Abstract: Disclosed herein are compositions comprising engineered antigen-specific Tregs that suppress antibody formation against the soluble therapeutic protein factor VIII in an MIC-independent fashion. Complexing TCR-based signaling with single-chain variable fragment (scFv) recognition to generate TCR fusion construct (TRUC)-Tregs delivered controlled antigen-specific signaling via engagement of the entire TCR complex, thereby directing functional suppression of the FVIII-specific antibody response.

Abstract: Provided are materials and methods for generating chimeric antigen receptors (CARs) specific for human factor VIII (huF.VIII), which huF.VIII CARs are expressed in regulatory T cells and used to treat inhibitor formation in hemophilia A patients. Further provided are novel huF.VIII proteins and nucleic acids encoding the novel huF.VIII CAR as well as methods to treat inhibitor formation using therapeutically effective amounts of Tregs expressing the novel huF.VIII CAR.