Domvanalimab: An Fc-Silent Anti-TIGIT Antibody for Cancer Immunotherapy

I. Executive Summary

Domvanalimab is an investigational, humanized immunoglobulin G1 (IgG1) monoclonal antibody at the forefront of a new generation of cancer immunotherapies. Developed by Arcus Biosciences in collaboration with Gilead Sciences, it targets the T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), a critical immune checkpoint. The central thesis of the Domvanalimab program is that its unique molecular engineering as an "Fc-silent" antibody confers a differentiated and potentially superior clinical profile compared to competing anti-TIGIT agents. This design is intended to block the TIGIT inhibitory pathway without causing the depletion of vital immune cell populations, thereby maximizing anti-tumor activity while mitigating immune-related toxicities.

The clinical development of Domvanalimab is focused on high-unmet-need solid tumors, primarily non-small cell lung cancer (NSCLC) and upper gastrointestinal (GI) cancers.[1] The strategy centers on its use in combination with an anti-PD-1 antibody, zimberelimab, with or without chemotherapy. This approach is supported by compelling, randomized Phase II data from the ARC-7 study in first-line, PD-L1-high NSCLC. In this trial, the combination of Domvanalimab and zimberelimab more than doubled median progression-free survival (PFS) compared to zimberelimab monotherapy (12.0 months vs. 5.4 months), a robust signal of efficacy that has propelled the combination into a comprehensive Phase III program.[3] Similarly, promising activity in the Phase II EDGE-Gastric study, which showed a median PFS exceeding one year in first-line upper GI cancers, has led to a pivotal Phase III trial in that setting.[6]