| Added by | alainmange |
|---|---|
| Group name | PlateformePP2I |
| Item Type | Journal Article |
| Title | Targeting platelet GPVI with glenzocimab: a novel mechanism for inhibition |
| Creator | Billiald et al. |
| Author | Philippe Billiald |
| Author | Alexandre Stephane Slater |
| Author | Martin Welin |
| Author | Joanne C. Clark |
| Author | Stéphane Loyau |
| Author | Martine Pugnière |
| Author | Isabella Gizzi Jiacomini |
| Author | Nadia Rose |
| Author | Kristell Lebozec |
| Author | Elie Toledano |
| Author | Deborah François |
| Author | Steve P. Watson |
| Author | Martine Jandrot-Perrus |
| Abstract | 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 the present study we show that glenzocimab, a clinical stage humanized antibody fragment (Fab) with high affinity for GPVI, blocks binding of both ligands through a combination of steric hindrance and structural change. A co-crystal 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 (i) glenzocimab binds to the D2 domain of GPVI; GPVI dimerisation was not observed in the crystal structure because glenzocimab prevented D2 homotypic interactions and the formation of dimers which have a high affinity for collagen and fibrin; (ii) the light variable (VL) 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 129-136, 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. |
| Publication | Blood Advances |
| Pages | bloodadvances.2022007863 |
| Date | 2022-11-14 |
| Journal Abbr | Blood Adv |
| Language | eng |
| DOI | 10.1182/bloodadvances.2022007863 |
| ISSN | 2473-9537 |
| Short Title | Targeting platelet GPVI with glenzocimab |
| Library Catalog | PubMed |
| Extra | PMID: 36375047 |
| Tags | author, original, pp2i |
| Date Added | 2022/12/14 - 14:23:56 |
| Date Modified | 2022/12/14 - 14:35:07 |
| Notes and Attachments | PubMed entry (Attachment) |
Institut de Recherche en Cancérologie de
