPriority: Jun 17, 2004Filed: Sep 30, 2004Published: Jan 12, 2006
Est. expiryJun 17, 2024(expired)· nominal 20-yr term from priority
Inventors:Willem P. C. StemmerD. Victor PerlrothSanjeev Satyal
G01N 2333/82G01N 33/566A61P 35/00G01N 2500/00C07K 14/705A61P 35/02G01N 2333/4753A61K 38/00C07K 14/47G01N 33/575C07K 7/08G01N 33/543
53
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Claims

Abstract

Polypeptides comprising monomer domains that bind to c-Met, or portions thereof, are provided.

Claims

exact text as granted — not AI-modified
1 . A polypeptide comprising a monomer domain that binds to c-Met, wherein the monomer domain: 
 is a non-naturally-occurring monomer domain consisting of 30 to 50 amino acids;    comprises at least one disulfide bond; and    binds to an ion.    
     
     
         2 . The polypeptide of claim, wherein binding of at least one monomer domain to c-Met inhibits dimerization of Met.  
     
     
         3 . The polypeptide of  claim 1 , wherein at least one monomer domain binds to the Sema domain of c-Met, thereby preventing binding of Met ligands to c-Met.  
     
     
         4 . The polypeptide of  claim 1 , wherein the polypeptide comprises at least one and no more than six monomer domains.  
     
     
         5 . The polypeptide of  claim 1 , wherein the polypeptide comprises at least two monomer domains and the monomer domains are linked by a linker.  
     
     
         6 . The polypeptide of  claim 5 , wherein the linker is a peptide linker.  
     
     
         7 . The polypeptide of  claim 6 , wherein the linker is between 4 to 12 amino acids long.  
     
     
         8 . The polypeptide of  claim 1 , wherein the monomer domains are each between 35 to 45 amino acids.  
     
     
         9 . The polypeptide of  claim 1 , wherein the polypeptide comprises at least one monomer domain with binding specificity for a blood factor, thereby increasing the serum half-life of the polypeptide compared to a polypeptide lacking the blood factor monomer domain.  
     
     
         10 . The polypeptide of  claim 9 , wherein the blood factor is serum albumin, an immunoglobulin or an erythrocyte.  
     
     
         11 . The polypeptide of  claim 1 , wherein each monomer domain comprises two disulfide bonds.  
     
     
         12 . The polypeptide of  claim 1 , wherein each monomer domain comprises three disulfide bonds.  
     
     
         13 . The polypeptide of  claim 1 , wherein the ion is a metal ion.  
     
     
         14 . The polypeptide of  claim 1 , wherein the ion is a calcium ion.  
     
     
         15 . The polypeptide of  claim 1 , wherein at least one of the monomer domains is derived from a LDL-receptor class A domain.  
     
     
         16 . The polypeptide of  claim 1 , wherein at least one of the monomer domains is derived from an EGF-like domain.  
     
     
         17 . The polypeptide of  claim 1 , wherein the monomer comprises an amino acid sequence in which: 
 at least 10% of the amino acids in the sequence are cysteine; and/or    at least 25% of the amino acids are non-naturally-occurring amino acids.    
     
     
         18 . A method for identifying a polypeptide that binds to c-Met, the method comprising, 
 screening a library of polypeptides for affinity to c-Met; and    selecting a polypeptide comprising at least one monomer domain that binds to c-Met, wherein the monomer domain:    is a non-naturally-occurring monomer domain;    comprises at least one disulfide bond; and    binds to an ion.    
     
     
         19 . The method of  claim 18 , wherein the selecting step comprises selecting a polypeptide that reduces HGF-mediated cell proliferation and/or migration.  
     
     
         20 . The method of  claim 18 , further comprising selecting a polypeptide that inhibits tumor growth in an animal.  
     
     
         21 . The method of  claim 18 , wherein the monomer comprises an amino acid sequence in which: 
 at least 10% of the amino acids in the sequence are cysteine; and/or    at least 25% of the amino acids are non-naturally-occurring amino acids.    
     
     
         22 . The method of  claim 18 , further comprising linking the monomer domain in the selected polypeptide to a second monomer domain to form a library of multimers, each multimer comprising at least two monomer domains; 
 screening the library of multimers for the ability to bind to c-Met; and    selecting a multimer that binds c-Met.    
     
     
         23 . The method of  claim 18 , further comprising linking the monomer domain in the selected polypeptide to a second monomer domain to form a library of multimers, each multimer comprising at least two monomer domains; 
 screening the library of multimers for the ability to bind to a target molecule other than the c-Met; and    selecting a multimer that binds to the target molecule.    
     
     
         24 . The method of  claim 18 , further comprising a step of mutating at least one monomer domain, thereby providing a library comprising mutated monomer domains.  
     
     
         25 . The method of  claim 18 , wherein the library of monomer domains is expressed as a phage display, ribosome display or cell surface display.  
     
     
         26 . The method of  claim 18 , wherein the polypeptide comprises at least two monomer domains and the monomer domains are linked by a linker.  
     
     
         27 . The method of  claim 26 , wherein the linker is a peptide linker.  
     
     
         28 . The method of  claim 27 , wherein the linker is between 4 to 12 amino acids long.  
     
     
         29 . The method of  claim 18 , wherein the monomer domains are each between 35 to 45 amino acids.  
     
     
         30 . The method of  claim 18 , wherein each monomer domain comprises two disulfide bonds.  
     
     
         31 . The method of  claim 18 , wherein each monomer domain comprises three disulfide bonds.  
     
     
         32 . The method of  claim 18 , wherein the ion is a metal ion.  
     
     
         33 . The method of  claim 18 , wherein the ion is a calcium ion.  
     
     
         34 . The method of  claim 18 , wherein at least one of the monomer domains is derived from a LDL-receptor class A domain.  
     
     
         35 . The method of  claim 18 , wherein at least one of the monomer domains is derived from an EGF-like domain.  
     
     
         36 . The method of  claim 18 , wherein the monomer domain comprises an amino acid sequence in which: 
 at least 10% of the amino acids in the sequence are cysteine; and/or    at least 25% of the amino acids are non-naturally-occurring amino acids.    
     
     
         37 . A polynucleotide encoding the polypeptide of  claim 1.

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