US2014328819A1PendingUtilityA1

Coagulation factor vii compositions and methods of making and using same

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Assignee: AMUNIX OPERATING INCPriority: Feb 3, 2009Filed: Mar 18, 2014Published: Nov 6, 2014
Est. expiryFeb 3, 2029(~2.6 yrs left)· nominal 20-yr term from priority
Inventors:Volker SchellenbergerJoshua SilvermanWillem P. StemmerChia-Wei WangBenjamin SpinkNathan GeethingWayne To
C07K 2319/31C07K 2319/00A61P 7/04C12Y 304/21022A61K 38/00C12N 9/6437C12N 15/70A61P 7/02C07K 14/001C12N 9/644C07K 2319/50
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Claims

Abstract

The present invention relates to compositions comprising factor VII coagulation factors linked to extended recombinant polypeptide (XTEN), isolated nucleic acids encoding the compositions and vectors and host cells containing the same, and methods of making and using such compositions in treatment of coagulation factor-related diseases, disorders, and conditions.

Claims

exact text as granted — not AI-modified
1 - 27 . (canceled) 
     
     
         28 . A factor VII fusion protein comprising a factor VII polypeptide fused to an extended recombinant polypeptide (XTEN), wherein the XTEN comprises an amino acid sequence at least 90% identical to SEQ ID NO: 37, and wherein the XTEN is characterized in that
 (a) the sum of glycine (C), alanine (A), serine (S), threonine (I), glutamate (E) and proline (P) residues constitutes at least 80% of the total amino acids of the XTEN; and   (b) the XTEN is non-repetitive such that
 (i) the XTEN contains no three contiguous amino acids that are identical unless the amino acids are serine; or 
 (ii) at least 80% of the XTEN comprises one or more sequence motifs, each of the sequence motifs comprises from 9 to 14 amino acid residues, wherein any two contiguous amino acid residues do not occur more than twice in each of the sequence motifs. 
   
     
     
         29 . The factor VII fusion protein of  claim 28 , wherein the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes at least 90% of the total amino acids of the XTEN. 
     
     
         30 . The factor VII fusion protein of  claim 28 , wherein the XTEN is characterized in that the sum of asparagine and glutamine residues is less than 10% of the total amino acids of the XTEN. 
     
     
         31 . The factor VII fusion protein of  claim 28 , Wherein the XTEN is further characterized in that the sum of methionine and tryptophan residues is less than 2% of the total amino acids of the XTEN. 
     
     
         32 . The factor VII fusion protein of  claim 28 , wherein the XTEN comprises at least 48 amino acid residues, at least 60 amino acid residues, at least 72 amino acid residues, at least 84 amino acid residues, or at least 96 amino acid residues. 
     
     
         33 . The factor VII fusion protein of  claim 28 , wherein the XTEN comprises 144 amino acid residues or 288 amino acid residues. 
     
     
         34 . The factor VII fusion protein of  claim 28 , wherein the XTEN comprises an amino acid sequence at least 90% identical to SEQ ID NO: 225, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 239, SEQ ID NO: 243, SEQ ID NO: 249, SEQ ID NO: 255, SEQ ID NO: 257, SEQ ID NO: 265, or SEQ ID NO: 283. 
     
     
         35 . The factor VII fusion protein of  claim 28 , wherein the XTEN comprises an amino acid sequence at least 95% identical to SEQ ID NO: 225, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 239, SEQ ID NO: 243, SEQ ID NO: 249, SEQ ID NO: 255, SEQ ID NO: 257, SEQ ID NO: 265, or SEQ ID NO: 283. 
     
     
         36 . The factor VII fusion protein of  claim 28 , wherein the XTEN comprises SEQ ID NO: 225, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 239, SEQ ID NO: 243, SEQ ID NO: 249, SEQ ID NO: 255, SEQ ID NO: 257, SEQ ID NO: 265, or SEQ ID NO: 283. 
     
     
         37 . The factor VII fusion protein of  claim 28 , wherein the XTEN comprises SEQ ID NO: 229. 
     
     
         38 . A factor VII fusion protein comprising a factor VII polypeptide fused to an XTEN, wherein the XTEN comprises two or more sequence motifs, wherein at least one of the two or more sequence motifs is SEQ ID NO: 37. 
     
     
         39 . The factor VII fusion protein of  claim 38 , wherein the XTEN is characterized in that
 (a) the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes at least 80% of the total amino acids of the XTEN; and   (b) the XTEN is non-repetitive such that
 (i) the XTEN contains no three contiguous amino acids that are identical unless the amino acids are serine; or 
 (ii) at least 80% of the XTEN comprises one or more sequence motifs, each of the sequence motifs comprises from 9 to 14 amino acid residues, wherein any two contiguous amino acid residues do not occur more than twice in each of the sequence motifs. 
   
     
     
         40 . The factor VII fusion protein of  claim 39 , wherein the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes at least 90% of the total amino acids of the XTEN. 
     
     
         41 . The factor VII fusion protein of  claim 28 , wherein a terminal half-life of the fusion protein is longer than the terminal half-life of a protein consisting of the factor VII polypeptide when administered to a subject. 
     
     
         42 . The factor VII fusion protein of  claim 28 , wherein the XTEN is fused to the C-terminus of the factor VII polypeptide. 
     
     
         43 . The factor VII fusion protein of  claim 28 , further comprising a cleavage sequence fused to the factor VII polypeptide, the XTEN, or both. 
     
     
         44 . The factor VII fusion protein of  claim 43 , wherein the cleavage sequence is cleavable by a mammalian protease selected from factor XIa, factor XIIa, kallikrein, factor VIIa, factor IXa, factor IIa (thrombin), Elastase-2, MMP-12, MMP12, MMP-17, MMP-20, or any combination thereof. 
     
     
         45 . The factor VII fusion protein of  claim 44 , wherein the cleavage sequence, when cleaved by a mammalian protease, releases the XTEN from the factor VII polypeptide. 
     
     
         46 . The factor VII fusion protein of  claim 28 , wherein the XTEN is incorporated between any two adjacent domains contained in the factor VII polypeptide. 
     
     
         47 . The factor VII fusion protein of  claim 46 , wherein the two adjacent domains are selected from Gla and EGF1, EGF1 and EGF2, EFG2 and activation peptide (AP), or activation peptide and peptidase S1 (Pro). 
     
     
         48 . The factor VII fusion protein of  claim 28 , comprising Formula VII:
   (Gla)-(XTEN) u -(EGF1)-(XTEN) v -(EGF2)-(AP1)-(XTEN) w -(AP2)-(XTEN) x -(Pro)-(S) y -(XTEN) z      wherein independently for each occurrence,   (a) Gla is a Gla domain of the factor VII polypeptide;   (b) EGF1 is an EGF1 domain of the factor VII polypeptide;   (c) EGF2 is an EGF2 domain of the factor VII polypeptide;   (d) AP 1 is a portion of an activator peptide domain of the factor VII polypeptide;   (e) AP2 is a portion of an activator peptide domain of factor IX that includes at least a first cleavage sequence;   (f) PRO is a protease domain of the factor VII polypeptide;   (g) S is a spacer sequence having between 1 to about 50 amino acid residues and comprising an optional cleavage sequence;   (h) u is either 0 or 1;   (i) v is either 0 or 1;   (j) x is either 0 or 1;   (k) y is either 0 or 1; and   (l) z is either 0 or 1, with the proviso that u+v+x+y+z>1.   
     
     
         49 . The factor VII fusion protein of  claim 48 , wherein v is 1. 
     
     
         50 . The factor VII fusion protein of  claim 28 , wherein the factor VII polypeptide comprises an amino acid sequence at least 90% identical to a sequence selected from SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30, wherein the factor VII polypeptide has factor VII activity. 
     
     
         51 . The factor VII fusion protein of  claim 50 , wherein the factor VII polypeptide comprises an amino acid sequence at least 95% identical to a sequence selected from SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30. 
     
     
         52 . The factor VII fusion protein of  claim 28 , wherein the factor VII polypeptide comprises an amino acid sequence selected from SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30. 
     
     
         53 . A pharmaceutical composition comprising the factor VII fusion protein of  claim 28  and a pharmaceutically acceptable carrier. 
     
     
         54 . A pharmaceutical composition comprising the factor VII fusion protein of  claim 38  and a pharmaceutically acceptable carrier. 
     
     
         55 . A method of treating coagulopathy in a subject, comprising administering to the subject a composition comprising a therapeutically effective amount of the factor VII fusion protein of  claim 28 . 
     
     
         56 . The method of  claim 55 , wherein the coagulopathy is hemophilia A or hemophilia B. 
     
     
         57 . The method of  claim 55 , wherein the therapeutically effective amount of the factor VII fusion protein is sufficient to bypass the need for exogenously administered factor VIII and/or factor IX to yield a comparable therapeutic effect. 
     
     
         58 . A method of treating a bleeding episode in a subject comprising: administering to the subject a composition comprising a therapeutically effective amount of the factor VII fusion protein of  claim 28 . 
     
     
         59 . A method of treating a subject deficient in a clotting protein, comprising: administering to the subject a composition comprising a therapeutically effective amount of the factor VII fusion protein of  claim 28 . 
     
     
         60 . The method of  claim 59 , wherein the clotting protein comprises wild-type factor VII, factor IX, or factor XI. 
     
     
         61 . The factor VII fusion protein of  claim 28 , wherein the XTEN comprises SEQ ID NO: 63 or SEQ ID NO:65. 
     
     
         62 . A factor VII fusion protein comprising a factor VII polypeptide fused to an XTEN, which comprises SEQ ID NO:63. 
     
     
         63 . A factor VII fusion protein comprising a factor VII polypeptide fused to an XTEN, which comprises SEQ ID NO:65. 
     
     
         64 . A method of controlling or ameliorating a bleeding episode in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the recombinant factor VII fusion protein of  claim 62 . 
     
     
         65 . A method of controlling or ameliorating a bleeding episode in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the recombinant factor VII fusion protein of  claim 63 .

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