Identification and characterization of M6903, an antagonistic anti-TIM-3 monoclonal antibody

Oncoimmunology. 2020 Apr 1;9(1):1744921. doi: 10.1080/2162402X.2020.1744921. eCollection 2020.


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.

Keywords: CEACAM1; Gal-9; PtdSer; TIM-3; antagonistic antibody.

MeSH terms

  • Animals
  • Antibodies, Monoclonal
  • Hepatitis A Virus Cellular Receptor 2*
  • Lymphocyte Activation
  • Mice
  • Neoplasms*
  • T-Lymphocytes


  • Antibodies, Monoclonal
  • Hepatitis A Virus Cellular Receptor 2

Grant support

This study was supported by EMD Serono, a biopharmaceutical business of Merck KGaA, Darmstadt, Germany.