250?SEA-TGT is a nonfucosylated antibody with distinct and amplified effector function activity that leverages the dependencies of anti-TIGIT anti-tumor activity upon Fc? R engagement

摘要

Background TIGIT is an immunoregulatory receptor expressed on activated and memory T cells, T regulatory cells (Tregs), and NK cells. TIGIT binding to CD155 and CD112 on tumor cells drives an inhibitory signal resulting in decreased T cell functionality. TIGIT targeting has been reported to release these inhibitory signals, drive Treg depletion, augment CD8 T cell generation, and promote anti-tumor responses. Methods To evaluate the impact of antibody backbone on anti-TIGIT action three distinct antibodies with differential backbone effector functions, wild type, Fc(gamma)R null (LALA), and Fc(gamma)R enhanced (nonfucosylated, SEA-TGT), were incorporated onto a human anti-TIGIT antibody and assessed. The nonfucosylated SEA-TGT backbone was distinct from the LALA and wild type backbone through increased binding to activating FcyRIIIa receptor while concomitantly decreasing binding to the inhibitory Fc(gamma)RIIb receptor. Results Independent of backbone all TIGIT antibodies blocked ligand binding and restored CD226 signaling. The effector null backbone neither mediated Treg depletion nor na?ve or memory CD8 T cell activation. However, the effector enhanced SEA-TGT significantly increased Treg depletion and activation of CD8 T cells over the comparator wild type anti-TIGIT antibody. The enhanced SEA-TGT also induced innate cell activation not seen with the other backbones. These in vitro results translated to curative in vivo anti-tumor activity in multiple syngeneic models as a single agent. Again, the effector null antibody was inactive in all models whereas the effector enhanced SEA-TGT drove curative responses beyond those seen with the standard wild type backbone. Increased activity correlated with a slight decrease in intra-tumoral Tregs and increases in CD8 memory T cells and innate cell activations. Anti-tumor response was associated with generation of long-term, antigen-specific immunity that resulted in complete tumor rejection upon tumor re-challenge. Conclusions Collectively, these data indicate that modulation of CD8 T cell functionality is not solely through alterations in the TIGIT/CD226 signaling axis and that our nonfucosylated Fc?R enhanced antibody uniquely activates both adaptive and innate arms of the immune system for maximal CD8 T cell responses. They also underscore the anti-tumor therapeutic potential of a nonfucosylated TIGIT targeting antibody (SEA-TGT) as a monotherapy agent and in combination with PD(L)1 agents. We have initiated a phase 1 trial testing the safety and activity of SEA-TGT in patients with advanced solid tumors and select lymphomas ( NCT04254107 ). Trial Registration NCT04254107 Ethics Approval Animals studies were approved by and conducted in accordance with Seattle Genetics Institutional Care and Use Committee protocol #SGE-029.