HMB-002: a monovalent antibody that elevates circulating VWF and FVIII levels for treatment of von Willebrand disease.

abstractVon Willebrand disease (VWD) is the most common inherited bleeding disorder, resulting from deficiency or dysfunction of von Willebrand factor (VWF), a protein crucial for hemostasis. Current prophylactic options present significant limitations including poor tolerability, short half-life, or the requirement for frequent IV administration. Here, we report HMB-002, a human Fc-silenced monovalent IgG4 antibody designed to provide convenient subcutaneous prophylaxis by binding and elevating levels of endogenous VWF. Binding studies and X-ray crystallography revealed that HMB-002 binds VWF with subnanomolar affinity at a well-defined epitope in the C-terminal cysteine-knot (CK) domain, which is spatially distant from regions mediating VWF's hemostatic functions. Consistent with structural analyses, in vitro functional studies demonstrated that HMB-002-bound VWF retained its ability to bind factor VIII (FVIII), platelet GPIbα, and collagen, as well as susceptibility to proteolytic regulation by ADAMTS13. In cynomolgus monkeys, IV and subcutaneous administration of HMB-002 resulted in time-dependent accumulation of endogenous VWF and FVIII antigen, reaching about twofold elevation with a proportional increase in VWF activity and with retained VWF multimer distribution. HMB-002 also extended the half-life of coadministered recombinant VWF by approximately threefold. Using a surrogate antibody with overlapping epitope specificity, similar VWF accumulation was observed in a type 1 VWD mouse model with improved hemostasis following vascular challenge. By elevating levels of circulating VWF and FVIII, HMB-002 represents a potential subcutaneous prophylactic treatment approach to mitigate the hemostatic impairment in VWD and address current limitations in disease management.