Hybrid human-porcine factor VIII proteins partially escape the inhibitory effects of anti-factor VIII inhibitor alloantibodies having A2 or C2 domain specificity

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Hybrid human-porcine factor VIII proteins partially escape the inhibitory effects of anti-factor VIII inhibitor alloantibodies having A2 or C2 domain specificity

Material type: 博士論文

Author: Mizumachi, Kuniyoshiほか

Publisher: Wiley

Publication date: 2024-01

Material Format: Digital

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Name of awarding university/degree: 奈良県立医科大学,博士（医学）

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Note (General)：: type:ThesisIntroduction: Porcine factor (pF)VIII has low cross-reactivity with anti-human (h)FVIII inhibitor alloantibodies. Clinical trials of pFVIII...

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Material Type: 博士論文
Title: Hybrid human-porcine factor VIII proteins partially escape the inhibitory effects of anti-factor VIII inhibitor alloantibodies having A2 or C2 domain specificity
Author/Editor: Mizumachi, Kuniyoshi
Nakajima, Yuto
Shimonishi, Naruto
Furukawa, Shoko
Ogiwara, Kenichi
Takeyama, Masahiro
Nogami, Keiji
Author Heading: Mizumachi, Kuniyoshi
Nakajima, Yuto
Shimonishi, Naruto
Furukawa, Shoko
Ogiwara, Kenichi
Takeyama, Masahiro
Nogami, Keiji
Publication, Distribution, etc.: Wiley
Publication Date: 2024-01
Publication Date (W3CDTF): 2024-01
Alternative Title: ブタ第VIII因子相同配列に組み換えたヒト-ブタハイブリッド第VIII因子はA2およびC2ドメイン特異的なインヒビターの阻害作用を部分的に回避する
Periodical title: Haemophilia
No. or year of volume/issue: 30 1
Volume: 30
Issue: 1
Pages: 140-150
ISSN (Periodical Title): ISSN : 1351-8216
Degree grantor/type: 奈良県立医科大学
Date Granted: 2024-03-14
Dissertation Number: 甲第922号
Degree Type: 博士（医学）
Text Language Code: eng
Subject Heading: inhibitor
porcine factor VIII
hemophilia A
epitope
neutralizing effect
Target Audience: 一般
Note (General): type:Thesis
Introduction: Porcine factor (pF)VIII has low cross-reactivity with anti-human (h)FVIII inhibitor alloantibodies. Clinical trials of pFVIII in congenital hemophilia A patients with inhibitor (PwHA-I) are in progress. Most FVIII inhibitors recognize the A2 and/or C2 domain(s), and recombinant human-porcine hybrid (hp)FVIII containing mutations within these domains may escape the neutralizing effects of these inhibitors. Aim: To evaluate the ability of hpFVIII to limit the anti-FVIII activity of inhibitor alloantibodies. Methods: Three hybrid mutants were created by substituting the A2, C2 domain or both in human hFVIII, with the corresponding domain of pFVIII (termed hp(A2), hp(C2), and hp(A2/C2), respectively). The reactivity of these mutants was assessed by one-stage clotting assays (OSA), thrombin generation assays (TGA), and rotational thromboelastometry (ROTEM) using FVIII-deficient samples. Results: OSA demonstrated that mutation restricted the inhibitory effects of both anti-FVIII A2 or C2 monoclonal antibodies (mAb) and polyclonal inhibitor-antibodies (polyAb) from PwHA-I. TGA indicated that peak thrombin with hp(A2) and hp(A2/C2) was not attenuated in the presence of anti-A2 polyAb, but that with hFVIII and hp(C2) was suppressed to levels equivalent to those of FVIII-deficient plasma. With anti-A2/C2 polyAb, the activity of hp(A2/C2) was unaffected. ROTEM demonstrated that the addition of hp(A2) or hp(A2/C2) to anti-A2 polyAb shortened clot times/clot formation times, whilst hFVIII or hp(C2) were ineffective. Similarly with anti-A2/C2 polyAb, hp(A2/C2) restored coagulation potential to a greater extent than hp(A2) and hp(C2). Conclusion: Hybrid FVIII mutations within the porcine A2 and/or C2 domain corresponding to respective inhibitor-epitopes could support effective therapy in PwHAI.
権利情報：© 2023 JohnWiley & Sons Ltd. This is the peer reviewed version of the following article: [https://onlinelibrary.wiley.com/doi/10.1111/hae.14911], which has been published in final form at [https://doi.org/10.1111/hae.14911]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
identifier:Haemophilia. 2024 Jan, vol.30, no.1, p.140-150
identifier:1351-8216
identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/4373
identifier:Haemophilia, 30(1): 140-150
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Access Restrictions: インターネット公開
Related Material (DOI): 10.1111/hae.14911
Periodical Title (NCID): AA11030122
https://ci.nii.ac.jp/ncid/AA11030122
Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）
https://irdb.nii.ac.jp
Original Data Provider (Database): 奈良県立医科大学 : 奈良県立医科大学機関リポジトリ GINMU