دورية أكاديمية
أعرض في EDS

Human Fc gamma receptor IIIA blockade inhibits platelet destruction in a humanized murine model of ITP.

التفاصيل البيبلوغرافية
العنوان: Human Fc gamma receptor IIIA blockade inhibits platelet destruction in a humanized murine model of ITP.
المؤلفون: Gil Gonzalez L; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada., Won KD; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.; Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada., Tawhidi Z; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada., Cummins E; adMare BioInnovations, Vancouver, BC, Canada., Cruz-Leal Y; Innovation and Portfolio Management, Canadian Blood Services, Ottawa, ON, Canada., Tundidor Cabado Y; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada., Sachs UJ; Institute for Clinical Immunology, Transfusion Medicine, and Haemostasis, Justus Liebig University, Giessen, Germany.; Department of Thrombosis and Haemostasis, Giessen University Hospital, Giessen, Germany., Norris PAA; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada., Shan Y; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada., Bhakta V; Innovation and Portfolio Management, Canadian Blood Services, Ottawa, ON, Canada., Li J; adMare BioInnovations, Vancouver, BC, Canada., Samudio I; adMare BioInnovations, Vancouver, BC, Canada., Silva-Moreno B; adMare BioInnovations, Vancouver, BC, Canada., Cerna-Portillo L; adMare BioInnovations, Vancouver, BC, Canada., Pavon Oro A; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada., Bergqvist P; adMare BioInnovations, Vancouver, BC, Canada., Chan P; adMare BioInnovations, Vancouver, BC, Canada., Moorehead A; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada., Sholzberg M; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.; Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada., Sheffield WP; Innovation and Portfolio Management, Canadian Blood Services, Ottawa, ON, Canada., Lazarus AH; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.; Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.; Innovation and Portfolio Management, Canadian Blood Services, Ottawa, ON, Canada.
المصدر: Blood advances [Blood Adv] 2024 Apr 23; Vol. 8 (8), pp. 1869-1879.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Society of Hematology Country of Publication: United States NLM ID: 101698425 Publication Model: Print Cited Medium: Internet ISSN: 2473-9537 (Electronic) Linking ISSN: 24739529 NLM ISO Abbreviation: Blood Adv Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Society of Hematology, [2016]-
مواضيع طبية MeSH: Purpura, Thrombocytopenic, Idiopathic*/drug therapy , Thrombocytopenia*, Humans ; Mice ; Animals ; Receptors, IgG/metabolism ; Disease Models, Animal ; Immunoglobulin G/therapeutic use ; Albumins/therapeutic use
مستخلص: Abstract: Fc gamma receptor (FcγR) IIIA is an important receptor for immunoglobulin G (IgG) and is involved in immune defense mechanisms as well as tissue destruction in some autoimmune diseases including immune thrombocytopenia (ITP). FcγRIIIA on macrophages can trigger phagocytosis of IgG-sensitized platelets, and prior pilot studies observed blockade of FcγRIIIA increased platelet counts in patients with ITP. Unfortunately, although blockade of FcγRIIIA in patients with ITP increased platelet counts, its engagement by the blocking antibody drove serious adverse inflammatory reactions. These adverse events were postulated to originate from the antibody's Fc and/or bivalent nature. The blockade of human FcγRIIIA in vivo with a monovalent construct lacking an active Fc region has not yet been achieved. To effectively block FcγRIIIA in vivo, we developed a high affinity monovalent single-chain variable fragment (scFv) that can bind and block human FcγRIIIA. This scFv (17C02) was expressed in 3 formats: a monovalent fusion protein with albumin, a 1-armed human IgG1 antibody, and a standard bivalent mouse (IgG2a) antibody. Both monovalent formats were effective in preventing phagocytosis of ITP serum-sensitized human platelets. In vivo studies using FcγR-humanized mice demonstrated that both monovalent therapeutics were also able to increase platelet counts. The monovalent albumin fusion protein did not have adverse event activity as assessed by changes in body temperature, whereas the 1-armed antibody induced some changes in body temperature even though the Fc region function was impaired by the Leu234Ala and Leu235Ala mutations. These data demonstrate that monovalent blockade of human FcγRIIIA in vivo can potentially be a therapeutic strategy for patients with ITP.
(© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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المشرفين على المادة: 0 (Receptors, IgG)
0 (Immunoglobulin G)
0 (Albumins)
تواريخ الأحداث: Date Created: 20240208 Date Completed: 20240411 Latest Revision: 20240425
رمز التحديث: 20240425
مُعرف محوري في PubMed: PMC11007428
DOI: 10.1182/bloodadvances.2023012155
PMID: 38330193
قاعدة البيانات: MEDLINE
الوصف
تدمد:2473-9537
DOI:10.1182/bloodadvances.2023012155