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Clinical trials of pFVIII in congenital haemophilia A patients with inhibitor (PwHA\u2010I) are in progress. Most polyclonal anti\u2010hFVIII inhibitors recognize its A2 and\/or C2 domain(s), and recombinant human\u2010porcine hybrid (hp)FVIII proteins may escape neutralization by these inhibitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To evaluate the ability of hpFVIII to limit the anti\u2010FVIII activity of inhibitor alloantibodies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Three hybrid proteins were created by substituting the hFVIII A2, C2 domain or both with the corresponding domains of pFVIII [termed hp(A2), hp(C2) and hp(A2\/C2), respectively]. The reactivity of these hybrids was assessed by one\u2010stage clotting assays (OSA), thrombin generation assays (TGA) and rotational thromboelastometry (ROTEM) by adding them to FVIII\u2010deficient samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>OSA demonstrated that the hybrid proteins avoided neutralization by anti\u2010FVIII A2 or C2 monoclonal antibodies (mAb) and polyclonal inhibitor\u2010antibodies (polyAb) from PwHA\u2010I. In TGA, thrombin generation with hp(A2) and hp(A2\/C2) was not attenuated in the presence of patient IgG recognizing anti\u2010A2 domain. In contrast, that with hFVIII and hp(C2) was suppressed by this IgG to levels equivalent to those of FVIII\u2010deficient plasma. With anti\u2010A2\/C2 polyAb, the activity of hp(A2\/C2) was unaffected. ROTEM demonstrated that the addition of hp(A2) or hp(A2\/C2) to anti\u2010A2 polyAb shortened clot times\/clot formation times, whilst hFVIII or hp(C2) were ineffective. Similarly with anti\u2010A2\/C2 polyAb, hp(A2\/C2) restored coagulation potential to a greater extent than hp(A2) and hp(C2).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Hybrid FVIII proteins containing porcine FVIII A2 and\/or C2 domain(s) could support effective therapy in PwHA\u2010I by avoiding neutralization.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.14911","type":"journal-article","created":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T23:55:30Z","timestamp":1701993330000},"page":"140-150","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hybrid human\u2010porcine factor VIII proteins partially escape the inhibitory effects of anti\u2010factor VIII inhibitor alloantibodies having A2 or C2 domain specificity"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2343-8147","authenticated-orcid":false,"given":"Kuniyoshi","family":"Mizumachi","sequence":"first","affiliation":[{"name":"Department of Pediatrics Nara Medical University  Kashihara Nara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5422-2782","authenticated-orcid":false,"given":"Yuto","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Nara Medical University  Kashihara Nara Japan"},{"name":"Advanced Medical Science of Thrombosis and Hemostasis Nara Medical University  Kashihara Nara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0157-5215","authenticated-orcid":false,"given":"Naruto","family":"Shimonishi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Nara Medical University  Kashihara Nara Japan"},{"name":"The 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