Abstract LB-114: a-TIGIT antagonist antibody EOS884448 shows dual mechanism of action by restoration of T cell effector functions and preferential depletion of Treg

Abstract

Abstract T cell Immunoreceptor with Ig and ITIM domains (TIGIT) is a co-inhibitory receptor expressed by lymphocytes, preferentially CD8+ T cells, NK, as well as by regulatory T cells (Treg). CD226 (DNAM-1), a co-stimulatory receptor also expressed on NK and T cells competes with TIGIT for PVR binding but with a lower affinity. Co-expression of TIGIT and CD226 receptors on T and NK effector cells suggests a role of these molecules in the fine control of cell activation. In cancer, TIGIT expression is upregulated on conventional and even more on regulatory T cells and co-expression with exhaustion markers such as PD-1 is frequent, giving a strong rationale for blocking TIGIT as a therapeutic approach to reverse T or NK cell dysfunction linked with cancer progression. Antagonistic anti-TIGIT antibodies were selected using a synthetic yeast display library of fully human antibodies and characterized for their binding and functional properties. EOS884448 anti-TIGIT mAb displays a strong affinity for recombinant and native TIGIT expressed on human primary T cells. It competes with CD155 for binding to human TIGIT and restores cytokine production when human primary T cells are suppressed in presence of CD155. To further explore its potency, EOS884448 was produced in a mammalian system on different human isotypes with different Fc effector functions. In the hIgG1 format, EOS884448 demonstrated preferential depletion of Treg cells in vitro when spiked in PBMC from healthy volunteers. Interestingly, the preferential depletion of Treg was also observed in PBMCs from cancer patients that harbour higher level of expression of TIGIT on Tregs but also on conventional CD4+ and CD8+ T cell populations. In vivo, two different isotypes of surrogate mouse anti-TIGIT mAb were used to evaluate the anti-tumor efficacy in the CT26 syngeneic murine model. Interestingly, only the ADCC enabling mIgG2a isotype was able to induce strong antitumor efficacy in monotherapy and in combination with an anti-PD1, resulting in a complete regression of pre-established tumors in the majority of animals. Anti-tumor efficacy was associated with an increased activity of conventional CD8+ and CD4+ T cells but also with Treg depletion within the tumor microenvironment, reaffirming the in vitro data generated on human PBMCs. The importance of depleting Treg using an a-TIGIT Ab isotype with effector functions was further confirmed in CT26 tumor bearing mice where the a-TIGIT mIgG1 isotype only shows efficacy when Treg are previously depleted using an anti-CD4 antibody. In summary, in vitro and in vivo data demonstrate for the first time the potential for a-TIGIT mAb EOS884448 to promote antitumor immunity by preferential depletion of Treg cells and activation of conventional T cells, which supports the rationale for its clinical evaluation. Citation Format: XAVIER LEROY, Catherine Hoofd, Julia Cuende, Sofie Denies, Virginie Rabolli, Julie Preillon, Florence Lambolez, Shruthi Prasad, Marjorie Mercier, Florence Nyawouame, Véronique Bodo, Noémie Wald, Grégory Driessens, Michel Detheux. a-TIGIT antagonist antibody EOS884448 shows dual mechanism of action by restoration of T cell effector functions and preferential depletion of Treg [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-114.