Binding promiscuity of therapeutic factor VIII.

The binding promiscuity of proteins defines their ability to indiscriminately bind multiple unrelated molecules. Binding promiscuity is implicated, at least in part, in the off-target reactivity, non-specific biodistribution, immunogenicity and/or short half-life of potentially efficacious protein drugs, thus affecting their clinical use. In this review, we discuss the current evidence for the binding promiscuity of factor VIII (FVIII), a protein used for the treatment of hemophilia A, which cumulates poor pharmacokinetics, and elevated immunogenicity. We summarize the different canonical and non-canonical molecular interactions that FVIII may establish in the circulation and that could be responsible for its therapeutic liabilities. We also provide information suggesting that the FVIII light chain, and notably its C1 and C2 domains, could play an important role in binding promiscuity. We believe that the knowledge accumulated over years of FVIII usage could be exploited for the development of tools that predict drug efficacy and toxicity and open a mutational space to reduce the binding promiscuity of newly generated protein drugs while conserving their therapeutic efficacy.