Factor VIII chimeric and hybrid polypeptides, and methods of use thereof
Inventors
Dumont, Jennifer A. • Low, Susan • Bitonti, Alan J. • Pierce, Glenn • Luk, Alvin • Jiang, Haiyan • McKinney, Byron • Ottmer, Matt • Sommer, Jurg • Nugent, Karen • Li, Lian • Peters, Robert T.
Assignees
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Publication Number
US-12186375-B2
Publication Date
2025-01-07
Expiration Date
Abstract
The present invention provides methods of administering Factor VIII (processed FVIII, single chain FVIII, or a combination thereof); methods of administering chimeric and hybrid polypeptides comprising Factor VIII; chimeric and hybrid polypeptides comprising Factor VIII; polynucleotides encoding such chimeric and hybrid polypeptides; cells comprising such polynucleotides; and methods of producing such chimeric and hybrid polypeptides using such cells.
Core Innovation
The invention relates to Factor VIII chimeric polypeptides and their use in treating hemophilia A. The chimeric polypeptides comprise a Factor VIII portion and a second portion, where the Factor VIII portion comprises processed Factor VIII and single chain Factor VIII, and a specified fraction of the Factor VIII portion is single chain Factor VIII.
The invention provides a method of treating a subject in need of surgical prophylaxis, peri-operative management, or treatment for surgery. The method administers a therapeutic dose of the chimeric polypeptide at a dosing interval of between about 12 hours and 24 hours to a subject having hemophilia A, with about 10% to about 40% of the Factor VIII portion being single chain Factor VIII.
The disclosure further includes sequence identity constraints for the single chain Factor VIII and for the second portion, as well as chimeric constructs such as Factor VIII-Fc and hybrids with Fc, including an FVIIIFc monomer dimer hybrid. It also references pharmacokinetic performance using metrics such as AUC, half-life, and clearance.
Claims Coverage
The claim set centers on treating hemophilia A subjects needing surgical prophylaxis, peri-operative management, or surgery using a Factor VIII chimeric polypeptide administered at a 12 to 24 hour dosing interval. Six inventive features are present in the consolidated claims coverage.
Dosing interval for surgical prophylaxis with a Factor VIII chimeric polypeptide
A method for treating a subject in need of surgical prophylaxis, peri-operative management, or treatment for surgery by administering a therapeutic dose of a chimeric polypeptide comprising a Factor VIII portion and a second portion, administered at a dosing interval between about 12 hours and 24 hours, wherein the subject has hemophilia A.
Processed and single chain Factor VIII composition ratio in the Factor VIII portion
The Factor VIII portion comprises processed Factor VIII and single chain Factor VIII, with about 10% to about 40% of the Factor VIII portion being single chain Factor VIII.
Therapeutic dose range for the chimeric polypeptide
The chimeric polypeptide is administered at a therapeutic dose of about 10 IU/kg to about 100 IU/kg.
Sequence identity constraint for the single chain Factor VIII portion
The single-chain Factor VIII comprises an amino acid sequence at least 95% identical to amino acids 20 to 1457 of SEQ ID NO: 2.
Sequence identity constraint for the second portion
The second portion contains an amino acid sequence that is at least 95% identical to amino acids 21 to 247 of SEQ ID NO: 4.
Specific chimeric polypeptide type as an FVIIIFc monomer dimer hybrid
The chimeric polypeptide is an FVIIIFc monomer dimer hybrid.
The claims are directed to a hemophilia A treatment method for surgical prophylaxis, peri-operative management, or surgery, using a Factor VIII chimeric polypeptide that contains processed Factor VIII and single chain Factor VIII in a specified fraction and is administered every about 12 to 24 hours. Dependent features further constrain dose, sequence identity, and chimeric polypeptide form.
Stated Advantages
Preserves FVIII functionality as indicated by chromogenic and one-stage aPTT activity, Factor Xa generation, interaction with Factor IXa and von Willebrand factor, and inactivation by activated protein C.
Provides in vivo efficacy in a HemA mouse tail vein transection model.
Documented Applications
Surgical prophylaxis for hemophilia A.
Peri-operative management for hemophilia A.
Treatment for surgery for a subject with hemophilia A.
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