Methods of reducing immunogenicity against factor VIII in individuals undergoing factor VIII therapy
Inventors
Jiang, Haiyan • Liu, Tongyao • Krishnamoorthy, Sriram • Josephson, Neil • Pierce, Glenn
Assignees
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Publication Number
US-12371747-B2
Publication Date
2025-07-29
Expiration Date
Abstract
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.
Core Innovation
The disclosed method reduces an inhibitory Factor VIII (FVIII) immune response in a subject who has hemophilia A and has developed inhibitory anti-FVIII antibodies. Administration involves a chimeric polypeptide comprising an FVIII polypeptide and an Fc sequence at least 95% identical to amino acids 1458 to 1684 of SEQ ID NO: 2. The subject exhibits specified risk characteristics, including receiving interferon therapy, receiving anti-viral therapy, or carrying a non-FVIII genetic mutation linked with an increased risk of an inhibitory response.
Preclinical studies associate rFVIIIFc treatment with lower anti-FVIII antibody responses than conventional products, reduced pro-inflammatory cytokines, and markers of tolerogenic pathways. Repeated low-dose administration reduces antibody responses upon subsequent challenge while maintaining coagulation activity. Additionally, the chimeric polypeptide exhibits prolonged exposure and an extended half-life relative to conventional recombinant FVIII, which supports less frequent dosing.
Claims Coverage
The provided claims identify one independent claim directed to reducing an inhibitory FVIII immune response in a subject with hemophilia A, comprising three inventive features.
Reducing an inhibitory FVIII immune response
The claim covers a method of reducing an inhibitory Factor VIII (FVIII) immune response in a subject who has hemophilia A and has developed an inhibitory FVIII immune response comprising inhibitory anti-FVIII antibodies.
Administration of an FVIII-Fc chimeric polypeptide
The method comprises administering a chimeric polypeptide comprising an FVIII polypeptide and an Fc comprising an amino acid sequence at least 95% identical to amino acids 1458 to 1684 of SEQ ID NO: 2.
Selection of a subject with specified risk characteristics
The subject is identified as receiving interferon therapy, receiving anti-viral therapy, having a genetic mutation in a gene other than the gene encoding FVIII linked with an increased risk of developing an inhibitory immune response, or having a combination of these characteristics.
The independent claim covers reducing an inhibitory FVIII immune response by administering the specified FVIII-Fc chimeric polypeptide to a subject with hemophilia A, existing inhibitory anti-FVIII antibodies, and at least one specified risk characteristic.
Stated Advantages
Preclinical studies report lower anti-FVIII antibody responses with rFVIIIFc than with conventional recombinant FVIII products such as XYNTHA or ADVATE in hemophilia A mice.
Reported findings include induction of tolerance, markers associated with tolerogenic pathways, and reduced pro-inflammatory cytokines.
Repeated low-dose rFVIIIFc is reported to reduce antibody responses to a subsequent high-dose challenge.
The chimeric polypeptide provides prolonged exposure and an extended half-life relative to conventional rFVIII, supporting less frequent dosing.
The chimeric polypeptide maintains coagulation activity comparable to referenced forms in hemophilia models.
Documented Applications
Reducing an inhibitory FVIII immune response in a subject with hemophilia A who has developed inhibitory anti-FVIII antibodies and is receiving interferon therapy, receiving anti-viral therapy, or has a non-FVIII gene mutation linked with an increased risk of an inhibitory immune response.
Clotting-factor-Fc compositions and kits for inducing immune tolerance.
Comparative animal studies evaluating rFVIIIFc and conventional FVIII products in relation to inhibitory FVIII immune responses, inhibitor titers, cytokines, regulatory T cells, and dendritic-cell markers.
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