Thromb Haemost
DOI: 10.1055/a-2358-0853

Alejandra Reyes Ruiz

1   Centre 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

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

,

Krishnan Venkataraman

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

,

Jordan D. Dimitrov

1   Centre 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

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

› Author Affiliations Funding This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Sorbonne Université, Université Paris Cité, Assistance Publique des Hôpitaux de Paris, and by grants from the Indo-French Center for Promotion of Advanced Research (CEFIPRA, Reference No. IFC//7126/ Hemophilia) and from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement n°859974 (EDUC8). The work at VIT Vellore was supported by the VIT International research fund (Ref No. VIN/2022–23/011 dated 9 February 2023). A.R.R. was recipient of fellowships from Fondation de la Recherche Médicale (n°FDT202304016725, FRM, Paris) and MSCA-ITN EDUC8 (n°859974).
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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 Authors' Contribution

A.R.R., J.D.D., and S.L-.D. contributed in writing the manuscript. A.R.R., A.S.B., and K.V. contributed to performing literature search. A.R.R., A.S.B., K.V., J.D.D., and S.L-.D. contributed in reading and reviewing the manuscript.

Publication History

Received: 08 April 2024

Accepted: 30 June 2024

Accepted Manuscript online:
01 July 2024

Article published online:
16 July 2024

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