IP Library › Granted Patent US 12,252,528
Granted Patent B2
US 12,252,528 · App. 17/279,961 · Granted Mar 18, 2025

Compositions and methods for modulating Factor VIII function

Inventors: Valder R. Arruda (Philadelphia, PA); Benjamin Samelson-Jones (Wynnewood, PA)
Assignee: THE CHILDREN'S HOSPITAL OF PHILADELPHIA
C07K14/755A61K38/00
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Quick Facts
Patent No.
US 12,252,528
App. No.
17/279,961
Granted
Mar 18, 2025
Kind
B2
Abstract

Factor VIII variants and methods of use thereof are disclosed.

Claims (28)

1. A Factor VIII (FVIII) variant, wherein said FVIII variant comprises SEQ ID NO: 1, except (i) wherein the Lys at position 659 is substituted with another amino acid, (ii) wherein the amino acids at positions 560, 561, 712, and 713 may be optionally substituted with another amino acid, and (wherein the B-domain, consisting of amino acids 741-1648 of SEQ ID NO: 1, is replaced with an amino acid sequence which shares at least 90% sequence identity with SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID No: 18.

2. The FVIII variant of claim 1 , wherein the B-domain is replaced with an amino acid sequence consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18.

3. The FVIII variant of claim 1 , wherein the B-domain is replaced with an amino acid sequence consisting of SEQ ID NO: 18.

4. The FVIII variant of claim 1 , further comprising a substitution mutation of the Asp at position 560, the Gln at position 561, the Asp at position 712, and/or the Lys at position 713.

5. A Factor VIII (FVIII) variant, wherein said FVIII variant comprises amino acids 1-740 and 1649-2332 of SEQ ID NO: 1, except (i) wherein the Lys at position 659 is substituted with another amino acid, and (ii) wherein the amino acids at positions 560, 561, 712, and 713 may be optionally substituted with another amino acid.

6. The FVIII variant of claim 5 ,

wherein the Lys at position 659 is substituted with Trp, Arg, Ala, His, Tyr, Asp, Thr, Ser, Val, Phe, Gln, or Cys.

7. The FVIII variant of claim 5 , further comprising a substitution mutation of the Asp at position 560.

8. The FVIII variant of claim 5 , further comprising a substitution mutation of the Gln at position 561.

9. The FVIII variant of claim 5 , further comprising a substitution mutation of the Asp at position 712.

10. The FVIII variant of claim 5 , further comprising a substitution mutation of the Lys at position 713.

11. A composition comprising at least one FVIII variant of claim 1 and at least one pharmaceutically acceptable carrier.

12. A method for treatment of a hemostasis related disorder in a patient in need thereof comprising administration of a therapeutically effective amount of the FVIII variant of claim 1 in a pharmaceutically acceptable carrier.

13. The method of claim 12 , wherein said hemostasis related disorder is hemophilia A.

14. An isolated nucleic acid molecule encoding the FVIII variant of claim 1 , optionally wherein said FVIII variant comprises a signal peptide.

15. An expression vector comprising the nucleic acid molecule of claim 14 operably linked to a regulatory sequence, optionally wherein the vector is selected from the group consisting of an adenoviral vector, an adenovirus-associated vector, a retroviral vector, a plasmid, and a lentiviral vector.

16. A host cell comprising the vector of claim 15 , optionally wherein said host cells are human cells.

17. A method for treatment of a hemostasis related disorder in a patient in need thereof comprising administration of a therapeutically effective amount of the vector of claim 15 in a pharmaceutically acceptable carrier.

18. The FVIII variant of claim 5 , wherein the Lys at position 659 is substituted with Cys.

19. A composition comprising at least one FVIII variant of claim 5 and at least one pharmaceutically acceptable carrier.

20. The FVIII variant of claim 1 , wherein the Lys at position 659 is substituted with Trp, Arg, Ala, His, Tyr, Asp, Thr, Ser, Val, Phe, Gln, or Cys.

21. The FVIII variant of claim 1 , wherein the Lys at position 659 is substituted with Val, Phe, Ser, Gln, or Cys.

22. The FVIII variant of claim 1 , wherein the Lys at position 659 is substituted with Val.

23. The FVIII variant of claim 5 , wherein the Lys at position 659 is substituted with Val, Phe, Ser, Gln, or Cys.

24. The FVIII variant of claim 5 , wherein the Lys at position 659 is substituted with Val.

25. The FVIII variant of claim 1 , wherein the B-domain is replaced with an amino acid sequence consisting of SEQ ID NO: 13.

26. The FVIII variant of claim 25 , wherein the Lys at position 659 is substituted with Val.

27. A heterotrimeric FVIIIa variant comprising amino acids 1-372, 373-740, and 1690-2332 of SEQ ID NO: 1, except (i) wherein the Lys at position 659 is substituted with another amino acid, and (ii) wherein the amino acids at positions 560, 561, 712, and 713 may be optionally substituted with another amino acid.

Assignments (2)
CONFIRMATORY LICENSE Recorded Nov 22, 2023
From: CHILDREN'S HOSPITAL OF PHILADELPHIA
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065649/0026 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 17, 2021
From: ARRUDA, VALDER; SAMELSON-JONES, BENJAMIN
To: THE CHILDREN'S HOSPITAL OF PHILADELPHIA
Reel/Frame 056578/0077 →
Continuity (2)
Provisional Application 62749182 · Oct 23, 2018
Related Publication 20220033475A1 · Feb 3, 2022
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