Tu83 - Anti-TIGIT Antibodies Promote Immune Activation in Combination with Immunotherapeutic Agents

TIGIT is an inhibitory receptor expressed on natural killer (NK) cells, CD8⁺, CD4⁺ T cells and regulatory T cells (T_regs). TIGIT  competes with an activating receptor, CD226, for binding to CD155 expressed by antigen-presenting and cancer cells. TIGIT has emerged as a key inhibitor of anti-tumor responses and blocking TIGIT results in immune activation and restored anti-tumor immunity. We have two anti-TIGIT antibodies, AB308 (IgG1) and AB154 (IgG1 with Fc-silencing mutations), that are undergoing clinical evaluation and biomarker assessment.

AB308 can promote Fc-mediated effector function, as evidenced by human NK cell-driven ADCC against TIGIT-expressing target cells. In mice, while combining Fc-silent or Fc-enabled anti-TIGIT with anti-PD-1 enhanced tumor growth inhibition, Fc-enabled anti-TIGIT was associated with intratumoral T_reg depletion. Anti-TIGIT also increased signaling in Jurkat T cells and IL-2 secretion in PBMC cultures both alone and in combination with zimberelimab (anti-PD-1). In addition, combination of AB308 with the dual A_2A/A_2B adenosine receptor antagonist etrumadenant is required for maximal signaling through the CD155-CD226 axis in the presence of adenosine. Finally, TIGIT and its co-expression with CD226 correlated with PD-1 expression on human tumor-infiltrating CD8⁺ T cells. Importantly, TIGIT and CD226 were co-expressed on circulating PD-1⁺ cells that are characterized by granzyme K expression and may represent a pre-dysfunctional stem-like T cell population that has been described as central to the therapeutic benefit of anti-PD-1 agents.

The data presented here support use of anti-TIGIT for cancer treatment and provides a rationale for combination with zimberelimab and adenosine pathway blocking agents such as etrumadenant.