Abstract 3240: EOS884448, a high affinity fully human antibody directed against TIGIT, mediates in vitro anti-tumor activity through multiples mechanisms of action involving activation of intratumor effector cells and depletion of regulatory T cells

T cell Immunoreceptor with Ig and ITIM domains (TIGIT) is a T cell co-inhibitory receptor recently described as a key checkpoint driving tumor cell immunosuppression. It is predominantly expressed on regulatory CD4+ T cells (Tregs), CD8+ T cells and NK cells from healthy individuals but further upregulated in cancer patients where it frequently co-expresses with exhaustion markers such as PD-1. TIGIT cognate receptors are members of the poliovirus receptors, among which CD155 has the highest affinity for TIGIT. They are expressed on antigen presenting cells but also on tumor cells which provides a strong rationale for blocking TIGIT as a therapeutic approach to reverse T or NK cell dysfunction linked with cancer progression. This anti-tumor mode of action of an aTIGIT antibody can be further enhanced with the selection of a FcγR interaction enabling isotype to allow for the potential depletion of TIGIT+ Tregs, described as highly immunosuppressive. EOS884448 was selected among antagonist anti-TIGIT antibodies, using a yeast display library of fully human antibodies and characterized for their binding and anti-tumor properties. EOS884448 displays a subnM affinity to primary T cells from healthy donors and cancer patients and potently prevents binding of TIGIT ligands. High affinity binding to cynomolgus TIGIT allows for its direct use in GLP Tox studies in non-human primates. EOS884448 potently prevents TIGIT activation and restores pro-inflammatory cytokine release in presence of CD155 ligand. This mode of action was assessed first in an IL-2 driven reporter-based system and also with primary T cells from healthy individuals or patients suffering from different solid tumor indications. Importantly, EOS884448 shows superior potency compared to antibodies from other anti-TIGIT programs in which sequences have been published. Interestingly, EOS884448-mediated restoration of cytokine release activity in presence of TIGIT ligand was observed both for conventional and non-conventional T cells. When evaluated with different isotype formats, EOS884448, as an hIgG1, shows preferential depletion of Tregs over memory CD4+ and CD8+ T cells. This key finding supports the use of an isotype with high affinity for activatory FcγR in cancer patients who could benefit from a drug acting simultaneously through depletion of highly suppressive Tregs and restoration of T and NK cell effector functions within tumor. Citation Format: Julia Cuende, Virginie Rabolli, Florence Nyawouame, Marjorie Mercier, Angela Pappalardo, Lucile Garnero, Julie Dechanet-Merville, Gregory Driessens, Catherine Hoofd. EOS884448, a high affinity fully human antibody directed against TIGIT, mediates in vitro anti-tumor activity through multiples mechanisms of action involving activation of intratumor effector cells and depletion of regulatory T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3240.