Abstract 3161: Preparation of aclinical trial with a-TIGIT antagonist antibody EOS884448, which demonstrates potent preclinical activity and safe toxicology profile

• Published in: Cancer research (Chicago, Ill.) Vol. 80; no. 16_Supplement; p. 3161
• Main Authors: Nguyen, Thi Lien-Anh, Cuende, Julia, Preillon, Julie, Garnero, Lucile, Rabolli, Virginie, Wald, Noémie, Hoofd, Catherine, Chevron, Patricia, Mercier, Marjorie, De Henau, Olivier, Bodo, Véronique, Driessens, Gregory
• Format: Journal Article
• Language: English
• Published: 15.08.2020
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2020-3161

Abstract T cell Immunoreceptor with Ig and ITIM domains (TIGIT) is a co-inhibitory receptor expressed by lymphocytes, preferentially CD8+, 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 their common ligand, CD155, 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. We have developed EOS884448, a fully human antagonist anti-TIGIT antibody that demonstrates strong potential in vitro to compete with TIGIT natural ligands and to prevent CD155-mediated inhibition of T cells from healthy volunteers and cancer patients. In addition, EOS884448 preferentially depletes Treg via an ADCC-triggered mechanism. In vivo, in mouse tumor models, a surrogate a-TIGIT antibody has shown potent antitumor activity through a combination of its antagonistic properties and its effector function through Fc gamma receptor engagement. EOS884448 was tested in a non-human primate GLP toxicology study and demonstrated a safe profile at all tested doses (≤10mg/kg) after repeated injection for up to 4 weeks at weekly intervals (5 doses in total). Pharmacokinetic data showed dose-dependent increase of EOS884448 concentration in the blood that correlated with gradual increased in TIGIT receptor occupancy measured on NK and T cells and that reached saturation in Cynomolgus monkeys dosed at 1mg/kg. In anticipation of the first-in-human (FIH) study of EOS884448, assays to measure PK, ADA and receptor occupancy in human blood samples were developed. In addition, to support the clinical strategy, multiple cancer indications were tested for expression of members of the TIGIT pathway. The frequency of TIGIT-expressing immune cells, analysed by FACS, was increased in PBMCs from cancer patients as compared to healthy donors. Further increase in TIGIT expression (both in proportion and density) was measured on TILs, and particularly on Treg cells that had the highest expression. CD155 expression analysed by IHC in solid cancers (n=284) was higher in tumor and seen in the nine tested indications, with close to 50% of CD155high tumor cells measured in indications including pancreatic, prostate, kidney, gastric and colon cancers. CD226 expression was confirmed by IHC on immune infiltrate in solid tumor samples (n=307). Altogether, preclinical, toxicology and translational medicine data support the initiation of a FIH study of a-TIGIT mAb EOS884448 in cancer patients. Citation Format: Thi Lien-Anh Nguyen, Julia Cuende, Julie Preillon, Lucile Garnero, Virginie Rabolli, Noémie Wald, Catherine Hoofd, Patricia Chevron, Marjorie Mercier, Olivier De Henau, Véronique Bodo, Gregory Driessens. Preparation of aclinical trial with a-TIGIT antagonist antibody EOS884448, which demonstrates potent preclinical activity and safe toxicology profile [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3161.