CTLA4-Ig prevents development of neutralizing antibody formation after continuous treatment with human FVIII in HA rats
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CTLA4-Ig prevents development of neutralizing antibody formation after continuous treatment with human FVIII in HA rats. / Øvlisen, Gabi Overgaard; Thygesen, Peter; Weldingh, Karin Nana; Bloem, Esther; Skov, Søren; Almholt, Kasper; Lövgren, Karin Maria; Ley, Carsten Dan; Holm, Thomas Lindebo.
I: Haemophilia, Bind 28, Nr. 4, 2022, s. 568-577.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - CTLA4-Ig prevents development of neutralizing antibody formation after continuous treatment with human FVIII in HA rats
AU - Øvlisen, Gabi Overgaard
AU - Thygesen, Peter
AU - Weldingh, Karin Nana
AU - Bloem, Esther
AU - Skov, Søren
AU - Almholt, Kasper
AU - Lövgren, Karin Maria
AU - Ley, Carsten Dan
AU - Holm, Thomas Lindebo
N1 - Publisher Copyright: © 2022 John Wiley & Sons Ltd.
PY - 2022
Y1 - 2022
N2 - Introduction: Immunogenicity causing development of anti-drug 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. Aim: To investigate if the immunosuppressive drug CTLA4 immunoglobulin (CTLA4-Ig) can induce tolerance in haemophilia A (HA) rats receiving recombinant human coagulation factor VIII (rhFVIII) treatment. Methods: Two different prophylactic rhFVIII compounds were given intravenously to HA rats for 4 weeks. Both rhFVIII compounds were co-administered with commercially available CTLA4-Ig 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. Results: 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-administration with CTLA4-Ig 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. Conclusion: In a rat model with spontaneous bleeding, co-administration of CTLA4-Ig with rhFVIII prevented antibody formation. No FVIII antibodies were detected, demonstrating that CTLA4-Ig co-administration can be applicable as a method to prevent immunogenicity, when evaluating human proteins in preclinical systems permitting continuous pharmacokinetic and pharmacodynamic assessment.
AB - Introduction: Immunogenicity causing development of anti-drug 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. Aim: To investigate if the immunosuppressive drug CTLA4 immunoglobulin (CTLA4-Ig) can induce tolerance in haemophilia A (HA) rats receiving recombinant human coagulation factor VIII (rhFVIII) treatment. Methods: Two different prophylactic rhFVIII compounds were given intravenously to HA rats for 4 weeks. Both rhFVIII compounds were co-administered with commercially available CTLA4-Ig 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. Results: 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-administration with CTLA4-Ig 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. Conclusion: In a rat model with spontaneous bleeding, co-administration of CTLA4-Ig with rhFVIII prevented antibody formation. No FVIII antibodies were detected, demonstrating that CTLA4-Ig co-administration can be applicable as a method to prevent immunogenicity, when evaluating human proteins in preclinical systems permitting continuous pharmacokinetic and pharmacodynamic assessment.
KW - animal model
KW - anti-drug antibodies
KW - FVIII
KW - haemophilia A
KW - immunogenicity
KW - inhibitor
KW - protein therapy
U2 - 10.1111/hae.14573
DO - 10.1111/hae.14573
M3 - Journal article
C2 - 35467059
AN - SCOPUS:85128668400
VL - 28
SP - 568
EP - 577
JO - Haemophilia
JF - Haemophilia
SN - 1351-8216
IS - 4
ER -
ID: 307374887