US2006204512A1PendingUtilityA1

Polypeptide compounds for inhibiting angiogenesis and tumor growth

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Assignee: VASGENE THERAPEUTICS INCPriority: Sep 23, 2004Filed: Sep 23, 2005Published: Sep 14, 2006
Est. expirySep 23, 2024(expired)· nominal 20-yr term from priority
Inventors:Valery KrasnoperovNathalie KerteszRamachandra ReddyParkash GillSergey Zozulya
A61P 35/00A61K 47/60A61K 38/00A61K 38/385A61P 35/04C07K 14/715A61P 43/00A61P 9/00A61P 35/02
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Claims

Abstract

In certain embodiments, this present invention provides polypeptide compositions, including compositions containing a modified polypeptide, and methods for inhibiting Ephrin B2 or EphB4 activity. In other embodiments, the present invention provides methods and compositions for treating cancer or for treating angiogenesis-associated diseases.

Claims

exact text as granted — not AI-modified
1 . An isolated soluble polypeptide comprising an amino acid sequence of an extracellular domain of an EphB4 protein, wherein the polypeptide is a monomer and binds specifically to an Ephrin B2 polypeptide.  
     
     
         2 . The polypeptide of  claim 1 , comprising a globular domain of an EphB4 protein or a sequence that is at least 90% identical to a globular domain of EphB4.  
     
     
         3 . The polypeptide of  claim 1 , comprising a sequence at least 90% identical to residues 29-197 of the amino acid sequence defined by  FIG. 65  (SEQ ID NO:10).  
     
     
         4 . The polypeptide of  claim 1 , further comprising a modification that increases serum half-life.  
     
     
         5 . The polypeptide of  claim 4 , wherein said modification comprises a polyethylene glycol group.  
     
     
         6 . The polypeptide of  claim 5 , wherein said modification is a single polyethylene glycol group covalently bonded to the polypeptide.  
     
     
         7 . The polypeptide of  claim 5 , wherein said polypeptide is covalently bonded to two polyethylene glycol groups.  
     
     
         8 . The polypeptide of  claim 5 , wherein said polypeptide is covalently bonded to multiple polyethylene glycol groups.  
     
     
         9 . The polypeptide of  claim 5 , wherein said polyethylene glycol group has a molecular weight of from about 10 to about 40 kDa.  
     
     
         10 . The polypeptide of  claim 5 , wherein the polyethylene glycol group has a molecular weight of from about 30 to about 40 kDa.  
     
     
         11 . The polypeptide of  claim 5 , wherein said polyethylene glycol group is selected from the group of linear PEG chains and branched PEG chains.  
     
     
         12 . The polypeptide of  claim 5 , wherein said polyethylene glycol group is attached to a group selected from the lysine side chains and the N-terminal amino group of the EphB4 polypeptide.  
     
     
         13 . The polypeptide of  claim 4 , wherein said polypeptide has a serum half-life in vivo at least 50% greater than that of an unmodified EphB4 polypeptide.  
     
     
         14 . The polypeptide of  claim 4 , wherein said polypeptide has a serum half-life in vivo at least 100% greater than that of an unmodified EphB4 polypeptide.  
     
     
         15 . The polypeptide of  claim 4 , wherein the polypeptide is a fusion protein.  
     
     
         16 . The polypeptide of  claim 15 , wherein the polypeptide comprises an albumin protein or fragments thereof.  
     
     
         17 . The polypeptide of  claim 16 , wherein said albumin protein is selected from the group consisting of a human serum albumin (HSA) and bovine serum albumin (BSA).  
     
     
         18 . The polypeptide of  claim 16 , wherein the albumin is a naturally occurring variant.  
     
     
         19 . The polypeptide of  claim 1 , wherein the polypeptide has one or more activities selected from the group consisting of: 
 (a) inhibition of EphrinB2 activity;    (b) inhibition of EphrinB2 kinase activity;    (c) inhibition of the interaction between EphB4 and EphrinB2;    (d) inhibition of EphB4 kinase activity;    (e) inhibition of clustering of Ephrin B2; and    (f) inhibition of clustering of EphB4.    
     
     
         20 . The polypeptide of  claim 4 , wherein the polypeptide has enhanced in vivo stability relative to the unmodified wildtype polypeptide.  
     
     
         21 . A pharmaceutical composition comprising a polypeptide of  claim 1 , and a pharmaceutically acceptable carrier.  
     
     
         22 . A method of inhibiting signaling through Ephrin B2/EphB4 pathway in a cell, comprising contacting the cell with an effective amount of a polypeptide of  claim 1 .  
     
     
         23 . A method of reducing the growth rate of a tumor, comprising administering an amount of a polypeptide of  claim 1 , sufficient to reduce the growth rate of the tumor.  
     
     
         24 . A method for treating a patient suffering from a cancer, comprising administering to the patient a polypeptide of  claim 1 .  
     
     
         25 . A method of inhibiting angiogenesis, comprising contacting a cell with a polypeptide of  claim 1 .  
     
     
         26 . A method for treating a patient suffering from an angiogenesis-associated disease, comprising administering to the patient a polypeptide of  claim 1 .  
     
     
         27 . The polypeptide of  claim 1 , wherein the polypeptide comprises one or more modified amino acid residues.  
     
     
         28 . A cosmetic composition comprising the polypeptide of  claim 1 , and a pharmaceutically acceptable carrier.  
     
     
         29 . A method of reducing the growth rate of a tumor, comprising administering an amount of a polypeptide agent sufficient to reduce the growth rate of the tumor, wherein the polypeptide agent is selected from the group consisting of: 
 (a) a soluble polypeptide comprising an amino acid sequence of an extracellular domain of an EphB4 protein, wherein the EphB4 polypeptide is a monomer and binds specifically to an Ephrin B2 polypeptide;    (b) a soluble polypeptide comprising an amino acid sequence of an extracellular domain of an Ephrin B2 protein, wherein the soluble Ephrin B2 polypeptide is a monomer and binds with high affinity to an EphB4 polypeptide.    
     
     
         30 . The method of  claim 29 , wherein the tumor comprises cells expressing a higher level of EphB4 and/or EphrinB2 than noncancerous cells of a comparable tissue.  
     
     
         31 . A method for treating a patient suffering from a cancer, comprising administering to the patient a polypeptide agent selected from the group consisting of: 
 (a) a soluble polypeptide comprising an amino acid sequence of an extracellular domain of an EphB4 protein, wherein the EphB4 polypeptide is a monomer and binds specifically to an Ephrin B2 polypeptide;    (b) a soluble polypeptide comprising an amino acid sequence of an extracellular domain of an Ephrin B2 protein, wherein the soluble Ephrin B2 polypeptide is a monomer and binds with high affinity to an EphB4 polypeptide.    
     
     
         32 . The method of  claim 31 , wherein the cancer comprises cancer cells expressing EphrinB2 and/or EphB4 at a higher level than noncancerous cells of a comparable tissue.  
     
     
         33 . The method of  claim 31 , wherein the cancer is metastatic cancer.  
     
     
         34 . The method of  claim 31 , wherein the tumor is selected from the group consisting of colon carcinoma, breast tumor, mesothelioma, prostate tumor, squamous cell carcinoma, Kaposi sarcoma, and leukemia.  
     
     
         35 . The method of  claim 31 , wherein the cancer is an angiogenesis-dependent cancer.  
     
     
         36 . The method of  claim 31 , wherein the cancer is an angiogenesis-independent cancer.  
     
     
         37 . The method of  claim 31 , wherein the polypeptide agent is a soluble polypeptide comprising an amino acid sequence of an extracellular domain of an Ephrin B2 protein, wherein the soluble Ephrin B2 polypeptide is a monomer and binds with high affinity to an EphB4 polypeptide and further comprises a modification that increases serum half-life.  
     
     
         38 . The method of  claim 31 , further including administering at least one additional anti-cancer chemotherapeutic agent that inhibits cancer cells in an additive or synergistic manner with the polypeptide agent.  
     
     
         39 . A method of inhibiting angiogenesis, comprising contacting a cell an amount of a polypeptide agent sufficient to inhibit angiogenesis, wherein the polypeptide agent is selected from the group consisting of: 
 (a) a soluble polypeptide comprising an amino acid sequence of an extracellular domain of an EphB4 protein, wherein the EphB4 polypeptide is a monomer and binds specifically to an Ephrin B2 polypeptide;    (b) a soluble polypeptide comprising an amino acid sequence of an extracellular domain of an Ephrin B2 protein, wherein the soluble Ephrin B2 polypeptide is a monomer and binds with high affinity to an EphB4 polypeptide.    
     
     
         40 . A method for treating a patient suffering from an angiogenesis-associated disease, comprising administering to the patient a polypeptide agent selected from the group consisting of: 
 (a) a soluble polypeptide comprising an amino acid sequence of an extracellular domain of an EphB4 protein, wherein the EphB4 polypeptide is a monomer and binds specifically to an Ephrin B2 polypeptide;    (b) a soluble polypeptide comprising an amino acid sequence of an extracellular domain of an Ephrin B2 protein, wherein the soluble Ephrin B2 polypeptide is a monomer and binds with high affinity to an EphB4 polypeptide.    
     
     
         41 . An isolated soluble polypeptide comprising an amino acid sequence of a fibronectin type 3 domain of an EphB4 protein, wherein the polypeptide inhibits tumor growth in a mouse xenograft model of cancer.  
     
     
         42 . The polypeptide of  claim 41 , wherein the polypeptide does not bind to EphrinB2.  
     
     
         43 . The polypeptide of  claim 41 , wherein the polypeptide does not include a substantial portion of the globular domain of an EphB4 protein.  
     
     
         44 . The polypeptide of  claim 41 , wherein the polypeptide comprises an amino acid sequence of amino acids 324-526 of the sequence of  FIG. 65  (SEQ ID NO:10).  
     
     
         45 . The polypeptide of  claim 41 , wherein the polypeptide is a monomer.  
     
     
         46 . The polypeptide of  claim 41 , wherein the polypeptide further comprises a modification that increases serum half-life.  
     
     
         47 . A polypeptide dimer or multimers comprising two or more polypeptides of  claim 41.

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