{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:43:26Z","timestamp":1790772206451,"version":"4.1.0"},"reference-count":28,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T00:00:00Z","timestamp":1650844800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Immunogenicity causing development of anti\u2010drug antibodies (ADAs) are major challenges in the treatment of haemophilia, as well as other diseases where proteins are used for treatment. Furthermore, it is a complication for preclinical testing of such therapies in animal models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To investigate if the immunosuppressive drug CTLA4 immunoglobulin (CTLA4\u2010Ig) can induce tolerance in haemophilia A (HA) rats receiving recombinant human coagulation factor VIII (rhFVIII) treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two different prophylactic rhFVIII compounds were given intravenously to HA rats for 4 weeks. Both rhFVIII compounds were co\u2010administered with commercially available CTLA4\u2010Ig or human IgG subclass 4 (hIgG4) as control, and blood samples were collected. To functionally test if pharmacological efficacy was retained, rats were subjected to a bleeding experiment under anaesthesia at end of study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The mean inhibitory level after 4 weeks in rats receiving rhFVIII and hIgG4 was 85.7 BU for octocog alfa and 37.4 BU for rurioctocog alfa pegol. In contrast, co\u2010administration with CTLA4\u2010Ig during rhFVIII therapy prevented the formation of ADAs (both binding and inhibitory) in 14\/14 rats receiving octocog alfa and in 7\/7 rats receiving rurioctocog alfa pegol. Moreover, we were able to show that the pharmacological efficacy of rhFVIII was preserved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In a rat model with spontaneous bleeding, co\u2010administration of CTLA4\u2010Ig with rhFVIII prevented antibody formation. No FVIII antibodies were detected, demonstrating that CTLA4\u2010Ig co\u2010administration can be applicable as a method to prevent immunogenicity, when evaluating human proteins in preclinical systems permitting continuous pharmacokinetic and pharmacodynamic assessment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.14573","type":"journal-article","created":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T09:44:27Z","timestamp":1650879867000},"page":"568-577","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["CTLA4\u2010Ig prevents development of neutralizing antibody formation after continuous treatment with human FVIII in HA rats"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3834-5464","authenticated-orcid":false,"given":"Gabi Overgaard","family":"\u00d8vlisen","sequence":"first","affiliation":[{"name":"Global Drug Discovery Novo Nordisk A\/S  Maloev 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