Dr Shitara on the Unique Mechanisms of Action of Domvanalimab Plus Zimberelimab in GI Cancer

"Blocking TIGIT has emerged as an attractive strategy in cancer immunotherapy; this is usually combined with an anti–PD-L1 agent to reduce the exhaustion of T cells. Domvanalimab is an Fc-silent monoclonal antibody, and because of the lack of T-cell depletion, its toxicity profile is expected to be feasible. Zimberelimab's [mechanism of action] is very similar to nivolumab and pembrolizumab, and these combinations have been tested in various clinical trials."

Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology at National Cancer Center Hospital East, discussed the rationale for dual immune checkpoint inhibition using domvanalimab and zimberelimab in the treatment of patients with solid tumors, including upper gastrointestinal malignancies. 

Domvanalimab is an investigational anti–TIGIT monoclonal antibody, and zimberelimab is an anti–PD-1 monoclonal antibody. Both agents are being evaluated in combination across several clinical trials targeting cancers with high unmet need.

TIGIT is an inhibitory receptor commonly co-expressed with PD-1 and LAG-3 on exhausted CD8-positive T cells and regulatory T cells (Tregs), particularly in later stages of immune dysfunction. TIGIT blockade is hypothesized to reinvigorate effector immune cells and restore antitumor immunity. Preclinical data suggest that TIGIT inhibition is most effective when combined with PD-1/PD-L1 pathway inhibition, given the overlapping and synergistic mechanisms of T-cell exhaustion and immune evasion.

Shitara emphasized that a key distinction among TIGIT-targeting agents lies in their Fc domain engineering. Some anti-TIGIT antibodies are Fc-competent (Fc-active), retaining the ability to engage Fcγ receptors and mediate antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. This structure allows for potential depletion of TIGIT-expressing Tregs and other immunosuppressive cells. However, this mechanism may also carry a higher risk of depleting activated effector T cells, increasing the likelihood of immune-related toxicities.

Conversely, domvanalimab is an Fc-silent IgG1 antibody, engineered to minimize Fcγ receptor engagement. Shitara noted that this design is expected to preserve effector T-cell function while mitigating immune-mediated adverse effects, making it a favorable candidate for combination immunotherapy. Zimberelimab, the PD-1 inhibitor partner in this combination, is mechanistically analogous to approved agents such as nivolumab (Opvido) and pembrolizumab (Keytruda), he stated.

Preclinical studies offer differing views on Fc domain design in TIGIT antibodies; data from one study published in Cancer Research support the use of Fc-silent constructs for optimal T-cell activation and lower toxicity, whereas a separate Nature publication advocated for Fc-active antibodies based on their ability to deplete suppressive immune cell subsets, Shitara detailed.

Taken together, the combination of domvanalimab and zimberelimab represents a promising Fc-silent immunotherapeutic approach aimed at enhancing antitumor immunity with a favorable safety profile, he said. This strategy is currently under clinical investigation in multiple tumor types, including gastrointestinal cancers, Shitara concluded.