Abstract 1583: SEA-TGT is an empowered anti-TIGIT antibody that displays superior combinatorial activity with several therapeutic agents

Abstract

Abstract TIGIT is an immunoregulatory receptor expressed on activated and memory T 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. Anti-TIGIT therapies have come to prominence recently as new strategies for anti-cancer therapy particularly in combination with other immune checkpoint inhibitors because of their complementary mechanisms of action. We have recently developed an investigational anti-TIGIT monoclonal antibody that employs our proprietary sugar engineered antibody (SEA) technology to create a nonfucosylated antibody, termed SEA-TGT. In the present studies, we have expanded our investigation of SEA-TGT and compared it to other antibody formats to understand how differences in complementarity-determining regions (CDR) and backbone effect both in vitro activity and in vivo anti-tumor response. We also investigated how these differences affect the ability of anti-TIGIT mAbs to combine with other anti-tumor therapies. The nonfucosylated SEA-TGT demonstrates a unique activating to inhibitory FcγR binding profile. SEA-TGT demonstrates enhanced FcγRIIIA binding with concomitant reduction in inhibitory FcγRIIb receptor binding. This binding with SEA-TGT was distinct from standard IgG1 backbones and gains effector function modifications compared to other anti-TIGIT mAbs. The differential ability to engage activating vs. inhibitory Fcγ receptors translated into distinct differences in preclinical activity. The differences seen in vitro were recapitulated in vivo as SEA-TGT led to enhanced tumor activity in syngeneic tumor models. Anti-TIGIT treatments are being pursued clinically in combination with other therapeutic modalities, as such we evaluated treatment with the TIGIT mAbs with different effector function backbones with various other anti-tumor therapies. When used at sub-therapeutic doses, SEA-TGT exhibited greatly enhanced anti-tumor activity in combination with both checkpoint therapy as well as with an ICD inducing vc-MMAE antibody-drug conjugate. Collectively, these data continue to strengthen our findings that the nonfucosylated effector function enhanced backbone of SEA-TGT confers superior preclinical anti-tumor activity as a monotherapy agent and in combination with PD(L)1 agents and vc-MMAE ADCs. We have initiated a phase 1 trial testing the safety and activity of SEA-TGT alone and in combination with anti-PD-1 therapy in patients with advanced solid tumors and select lymphomas. Citation Format: Alyson Smith, Weiping Zeng, Sasha Lucas, Bryan Grogan, Amber Blackmarr, Serena Wo, Scott Peterson, Shyra Gardai. SEA-TGT is an empowered anti-TIGIT antibody that displays superior combinatorial activity with several therapeutic agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1583.