Fc-enhanced anti-TIGIT antibody 30,278-IgG1 RMD amplifies antitumor immunity through effector cell activation and synergizes with PD-1 blockade.

TIGIT is an inhibitory immune checkpoint receptor, and its blockade has shown clinical promise in combination with PD-1 pathway inhibitors.

However, whether anti-TIGIT antibodies should engage immune effector functions via Fcγ receptors (FcγRs) remains an open question. We developed 30,278-IgG1 RMD, a novel Fc-enhanced anti-TIGIT antibody, to amplify effector cell activation through FcγR engagement while preserving TIGIT binding and blockade. 30,278-IgG1 RMD was generated by Fc glycoengineering to increase affinity for activating FcγRs. This variant was compared to wild-type IgG1, an Fc-inert IgG4, and tiragolumab in in vitro assays (TIGIT binding/blockade, ADCC, ADCP, Treg depletion, immune cell activation in human PBMCs) and in an hTIGIT/hPD-1 knock-in mouse colon carcinoma model (CT26) combined with PD-1 blockade. 30,278-IgG1 RMD maintained high TIGIT affinity and blockade activity, while exhibiting markedly increased binding to activating FcγRs. It triggered more potent ADCC and ADCP than wild-type or tiragolumab, resulting in efficient depletion of TIGIT+ Tregs and activation of NK cells and dendritic cells.

In human PBMC assays, the Fc-enhanced antibody augmented T cell activation and cytokine production relative to Fc-silent and wild-type controls. In vivo, 30278-IgG1 RMD plus PD-1 blockade yielded superior tumor control, including complete tumor regressions in some mice, whereas Fc-inert or wild-type anti-TIGIT combinations did not. Fc engineering of an anti-TIGIT antibody substantially improves immune effector engagement and anti-tumor efficacy. Augmenting FcγR interactions alongside checkpoint blockade can potentiate T cell responses and drive tumor regression, underscoring the translational potential of Fc-optimized checkpoint immunotherapies.