{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:43:12Z","timestamp":1790772192341,"version":"4.1.0"},"reference-count":147,"publisher":"Georg Thieme Verlag KG","issue":"03","funder":[{"DOI":"10.13039\/501100001852","name":"Indo-French Centre for the Promotion of Advanced Research","doi-asserted-by":"crossref","award":["Reference No. IFC\/\/7126\/ Hemophilia"],"award-info":[{"award-number":["Reference No. IFC\/\/7126\/ Hemophilia"]}],"id":[{"id":"10.13039\/501100001852","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Union\u2019s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie","award":["n\u00b0859974 (EDUC8)"],"award-info":[{"award-number":["n\u00b0859974 (EDUC8)"]}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"crossref","award":["FDT202304016725"],"award-info":[{"award-number":["FDT202304016725"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1055\/a-2358-0853","type":"journal-article","created":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T23:20:41Z","timestamp":1719876041000},"page":"194-206","source":"Crossref","is-referenced-by-count":1,"title":["Binding Promiscuity of Therapeutic Factor VIII"],"prefix":"10.1055","volume":"125","author":[{"given":"Alejandra","family":"Reyes Ruiz","sequence":"additional","affiliation":[{"name":"Centre de Recherche des Cordeliers, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, CNRS, Sorbonne Universit\u00e9, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishwarya S.","family":"Bhale","sequence":"additional","affiliation":[{"name":"Centre for Bio-Separation Technology (CBST), Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishnan","family":"Venkataraman","sequence":"additional","affiliation":[{"name":"Centre for Bio-Separation Technology (CBST), Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan D.","family":"Dimitrov","sequence":"additional","affiliation":[{"name":"Centre de Recherche des Cordeliers, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, CNRS, Sorbonne Universit\u00e9, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Lacroix-Desmazes","sequence":"additional","affiliation":[{"name":"Centre de Recherche des Cordeliers, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, CNRS, Sorbonne Universit\u00e9, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2024,7,16]]},"reference":[{"issue":"04","key":"ref1","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/mt.2015.214","article-title":"Modulation of protein-protein interactions for the development of novel therapeutics","volume":"24","author":"I Petta","year":"2016","journal-title":"Mol Ther"},{"issue":"8294","key":"ref2","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/S0140-6736(82)90548-7","article-title":"Biosynthetic human insulin in the treatment of diabetes. 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