Bispecific antibody to target FVIII-specific B cells

Abstract: The antibody response to factor VIII (FVIII) in hemophilia A patients is a critical problem since these antibodies (called inhibitors) block the therapeutic activity of FVIII. The current treatment for inhibitor patients, called immune tolerance induction (ITI) is expensive and fails in many cases. Thus, improved methods to eliminate inhibitors is an unmet need. We propose to achieve this by direct targeting and deletion of FVIII-specific B cells. Our lab has developed several cellular approaches to prevent and reverse inhibitor formation, including the creation of novel engineered FVIII-specific regulatory or cytotoxic T cells. These human and mouse T cells were engineered to express FVIII- specific chimeric receptors or FVIII antigen domains, the latter which can interact with naïve or memory B-cell precursors of FVIII-specific plasma cells to block or reverse inhibitor formation. We named these latter cells “BAR” for B-cell-targeting Antibody Receptor cells. These personalized cellular therapies are effective at suppressing FVIII-specific B-cell responses. Our overall goal herein is to build on our successful cellular approaches by creating protein therapeutics that would target and eliminate FVIII-specific B cells, using new B-cell receptor transgenics specific to a FVIII domain. Thus, we have designed chimeric immune conjugates that link cytotoxic CD8 T cells with FVIII-specific B cells via expression of FVIII domains, as in the “BAR” approach above. We propose to evaluate them for cytotoxicity against FVIII-specific B cells, and to provide proof of principle to modulate anti-FVIII responses in vitro and in vivo in a mouse model of hemophilia A. These immunoconjugates have the potential to eliminate anti-FVIII inhibitors in patients. 1