An Fc-Competent Anti-Human TIGIT Blocking Antibody Ociperlimab (BGB-A1217) Elicits Strong Immune Responses and Potent Anti-Tumor Efficacy in Pre-Clinical Models.

Abstract

TIGIT (T-cell immunoglobulin and ITIM domain) has emerged as a promising target in cancer immunotherapy. It is an immune "checkpoint" inhibitor primarily expressed on activated T cells, NK cells and Tregs. Engagement of TIGIT to its ligands PVR and PVR-L2 leads to inhibitory signaling in T cells, promoting functional exhaustion of tumor-infiltrating T lymphocytes. Here, we described the pre-clinical characterization of Ociperlimab (BGB-A1217), a novel humanized IgG1 anti-TIGIT antibody (mAb), and systemically evaluated the contribution of Fc functions in the TIGIT mAb-mediated anti-tumor activities. BGB-A1217 binds to the extracellular domain of human TIGIT with high affinity (KD = 0.135 nM) and specificity, and efficiently blocks the interaction between TIGIT and its ligands PVR or PVR-L2. Cell-based assays show that BGB-A1217 significantly enhances T-cell functions. In addition, BGB-A1217 induces antibody dependent cellular cytotoxicity (ADCC) against Treg cells, activates NK cells and monocytes, and removes TIGIT from T cell surfaces in an Fc-dependent manner, In vivo, BGB-A1217, either alone or in combination with an anti-PD-1 mAb elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models. Moreover, the Fc effector function is critical for the anti-tumor activity of BGB-A1217 in a syngeneic human TIGIT-knock-in mouse model. The observed anti-tumor efficacy is associated with a pharmacodynamic change of TIGIT down-regulation and Treg reduction. These data support the selection of BGB-A1217 with an effector function competent Fc region for clinical development for the treatment of human cancers.

• Authors: Xin Chen, Liu Xue, Xiao Ding, Jing Zhang, Lei Jiang, Sha Liu, Hongjia Hou, Bin Jiang, Liang Cheng, Qing Zhu, Lijie Zhang, Xiaosui Zhou, Jie Ma, Qi Liu, Yucheng Li, Zhiying Ren, Beibei Jiang, Xiaomin Song, Jing Song, Wei Jin, Min Wei, Zhirong Shen, Xuesong Liu, Lai Wang, Kang Li, Tong Zhang
• Journal: Frontiers in immunology (Front Immunol) Vol. 13 Pg. 828319 ( 2022) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 35273608 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Chen, Xue, Ding, Zhang, Jiang, Liu, Hou, Jiang, Cheng, Zhu, Zhang, Zhou, Ma, Liu, Li, Ren, Jiang, Song, Song, Jin, Wei, Shen, Liu, Wang, Li and Zhang.

Chemical References

• Antibodies, Monoclonal
• Immune Checkpoint Inhibitors
• Ligands
• Receptors, Immunologic

Topics

• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Immune Checkpoint Inhibitors
• Immunity
• Ligands
• Mice
• Neoplasms (drug therapy)
• Receptors, Immunologic (metabolism)