Identification and characterization of M6903, an antagonistic anti–TIM-3 monoclonal antibody
| Autor: | Molly H. Jenkins, Vanita D. Sood, Feng Jiang, Christel Iffland, An Qi, Hui Huang, Xinyan Zhao, Joern-Peter Halle, Qingyong Ji, Hong Wang, Melissa G Derner, Dong Zhang, John S. Wesolowski, Djordje Musil, Andrea Paoletti, Rinat Zaynagetdinov, Tin Bartholomew, D.P. Nannemann, Youbin Wang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.drug_class T cell T-Lymphocytes Immunology Monoclonal antibody Lymphocyte Activation ptdser 03 medical and health sciences Mice 0302 clinical medicine Immune system gal-9 Neoplasms medicine tim-3 Immunology and Allergy Animals Hepatitis A Virus Cellular Receptor 2 RC254-282 Galectin Original Research ceacam1 biology Effector Chemistry Antibodies Monoclonal Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC581-607 Fusion protein Immune checkpoint 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research biology.protein antagonistic antibody Antibody Immunologic diseases. Allergy |
| Zdroj: | OncoImmunology, Vol 9, Iss 1 (2020) Oncoimmunology |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|