Methods of treating hemophilic arthropathy using chimeric clotting factors
Inventors
Dumont, Jennifer • Jain, Nisha • GLAZEBROOK, Desilu
Assignees
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Publication Number
US-12161696-B2
Publication Date
2024-12-10
Expiration Date
Abstract
The present disclosure provides methods treating reversible hemophilic arthropathy of a joint in a human having hemophilia comprising administering to the human an effective amount of a chimeric protein or composition comprising a clotting factor and an Fc region.
Core Innovation
The disclosed subject matter relates to engineering chimeric clotting-factor proteins that include factor IX (FIX) and an Fc region (rFIXFc), including FIX and Fc-fusion approaches. The engineering options include insertion of half-life-extending moieties into mature Padua FIX at specified residues, including within the activation peptide domain and immediately downstream of residue 166 within FIX.
The document further outlines alternative chimeric half-life extension or targeting moieties for chimeric FIX proteins. Such moieties include albumin or albumin-binding polypeptide (ABP) such as an Albu tag, XTEN, VWF fragments including VWF D' and D3 domains, C-terminal peptide (CTP), PAS, HAP, transferrin, PEG, HES, and PSA, as well as clearance receptor fragments including LRP1 and related receptors such as LDLR, VLDLR, and megalin (LRP-2).
In addition, the disclosed material connects these protein-construct designs to therapeutic contexts involving reversal of hemophilic arthropathy and associated joint pathology, including arthropathy with synovitis. It further indicates that rFIXFc and related Fc-containing constructs are associated with immune-modulation and biodistribution studies, including characterization of interactions with Fcγ receptors and immune cell markers described in the document.
Claims Coverage
Independent claim coverage includes one independent method claim directed to prophylactically reversing hemophilic arthropathy in a human with hemophilia B using a chimeric FIX-Fc protein (rFIXFc) without surgical intervention. The independent claim is supported by dependent claims that refine subject stage and synovitis status and add specific joint pathology features, receptor-binding specificity, and quantitative dosing and dosing-interval constraints.
Prophylactic rFIXFc administration without surgical intervention
Selecting a human subject with hemophilia B and stage I, II, or III hemophilic arthropathy with synovitis, and prophylactically administering an effective amount of a chimeric protein comprising FIX and an Fc region (rFIXFc) such that the hemophilic arthropathy is reversed without surgical intervention.
Hemophilic arthropathy including microbleed
The hemophilic arthropathy includes a microbleed.
Reduced vascular remodeling
Reducing vascular remodeling in one or more target joints.
Fc region binding to FcγRII-b (FcγRIB)
The Fc region specifically binds to FcγRII-b (FcγRIB).
Effective rFIXFc dose range
Using an effective amount of the chimeric protein comprising rFIXFc within about 20 IU/kg to about 100 IU/kg.
rFIXFc dosing interval
Administering the chimeric protein comprising rFIXFc at a dosing interval of about three to about 28 days.
The independent claim centers on prophylactically administering an effective amount of a chimeric FIX-Fc protein (rFIXFc) to a human with hemophilia B having stage I–III arthropathy with synovitis to reverse hemophilic arthropathy without surgical intervention; the disclosed refinements include microbleeds, reduced vascular remodeling, Fc region receptor binding (FcγRII-b/FcγRIB), and quantitative dosing and dosing-interval limitations.
Stated Advantages
Reversing hemophilic arthropathy in the subject without surgical intervention.
Reversal/reduction of vascular remodeling in one or more target joints.
Reversal is achieved prophylactically by administering an effective amount of a chimeric FIX and Fc region protein (rFIXFc).
Documented Applications
Treating reversible hemophilic arthropathy in a human subject, including synovitis and microbleeds, by prophylactically administering chimeric clotting-factor–Fc fusion proteins (including rFIXFc for hemophilia B) without surgical intervention.
Reversing hemophilic arthropathy of a target joint in a human subject with hemophilia B and stage I, II, or III hemophilic arthropathy with synovitis, using prophylactic rFIXFc administration without surgical intervention.
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