9GWT

crystal structure of 23ME-00610 Fab in complex with human CD200R1

9GWT の概要

• エントリーDOI: 10.2210/pdb9gwt/pdb
• 関連するPDBエントリー: 9GWZ
• 分子名称: 23ME-00610 Fab (heavy), 23ME-00610 Fab (light), Isoform 1 of Cell surface glycoprotein CD200 receptor 1, ... (9 entities in total)
• 機能のキーワード: 23me-00610, human cd200r1, immune checkpoint inhibitor, immuno-oncology, antitumor protein
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 82261.62

構造登録者

Huang, Y.M.,Ganichkin, O.M. (登録日: 2024-09-27, 公開日: 2024-10-23)

主引用文献

Melero, C.,Budiardjo, S.J.,Daruwalla, A.,Larrabee, L.,Ganichkin, O.,Heiler, A.J.,Fenaux, J.,Chung, B.,Fuh, G.,Huang, Y.M.
CD200R1 immune checkpoint blockade by the first-in-human anti-CD200R1 antibody 23ME-00610: molecular mechanism and engineering of a surrogate antibody.
Mabs, 16:2410316-2410316, 2024

PubMed Abstract: Human CD200R1 (hCD200R1), an immune inhibitory receptor expressed predominantly on T cells and myeloid cells, was identified as a promising immuno-oncology target by the 23andMe database. Blockade of CD200R1-dependent signaling enhances T cell-mediated antitumor activity in vitro and in vivo. 23ME-00610 is a potential first-in-class, humanized IgG1 investigational antibody that binds hCD200R1 with high affinity. We have previously shown that 23ME-00610 inhibits the hCD200R1 immune checkpoint function. Herein, we dissect the molecular mechanism of 23ME-00610 blockade of hCD200R1 by solving the crystal structure of 23ME-00610 Fab in complex with hCD200R1 and performing mutational studies, which show 23ME-00610 blocks the interaction between hCD200 and hCD200R1 through steric hindrance. However, 23ME-00610 does not bind CD200R1 of preclinical species such as cynomolgus monkey MfCD200R1. To enable preclinical toxicology studies of CD200R1 blockade in a pharmacologically relevant non-clinical species, we engineered a surrogate antibody with high affinity toward MfCD200R1. We used phage display libraries of 23ME-00610 variants with individual CDR residues randomized to all 20 amino acids, from which we identified mutations that switched on MfCD200R1 binding. Structural analysis suggests how the surrogate, named 23ME-00611, acquires the ortholog binding ability at the equivalent epitope of 23ME-00610. This engineering approach does not require knowledge of structural and functional mapping of antibody-antigen interaction and thus is generally applicable for therapeutic antibody development when desired ortholog binding is lacking. These findings provide foundational insights as 23ME-00610 advances in clinical studies to gain understanding of the hCD200R1 immune checkpoint as a target in immuno-oncology.

PubMed: 39402718
DOI: 10.1080/19420862.2024.2410316

実験手法

X-RAY DIFFRACTION (2.89 Å)