Abstract Number: OC 09.5
Meeting: ISTH 2020 Congress
Background: Current Factor VIII (FVIII) replacement therapies still have several limitations such as a short plasma half-life, the lack of subcutaneous bioavailability, and a high immunogenic potential resulting in the development of inhibitory antibodies or precluding the subcutaneous administration route.
Aims: The development of novel recombinant FVIII molecules addressing all major limitations of current FVIII substitution therapy.
Methods: Biotest’s Hemophilia A Therapeutic (HAT) molecule was generated by introducing four albumin-binding domains into a single chain FVIII sequence. In parallel, 19 deimmunizing mutations were incorporated into the FVIII sequence of HAT resulting in HAT RI (Reduced Immunogenicity). Both molecules were produced in a human cell line, purified and extensively tested in vitro. Half-life extension was investigated after i.v. injection in hemophilia A mice, Göttingen minipigs and albumin-deficient mice expressing the human FcRn a-chain. Subcutaneous administration was tested in hemophilia A mice and Göttingen minipigs. A tail transection assay in hemophilia A mice was used to determine in vivo functionality. As FVIII-bound albumin may shield HAT and HAT RI from present FVIII inhibitors, the bypassing activity of both molecules was assessed by a modified Bethesda assay. Additionally, immunological aspects were investigated by LC-MS to identify MHC II-presented peptides of HAT RI on dendritic cells.
Results: Both FVIII molecules HAT and HAT RI demonstrated full in vitro and in vivo functionality while providing up to a 4-fold longer half-life compared to Moroctocog alfa in the albumin-deficient mouse model. Subcutaneous administration resulted in up to 50% bioavailability in the minipig model. Bypassing activity in the presence of inhibitors was observed in combination with reduced MHC II-presentation showing improved immunological compatibility.
Conclusions: HAT and HAT RI address the major challenges of FVIII substitution therapy as both molecules have a superior half-life, show high subcutaneous bioavailability in mice and pig models, and reduce FVIII immunogenicity according to utilized in vitro models.
To cite this abstract in AMA style:Herbener P, Daufenbach J, Schüttrumpf J, Kistner S. HAT and HAT RI: Novel Factor VIII Molecules Addressing Patients’ Needs [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/hat-and-hat-ri-novel-factor-viii-molecules-addressing-patients-needs/. Accessed January 28, 2022.
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