US2012064075A1PendingUtilityA1

Chimeric factor vii molecules with enhanced half life and methods of use

53
Individually held — no corporate assignee on recordPriority: Jun 25, 2009Filed: Apr 29, 2011Published: Mar 15, 2012
Est. expiryJun 25, 2029(~2.9 yrs left)· nominal 20-yr term from priority
Inventors:Darrel W. StaffordDengmin FengDavid Mann
C12N 9/6437A61P 7/00C12Y 304/21021A61K 38/00A61P 7/04A61K 38/4846C12N 9/644C12Y 304/21022A61P 7/02H10W 74/137H10W 74/43H10D 62/8503H10D 64/411H10D 30/4755H10D 30/015
53
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Claims

Abstract

The present invention relates to novel proteins and methods of using chimeric Factor VIIa polypeptides.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of treating a bleeding disorder in a subject in need thereof, comprising administering to the subject an effective amount of a chimeric Factor VIIa polypeptide with a prolonged functional lifespan in vivo or prolonged functional half life in vivo as compared with a non-chimeric Factor VIIa polypeptide. 
     
     
         2 . The method of  claim 1 , wherein the chimeric Factor VIIa polypeptide further comprises a domain that mediates binding of a protein to a structural molecule of the extravascular tissue such as a basement membrane component. 
     
     
         3 . The method of  claim 2 , wherein the domain is selected from the group consisting of:
 a) a single chain antibody Fab fragment or single chain variable fragment (scFv) that specifically binds a structural molecule of the extravascular tissue such as a basement membrane component;   b) a laminin binding domain of a laminin binding receptor;   c) a laminin binding domain of a proteoglycan;   d) a laminin binding domain of a bacterial adhesin protein;   e) a nidogen/entactin binding domain;   f) a collagen type 4 binding domain; and   g) any combination of (a)-(f) above.   
     
     
         4 . The method of  claim 1 , wherein the chimeric Factor VIIa polypeptide further comprises a GLA domain of a vitamin K dependent coagulation protein. 
     
     
         5 . The method of  claim 4 , wherein the GLA domain is a Factor IX GLA domain or a Protein S GLA domain. 
     
     
         6 . The method of  claim 1 , wherein the chimeric Factor VIIa polypeptide further comprises an EGF-1 domain of a vitamin K dependent coagulation protein. 
     
     
         7 . The method of  claim 6 , wherein the EGF-1 domain is a Factor IX EGF-1 domain, a Protein S EGF-1 domain, a Factor X EGF-1 domain, a Factor VII EGF-1 domain, a Protein C EGF-1 domain or a Gas 6 EGF-1 domain. 
     
     
         8 . The method of  claim 5 , wherein the chimeric Factor VIIa polypeptide further comprises an EGF-1 domain of Factor IX or an EGF-1 domain of Protein S or an EGF-1 domain of Factor X. 
     
     
         9 . The method of  claim 5 , wherein the GLA domain is a Factor IX GLA domain comprising a substitution of lysine at residue 51 in the amino acid sequence of SEQ ID NO:19 by arginine. 
     
     
         10 . The method of  claim 8 , wherein the GLA domain is a Factor IX GLA domain comprising a substitution of lysine at residue 51 in the amino acid sequence of SEQ ID NO:19 by arginine. 
     
     
         11 . The method of  claim 5 , wherein the GLA domain is a Factor IX GLA domain comprising a substitution of lysine at residue 51 in the amino acid sequence of SEQ ID NO:19 by alanine and/or a substitution of valine at residue 56 in the amino acid sequence of SEQ ID NO:19 by another amino acid. 
     
     
         12 . The method of  claim 8 , wherein the GLA domain is a Factor IX GLA domain comprising a substitution of lysine at residue 51 in the amino acid sequence of SEQ ID NO:19 by alanine and/or a substitution of valine at residue 56 in the amino acid sequence of SEQ ID NO:19 by another amino acid. 
     
     
         13 . The method of  claim 7 , wherein the EGF-1 domain is a Factor VII EGF-1 domain comprising a substitution of isoleucine at residue 129 in the amino acid sequence of SEQ ID NO:18 by alanine. 
     
     
         14 . The method of  claim 7 , wherein the EGF-1 domain is a Factor VII EGF-1 domain comprising a substitution of arginine at residue 139 in the amino acid sequence of SEQ ID NO:18 by alanine. 
     
     
         15 . The method of  claim 8 , wherein the catalytic domain of Factor VII comprises a substitution of methionine at residue 366 of the amino acid sequence of SEQ ID NO:18 with alanine, valine or isoleucine. 
     
     
         16 . The method of  claim 8 , wherein the catalytic domain of Factor VII comprises a substitution of valine at residue 218 of the amino acid sequence of SEQ ID NO:18 with aspartate. 
     
     
         17 . The method of  claim 8 , wherein the catalytic domain of Factor VII comprises a substitution of glutamate at residue 356 of the amino acid sequence of SEQ ID NO:18 with valine. 
     
     
         18 . The method of  claim 8 , wherein the catalytic domain of Factor VII comprises a substitution of methionine at residue 358 of the amino acid sequence of SEQ ID NO:18 with glutamine. 
     
     
         19 . The method of  claim 8 , wherein the chimeric Factor VIIa polypeptide further comprises a domain that mediates binding of a protein to a structural molecule of the extravascular tissue such as a basement membrane component. 
     
     
         20 . The method of  claim 19 , wherein the domain is selected from the group consisting of:
 a) a single chain antibody Fab fragment or single chain variable fragment (scFv) that specifically binds a structural molecule of the extravascular tissue such as a basement membrane component;   b) a laminin binding domain of a laminin binding receptor;   c) a laminin binding domain of a proteoglycan;   d) a laminin binding domain of a bacterial adhesin protein;   e) a nidogen/entactin binding domain;   f) a collagen type 4 binding domain; and   g) any combination of (a)-(f) above.   
     
     
         21 . The method of  claim 1 , wherein the bleeding disorder is selected from the group consisting of: a clotting factor deficiency; defective platelet function; thrombocytopenia; von Willebrand's disease; inhibition of clotting factors; bleeding induced by surgery; bleeding induced by trauma and any combination thereof. 
     
     
         22 . The method of  claim 21 , wherein the bleeding disorder is a clotting factor deficiency. 
     
     
         23 . The method of  claim 22 , wherein the clotting factor deficiency is hemophilia. 
     
     
         24 . The method of  claim 1 , wherein treating the bleeding disorder comprises administering to the subject a nucleic acid molecule comprising a nucleotide sequence encoding the chimeric Factor VIIa polypeptide. 
     
     
         25 . A method of treating a bleeding disorder in a subject in need thereof, comprising administering to the subject an effective amount of a modified Factor VIIa polypeptide that has a reduced affinity for tissue factor as compared with a non-modified Factor VIIa polypeptide. 
     
     
         26 . A method of treating a bleeding disorder in a subject in need thereof, comprising administering to the subject an effective amount of a modified Factor VIIa polypeptide that has an increased binding affinity for a basement membrane component as compared with a non-modified Factor VIIa polypeptide. 
     
     
         27 . A method of treating a bleeding disorder in a subject in need thereof, comprising administering to the subject an effective amount of a modified Factor VIIa polypeptide that has a reduced clearance rate from the body of the subject or reduced binding to Factor VIIa protease inhibitors that inactivate FVIIa protease activity or facilitate the clearance of bound FVIIa in the body of the subject as compared with a non-modified Factor VIIa polypeptide.

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