6TXZ

FAB PART OF M6903 IN COMPLEX WITH HUMAN TIM3

6TXZ の概要

• エントリーDOI: 10.2210/pdb6txz/pdb
• 分子名称: Hepatitis A virus cellular receptor 2, Fab H, Fab L (3 entities in total)
• 機能のキーワード: fab, antibody, tim3, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 236808.41

構造登録者

Musil, D.,Sood, V. (登録日: 2020-01-15, 公開日: 2020-04-08, 最終更新日: 2024-11-13)

主引用文献

Zhang, D.,Jiang, F.,Zaynagetdinov, R.,Huang, H.,Sood, V.D.,Wang, H.,Zhao, X.,Jenkins, M.H.,Ji, Q.,Wang, Y.,Nannemann, D.P.,Musil, D.,Wesolowski, J.,Paoletti, A.,Bartholomew, T.,Derner, M.G.,An, Q.,Iffland, C.,Halle, J.P.
Identification and characterization of M6903, an antagonistic anti-TIM-3 monoclonal antibody.
Oncoimmunology, 9:1744921-1744921, 2020

PubMed Abstract: T cell immunoglobulin and mucin domain-3 (TIM-3) is an immune checkpoint that regulates normal immune responses but can be exploited by tumor cells to evade immune surveillance. TIM-3 is primarily expressed on immune cells, particularly on dysfunctional and exhausted T cells, and engagement of TIM-3 with its ligands promotes TIM-3-mediated T cell inhibition. Antagonistic ligand-blocking anti-TIM-3 antibodies have the potential to abrogate T cell inhibition, activate antigen-specific T cells, and enhance anti-tumor immunity. Here we describe M6903, a fully human anti-TIM-3 antibody without effector function and with high affinity and selectivity to TIM-3. We demonstrate that M6903 blocks the binding of TIM-3 to three of its ligands, phosphatidylserine (PtdSer), carcinoembryonic antigen cell adhesion-related molecule 1 (CEACAM1), and galectin 9 (Gal-9). These results are supported by an atomic resolution crystal structure and functional assays, which demonstrate that M6903 monotherapy enhanced T cell activation. This activation was further enhanced by the combination of M6903 with bintrafusp alfa, a bifunctional fusion protein that simultaneously blocks the transforming growth factor-β (TGF-β) and programmed death ligand 1 (PD-L1) pathways. M6903 and bintrafusp alfa combination therapy also enhanced anti-tumor efficacy in huTIM-3 knock-in mice, relative to either monotherapy. These in vitro and in vivo data, along with favorable pharmacokinetics in marmoset monkeys, suggest that M6903 as a monotherapy warrants further pre-clinical assessment and that M6903 and bintrafusp alfa may be a promising combination therapy in the clinic.

PubMed: 32313722
DOI: 10.1080/2162402X.2020.1744921

実験手法

X-RAY DIFFRACTION (3.06 Å)