Data from Fc-Silent Anti-TIGIT Antibodies Potentiate Antitumor Immunity without Depleting Regulatory T Cells

<div>Abstract<p>T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor on immune cells that outcompetes an activating receptor, CD226, for shared ligands. Tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg) and on CD8⁺ T cells with tumor-reactive or exhausted phenotypes, supporting the potential of therapeutically targeting TIGIT to enhance antitumor immunity. To optimize the efficacy of therapeutic antibodies against TIGIT, it is necessary to understand IgG Fc (Fcγ) receptor binding for therapeutic benefit. In this study, we showed that combining Fc-enabled (Fc_e) or Fc-silent (Fc_s) anti-TIGIT with antiprogrammed cell death protein 1 in mice resulted in enhanced control of tumors by differential mechanisms: Fc_e anti-TIGIT promoted the depletion of intratumoral Treg, whereas Fc_s anti-TIGIT did not. Despite leaving Treg numbers intact, Fc_s anti-TIGIT potentiated the activation of tumor-specific exhausted CD8⁺ populations in a lymph node–dependent manner. Fc_e anti-TIGIT induced antibody-dependent cell-mediated cytotoxicity against human Treg <i>in vitro</i>, and significant decreases in Treg were measured in the peripheral blood of patients with phase I solid tumor cancer treated with Fc_e anti-TIGIT. In contrast, Fc_s anti-TIGIT did not deplete human Treg <i>in vitro</i> and was associated with anecdotal objective clinical responses in two patients with phase I solid tumor cancer whose peripheral Treg frequencies remained stable on treatment. Collectively, these data provide evidence for pharmacologic activity and antitumor efficacy of anti-TIGIT antibodies lacking the ability to engage Fcγ receptor.</p>Significance:<p>Fc_s-silent anti-TIGIT antibodies enhance the activation of tumor-specific pre-exhausted T cells and promote antitumor efficacy without depleting T regulatory cells.</p></div>