Abstract 2954: MAIT engagers: An efficacious novel modality in the field of T-cell engagers for the treatment of solid tumors

Abstract

Abstract Background: Mucosal-Associated Invariant T cells (MAITs) are an abundant subset of non-conventional T-cells with potent cytotoxic capacity (up to 20% of circulating T-cells) that are naturally resident in many tissues and solid tumors. T-cell redirection is a clinically validated approach to treating haematological cancers but has limited success in solid tumors. Classical T-cell engagers (TCE) bind the epsilon chain of the TCR leading to activation of all T-cells. MAIT cells utilize a semi-invariant TCR and recognize bacterial metabolites presented in the context of the MR1 protein. Biomunex has generated bispecific antibodies that bind the MAIT semi-invariant TCR (iTCR) and the HER2 receptor tyrosine kinase expressed on tumor cells. This enables the formation of an efficient immunological synapse and exclusive redirection of MAIT cells to directly kill cancer cells. Methods: Using the Biomunex proprietary BiXAb® platform, bispecific, tetravalent antibodies were generated that target the MAIT iTCR and HER2. Specific binding to the two targets was demonstrated by ELISA, DUAL ELISA and in FACS. In general, BiXAb®-mediated MAIT-cell activation, proliferation and degranulation were followed by gating on MAIT cells within a purified CD8 cell population. Tumor cell lines expressing varying amounts of HER2 were co-cultured with MAIT cells (peripheral and tumor-resident) and the BiXAb®s in several cytotoxic assays which were evaluated by measuring Chromium release, LDH release and FACS. Results: The iTCR x HER2 BiXAb® efficiently binds both target proteins with similar affinities to the parental Mabs and can bind both simultaneously, as judged by Dual ELISA. The iTCR x HER2 BiXAb® binds the MAIT-cell TCR and can bind cancer cells over a wide range of HER2 expression. BiXAb® engagement of MAIT cells and cancer cells leads to rapid activation, proliferation and degranulation of MAIT cells. In a population of PBMCs, only MAIT cells are activated by the BiXAb®. Even at low effector to target ratios (E:T = 2:1), MAIT cells efficiently kill engaged cancer cells in a HER2-dependent manner (over 50% cytotoxicity in 18 hrs). The MAIT-directed BiXAb® does not activate other T-cell subsets and hence has significantly reduced cytokine release when compared to a classical T-cell engager. Conclusions: BiXAb® mediated MAIT cell redirection leads to efficient killing of cancer cells and is a promising new approach for the treatment of solid tumors. The iTCR x HER2 BiXAb® has no impact on the general CD8 or CD4 T-cell population which may address some of the clinical limitations of classical TCEs. Citation Format: Simon Edward Plyte, Marie Fraudeau, Jonathan Grivel, Paloma Hougron, Katja Klausz, Dorothee Winterberg, Britta von Below, Alexandre Ivagnes, Claire Germain, Sebastian Amigorena, Eugene Zhukovsky, Matthias Peipp, Pierre-Emmanuel Gerard, Olivier Lantz, Julie Prigent. MAIT engagers: An efficacious novel modality in the field of T-cell engagers for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2954.