TIGIT is co-expressed with PD-1 on tumor-infiltrating lymphocytes or NK cells and has been associated with poor prognosis in a variety of cancers.
TIGIT and PD-1 have distinct, non-redundant functions in controlling anti-tumor immune responses. Preclinical studies have shown synergistic anti-tumor activity with combined inhibition of TIGIT and PD-1.
PD-L1 expressed on tumor cells binds to the checkpoint receptor PD1 on T and NK cells and leads to immunosuppression
TIGIT is another checkpoint receptor expressed on immune cells that binds CD155 on tumor cells, leading to further evasion of anti-tumor immunity
Combined inhibition of TIGIT and PD1 may have a synergistic effect, unleashing robust immune activity against certain tumor cells
Arcus is developing two anti-TIGIT monoclonal antibodies: domvanalimab (Fc-silent) and AB308 (Fc-enabled). Both bind to TIGIT and may enable CD155:CD226 interaction and subsequent immune cell activation.
Domvanalimab, our most advanced anti-TIGIT candidate, is an Fc-silent investigational monoclonal antibody that blocks TIGIT and has demonstrated complete receptor coverage on all TIGIT-expressing peripheral leukocytes. This investigational medicine is designed to treat solid tumors because the silent Fc domain is believed to eliminate the potential for depletion of TIGIT-bearing immune cells, which are critical for anti-tumor immune activity. Domvanalimab is currently being evaluated in an ongoing Phase 3 registrational study in combination with zimberelimab, our anti-PD-1 monoclonal antibody in first-line locally advanced or metastatic, PD-L1>50% non-small cell lung cancer.
AB308 is a second investigational anti-TIGIT monoclonal antibody that is Fc-enabled. We believe an Fc-enabled antibody like AB308 may be applicable to hematologic malignancies (eg, B cell malignancies) where the depletion of TIGIT-expressing cancer cells via antibody directed cytotoxicity may be beneficial. AB308 in combination with zimberelimab is currently being investigated in a Phase 1b study of people with advanced solid and hematologic malignancies.
A randomized Phase 3, open-label, study to evaluate the efficacy of zimberelimab (AB122) monotherapy compared to standard chemotherapy or zimberelimab combined with domvanalimab (AB154) in front-line, PD-L1-positive locally advanced or metastatic non-small cell lung cancer.
A Phase 2 trial to evaluate the safety and efficacy of zimberelimab monotherapy, domvanalimab + zimberelimab, and domvanalimab + zimberelimab + etrumadenant in front-line non-small cell lung cancer.
A Phase 1b trial to evaluate the safety, tolerability, PK, PD, and clinical activity of domvanalimab ± zimberelimab in participants with advanced solid malignancies.
A Phase 1/1b, multicenter, open-label, dose-escalation, and dose-expansion study to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and clinical activity of AB308 in combination with zimberelimab in participants with advanced malignancies.
