Surrogate chaperons to extend the half-life of therapeutic factor VIII – nanoF8

Hemophilia A is a rare X-linked bleeding disorder that results from insufficient levels of procoagulant factor VIII. Replacement therapy using exogenous factor VIII remains the most efficient strategy to prevent or treat bleeds. It is however limited by the short half-life of factor VIII, that imposes weekly FVIII injections to the patients to ensure high enough trough levels for joint protection, and immunogenicity. Novel drugs derived from factor VIII have been engineered to extend their circulation time in blood, for instance following Fc-fusion or PEGylation, but their half-lives do not exceed 20-35 hours. Conversely, a factor VIII mimicking bi-specific antibody, that has a 3 week-long half-life, has been developed. It however only partially compensates the lack in factor VIII and exposes the patients to thrombotic risk if associated with other procoagulant drugs used to treat breakthrough bleeds. In this project, by developing an integrative multidisciplinary strategy that allies hemostasis, immunology, protein engineering and in vivo validation of biological drugs in novel animal models, we will engineer a novel factor VIII product with drastically increased half-life and potentially decreased immunogenicity. Our preliminary data support the feasibility of our approach with two different candidate molecules that will escape the glass ceiling imposed on factor VIII half-life by its physiological molecular chaperon, von Willebrand factor. The expected deliverables include the proof towards a new concept for increasing the half-life of soluble proteins, an engineered factor VIII fusion protein with increased half-life, and a novel preclinical animal model to foster translation of our findings to the clinic. Together, this project will bring about an innovative drug that will fulfil unmet clinical needs in a rare bleeding disorder.