Binding Promiscuity of Therapeutic Factor VIII

Alejandra Reyes Ruiz; Aishwarya S. Bhale; Krishnan Venkataraman; Jordan D. Dimitrov; Sébastien Lacroix-Desmazes

doi:10.1055/a-2358-0853

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2025; 125(03): 194-206
DOI: 10.1055/a-2358-0853

Review Article

Binding Promiscuity of Therapeutic Factor VIII

Authors

Alejandra Reyes Ruiz

¹Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, CNRS, Sorbonne Université, Université Paris Cité, Paris, France
Aishwarya S. Bhale

²Centre for Bio-Separation Technology (CBST), Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
Krishnan Venkataraman

²Centre for Bio-Separation Technology (CBST), Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
Jordan D. Dimitrov

¹Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, CNRS, Sorbonne Université, Université Paris Cité, Paris, France
Sébastien Lacroix-Desmazes

¹Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, CNRS, Sorbonne Université, Université Paris Cité, Paris, France

Abstract

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, nonspecific 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 displays poor pharmacokinetics, and elevated immunogenicity. We summarize the different canonical and noncanonical 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 especially its C1 and C2 domains, could play an important role in the binding promiscuity. We believe that the knowledge accumulated over years of FVIII usage could be exploited for the development of strategies to predict protein binding promiscuity and therefore anticipate drug efficacy and toxicity. This would open a mutational space to reduce the binding promiscuity of emerging protein drugs while conserving their therapeutic potency.

Keywords

binding promiscuity - protein therapeutics - factor VIII - FVIII interactome - pharmacokinetics - immunogenicity

Full Text

References

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