Methods of reducing immunogenicity against factor VIII in individuals undergoing factor VIII therapy
The present disclosure provides methods of administering chimeric and hybrid Factor VIII (FVIII) polypeptides comprising FVIII and Fc to subjects at risk of developing inhibitory FVIII immune responses, including anti-FVIII antibodies and/or cell-mediated immunity. The administration is sufficient to promote coagulation and to induce immune tolerance to FVIII. The chimeric polypeptide can comprise full-length FVIII or a FVIII polypeptide containing a deletion, e.g., a full or partial deletion of the B domain.
1. A method of inhibiting development of an inhibitor of a clotting factor in a subject in need thereof, wherein the subject is a fetus, the method comprising administering to the mother of the subject a chimeric polypeptide comprising a Factor VIII (“FVIII”) portion and an Fc portion,
wherein the subject has a mutation in a FVIII gene, and
wherein the FVIII portion consists essentially of or consists of the A2 domain of FVIII, the C2 domain of FVIII, or both the A2 domain and the C2 domain of FVIII.
2. The method of claim 1 , wherein the chimeric polypeptide is a FVIII monomer dimer hybrid.
3. The method of claim 1 , wherein the subject has a genetic polymorphism associated with decreased CTLA-4.
4. The method of claim 1 , wherein the subject has a genetic polymorphism associated a mutation in DR15 or DQB0602 MHC Class II molecules.
5. The method of claim 1 , wherein the chimeric polypeptide comprises one or more half-life extending moieties in addition to the Fc portion.
6. The method of claim 1 , wherein the chimeric polypeptide is administered intravenously.
7. The method of claim 1 , wherein the subject has severe hemophilia.
8. The method of claim 1 , wherein the subject has a relative who has previously developed an inhibitory immune response.
9. The method of claim 1 , wherein the subject has a genetic polymorphism associated with increased TNF-α.
10. The method of claim 1 , wherein the subject has a genetic polymorphism associated with increased IL10.
11. The method of claim 1 , wherein the Fc portion is identical to amino acids 1458 to 1683 of SEQ ID NO:2 or amino acids 2352 to 2577 of SEQ ID NO:6.
12. The method of claim 1 , wherein the chimeric polypeptide is in the form of a hybrid comprising a second polypeptide in association with the chimeric polypeptide, wherein the second polypeptide consists essentially of an Fc.
13. The method of claim 1 , wherein the chimeric polypeptide is administered at a dose of 10-100 IU/kg.
14. The method of claim 1 , wherein said administration decreases the incidence of spontaneous bleeding.