IP Library › Patent Application 14862934
Patent Application
App. No. 14/862,934

FACTOR VIII VARIANTS HAVING A DECREASED CELLULAR UPTAKE

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Patent No.
US None
App. No.
14/862,934
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 (21)

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.