Nonfucosylation of an anti-TIGIT antibody enhances FcR engagement, driving innate immune activation and antitumor activity

TIGIT is an immune checkpoint receptor expressed on activated and memory T cells, immunosuppressive T regulatory cells, and natural killer (NK) cells. TIGIT has emerged as an attractive target for antitumor therapies, due to its proposed immunosuppressive effects on lymphocyte function and T cell activation. We generated an anti-TIGIT monoclonal antibody (mAb) that binds with high affinity to human, non-human primate, and murine TIGIT and through multiple experimental methodologies demonstrated that checkpoint blockade alone is insufficient for antitumor activity. Generating anti-TIGIT mAbs with various Fc backbones we show that muting the Fc-Fc gamma receptor (Fc gamma R) interaction failed to drive antitumor activity, while mAbs with Fc functional backbones demonstrate substantial antitumor activity, mediated through activation of antigen-presenting cells (APCs), T cell priming, and NK-mediated depletion of suppressive Tregs and exhausted T cells. Further, nonfucosylation of the Fc backbone resulted in enhanced immune responses and antitumor activity relative to the intact IgG1 backbone. The improved activity correlated with the biased Fc gamma R interaction profile of the nonfucosylated anti-TIGIT mAb, which supports that Fc gamma RIIIa binding with decreased Fc gamma RIIb binding favorably activates APCs and enhances tumor-specific CD8(+) T cell responses. The anti-TIGIT mAbs with intact Fc gamma R interacting backbones also demonstrated synergistic enhancement of other standard antitumor treatments, including anti-PD-1 treatment and a model monomethyl auristatin E antibody-drug conjugate. These findings highlight the importance of the anti-TIGIT mAb's Fc backbone to its antitumor activity and the extent to which this activity can be enhanced through nonfucosylation of the backbone.