Targeting platelet GPVI with glenzocimab: a novel mechanism for inhibition

التفاصيل البيبلوغرافية
العنوان: Targeting platelet GPVI with glenzocimab: a novel mechanism for inhibition
المؤلفون: Philippe Billiald, Alexandre Slater, Martin Welin, Joanne C. Clark, Stéphane Loyau, Martine Pugnière, Isabella G. Jiacomini, Nadia Rose, Kristell Lebozec, Elie Toledano, Déborah François, Steve P. Watson, Martine Jandrot-Perrus
المصدر: Blood Advances. 7:1258-1268
بيانات النشر: American Society of Hematology, 2023.
سنة النشر: 2023
مصطلحات موضوعية: Hematology
الوصف: Platelet glycoprotein VI (GPVI) is attracting interest as a potential target for the development of new antiplatelet molecules with a low bleeding risk. GPVI binding to vascular collagen initiates thrombus formation and GPVI interactions with fibrin promote the growth and stability of the thrombus. In this study, we show that glenzocimab, a clinical stage humanized antibody fragment (Fab) with a high affinity for GPVI, blocks the binding of both ligands through a combination of steric hindrance and structural change. A cocrystal of glenzocimab with an extracellular domain of monomeric GPVI was obtained and its structure determined to a resolution of 1.9 Å. The data revealed that (1) glenzocimab binds to the D2 domain of GPVI, GPVI dimerization was not observed in the crystal structure because glenzocimab prevented D2 homotypic interactions and the formation of dimers that have a high affinity for collagen and fibrin; and (2) the light variable domain of the GPVI-bound Fab causes steric hindrance that is predicted to prevent the collagen-related peptide (CRP)/collagen fibers from extending out of their binding site and preclude GPVI clustering and downstream signaling. Glenzocimab did not bind to a truncated GPVI missing loop residues 129 to 136, thus validating the epitope identified in the crystal structure. Overall, these findings demonstrate that the binding of glenzocimab to the D2 domain of GPVI induces steric hindrance and structural modifications that drive the inhibition of GPVI interactions with its major ligands.
تدمد: 2473-9537
2473-9529
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f56b7c37729291f5ffcac82d30409c30
https://doi.org/10.1182/bloodadvances.2022007863
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....f56b7c37729291f5ffcac82d30409c30
قاعدة البيانات: OpenAIRE