Factor VIII chimeric proteins and uses thereof
Inventors
Chhabra, Ekta Seth • Liu, Tongyao • Peters, Robert T. • Kulman, John
Assignees
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Publication Number
US-12617839-B2
Publication Date
2026-05-05
Expiration Date
Abstract
The present invention provides a chimeric protein comprising a first polypeptide which comprises a FVIII protein and a first Ig constant region or a portion thereof and a second polypeptide which comprises a VWF protein comprising the D′ domain and D3 domain of VWF, a XTEN sequence having less than 288 amino acids in length, and a second Ig constant region or a portion thereof, wherein the first polypeptide and the second polypeptide are associated with each other. The invention also includes nucleotides, vectors, host cells, methods of using the chimeric proteins.
Core Innovation
The disclosure relates to Factor VIII (FVIII) and von Willebrand Factor (VWF) chimeric proteins comprising two polypeptide chains. The chimeric constructs combine FVIII protein components and VWF D′ and D3 domains with XTEN sequences and associated immunoglobulin constant or Fc regions. Certain embodiments further incorporate a thrombin-cleavable linker comprising an FVIII a2 region, with XTEN sequences positioned within FVIII or between VWF and immunoglobulin regions.
The chimeric platform addresses endogenous VWF-mediated clearance of Factor VIII. The VWF D′ and D3 domains shield, stabilize, and protect the Factor VIII component, while the associated XTEN sequences and Fc regions provide pharmacokinetic enhancement and extended half-life. Therapeutic methods utilize these chimeric proteins for the treatment of Factor VIII deficiency disorders, such as hemophilia A, across prophylactic and on-demand treatment contexts.
The chimeric heterodimers maintain Factor VIII activity and acute efficacy comparable to B-domain-deleted FVIII, while providing extended bleeding protection and survival. Thrombin-mediated release of the VWF D′ and D3 domains occurs without adverse effects on pharmacokinetics or in vivo activity. The constructs serve in therapeutic and prophylactic administration methods for conditions comprising Factor VIII deficiency, hemophilia A, and von Willebrand Disease.
Claims Coverage
The independent claims include 14 claims: claims 1, 11, 12, 13, 55, 65, 66, 81, 90, 91, 92, 123, 130, and 131. They cover methods of treating Factor VIII-deficiency disorders or administering two-chain chimeric proteins, with variations in chain structure, XTEN sequences, linkers, and immunoglobulin or Fc regions.
FVIII and VWF chimeric protein with immunoglobulin constant regions
Independent claim 1 covers treating a disorder caused by Factor VIII deficiency using associated FVIII and VWF polypeptide chains, wherein the FVIII chain contains an inserted XTEN sequence and an immunoglobulin constant region, and the VWF chain contains a second XTEN sequence, non-cysteine substitutions, a thrombin-cleavable FVIII a2-region linker, and a second immunoglobulin constant region.
Intravenous treatment using FVIII and VWF chains with disulfide-bonded Fc regions
Independent claims 11 and 55 cover intravenous treatment of a Factor VIII-deficiency disorder using an XTEN-containing FVIII chain and a VWF chain comprising D′ and D3 domains, specified alanine substitutions, a second XTEN sequence, and a thrombin-cleavable linker, with the chains associated through disulfide-bonded Fc regions.
Intravenous treatment with a sequence-defined FVIII and VWF chimeric protein
Independent claim 12 covers intravenous treatment of a Factor VIII-deficiency disorder using an FVIII chain having an inserted XTEN sequence and an Fc region, paired with a VWF D′ and D3 chain having non-cysteine substitutions, a second XTEN sequence, a thrombin-cleavable FVIII a2-region linker, and disulfide-associated Fc regions.
FVIII and VWF chains linked through immunoglobulin constant regions
Independent claims 13 and 92 cover intravenous administration of a chimeric protein comprising an XTEN-containing FVIII chain and a VWF D′ and D3 chain linked through an XTEN sequence and a linker to a second immunoglobulin constant region, with the chains associated through their immunoglobulin constant regions.
Prophylactic treatment of hemophilia A with an FVIII and VWF chimeric protein
Independent claim 65 covers prophylactic intravenous treatment of hemophilia A using an XTEN-containing FVIII chain and a VWF D′ and D3 chain with alanine substitutions, joined by a thrombin-cleavable FVIII a2-region linker and disulfide-bonded Fc regions.
Hemophilia A treatment with defined XTEN sequence length ranges
Independent claims 66 and 131 cover intravenous treatment of hemophilia A using an FVIII chain comprising a first XTEN sequence and an Fc region paired with a VWF D′ and D3 chain comprising a second XTEN sequence, specifying defined length ranges for the XTEN sequences, a thrombin-cleavable linker, and disulfide-associated Fc regions.
Administration of an immunoglobulin constant region chimeric protein
Independent claim 81 covers intravenous administration to a subject with hemophilia A of a two-chain chimeric protein comprising an XTEN-inserted FVIII chain, a VWF D′ and D3 chain, XTEN sequences, a thrombin-cleavable FVIII a2-region linker, and associated immunoglobulin constant regions.
Administration of an FVIII and VWF chimeric protein with disulfide-bonded Fc regions
Independent claims 90 and 123 cover intravenous administration to a subject with hemophilia A of an FVIII–XTEN–Fc chain and a VWF chain comprising specified alanine substitutions, an XTEN sequence, a thrombin-cleavable linker, and an Fc region associated through a disulfide bond.
Administration of an FVIII variant with a shorter VWF-associated XTEN sequence
Independent claim 91 covers intravenous administration to a subject with hemophilia A of a sequence-defined FVIII variant with an inserted XTEN sequence and an Fc region, paired with a VWF chain containing specified substitutions, a shorter second XTEN sequence, a thrombin-cleavable linker, and disulfide-associated Fc regions.
Prophylactic administration of an FVIII and VWF chimeric protein
Independent claim 130 covers prophylactic intravenous administration to a subject with hemophilia A of an FVIII–XTEN–Fc chain paired with a VWF chain comprising specified alanine substitutions, a second XTEN sequence, a thrombin-cleavable FVIII a2-region linker, and disulfide-associated Fc regions.
The independent claims cover treatment or administration methods using two-chain FVIII and VWF chimeric proteins. Shared claim elements encompass XTEN-containing polypeptide chains and associated immunoglobulin constant or Fc regions, with claim-specific variations in VWF substitutions, linker structure, XTEN sequence lengths, and prophylactic or on-demand administration contexts.
Stated Advantages
The VWF D′ and D3 fragment shields FVIII from endogenous VWF-mediated clearance while stabilizing and protecting FVIII.
XTEN sequences and Fc regions provide pharmacokinetic and solubility benefits, including extended half-life.
A shorter VWF-associated XTEN sequence improves pharmacokinetics, including increased terminal half-life, increased area under the curve, and reduced clearance compared with reference embodiments.
The described constructs retain Factor VIII activity, acute efficacy comparable to B-domain-deleted FVIII, and protection against rebleeding after pre-injury administration.
The thrombin-cleavable linker enables D′D3 release without observed adverse effects on pharmacokinetics or in vivo activity.
Fc-mediated tuning and FcRn binding are associated with extended half-life.
Documented Applications
Treatment of disorders caused by or comprising Factor VIII deficiency, including hemophilia A.
Prophylactic or on-demand treatment of bleeding disorders, including acute bleeding and surgical contexts.
Treatment of Von Willebrand Disease, including type 3.
Experimental assessment of bleeding outcomes, survival, and acute efficacy in hemophilia A mouse models.
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