US2016002314A1PendingUtilityA1

Factor viii variants having a decreased cellular uptake

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Assignee: NOVO NORDISK ASPriority: Sep 15, 2010Filed: Sep 23, 2015Published: Jan 7, 2016
Est. expirySep 15, 2030(~4.2 yrs left)· nominal 20-yr term from priority
Inventors:Henriet MeemsAlexander Benjamin MeijerKoenraad MertensOle Hvilsted OlsenKasper LamberthPeder Lisby NoerbyLaust Bruun JohnsenMarianne Hjortnes KjalkeHenning Ralf StennickeJohannes Jacobus VoorbergMaartje Van Den Biggelaar
A61K 38/00A61P 7/04C07K 14/755A61P 7/00
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Claims

Abstract

The present invention relates to modified coagulation factors. In particular, the present invention relates to modied Factor VIII molecules having decreased cellular uptake.

Claims

exact text as granted — not AI-modified
1 . A recombinant FVIII variant having FVIII activity, wherein said variant comprises 2-10 substitutions of surface accessible positively charged amino acid residues in the FVIII C1 foot and/or the C2 foot, wherein said surface accessible charged amino acid residues are substituted with alanine or glutamine and wherein the substitutions result in decreased cellular uptake of said FVIII variant. 
     
     
         2 . The recombinant FVIII variant according to  claim 1 , wherein said variant comprises at least two substitutions of surface accessible positively charged amino acid residues in the C1 foot. 
     
     
         3 . The recombinant FVIII variant according  claim 1 , wherein said variant comprises at least two substitutions of surface accessible positively charged amino acid residues in the C2 foot. 
     
     
         4 . The recombinant FVIII variant according to  claim 1 , wherein said variant comprises at least one substitution of a surface accessible positively charged amino residue in the C1 foot and at least one substitution of a surface accessible charged amino acid residue in the C2 foot. 
     
     
         5 . The recombinant FVIII variant according to  claim 1 , wherein said variant comprises a pair of substitutions of surface accessible positively charged amino acid residues, wherein the distance between the pair of substitutions is at least 15 Å. 
     
     
         6 . The recombinant FVIII variant according to  claim 1 , wherein said variant comprises a substitution of K2092. 
     
     
         7 . The recombinant FVIII variant according to  claim 6 , wherein said K2092 substitution is combined with a substitution of R2215. 
     
     
         8 . The recombinant FVIII variant according to  claim 6 , wherein said K2092 substitution is combined with a substitution of K2249. 
     
     
         9 . The recombinant FVIII variant according to  claim 1 , wherein said variant comprises a substitution of R2090. 
     
     
         10 . The recombinant FVIII variant according to  claim 1 , wherein said variant comprises a substitution of K2065. 
     
     
         11 . The recombinant FVIII variant according to  claim 10 , wherein said K2065 substitution is combined with a substitution of R2215. 
     
     
         12 . The recombinant according to  claim 10 , wherein said K2065 substitution is combined with a substitution of K2249. 
     
     
         13 . The recombinant FVIII variant according to  claim 1 , wherein said variant has decreased LRP binding. 
     
     
         14 . The recombinant FVIII variant according to  claim 1 , wherein said variant has decreased immunogencity. 
     
     
         15 . The recombinant FVIII variant according to  claim 1 , wherein the FVIII variant is conjugated to a half life extending moiety. 
     
     
         16 . The recombinant FVIII variant according to  claim 1 , wherein said variant furthermore comprises the F2093A mutation. 
     
     
         17 . A recombinant FVIII variant, wherein said variant comprises a K2092A substitution and a F2093A substitution, wherein said variant is conjugated with a half life extending moiety. 
     
     
         18 . A pharmaceutical composition comprising the recombinant FVIII variant according to  claim 1 . 
     
     
         19 . The pharmaceutical composition comprising the recombinant FVIII variant of  claim 17 . 
     
     
         20 . A method for treating haemophilia comprising administering the recombinant FVIII variant according to  claim 1  to a subject in need thereof. 
     
     
         21 . The method for treating haemophilia comprising administering the recombinant FVIII variant according to  claim 17  to a subject in need thereof.

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