PT  - JOURNAL ARTICLE
AU  - Plyte, Simon E
AU  - Fraudeau, Marie
AU  - Germain, Claire
AU  - Winterberg, Dorothee
AU  - Rousseau, Camille
AU  - Sodaro, Gaetano
AU  - Audin, Maxime
AU  - Ivagnes, Alexandre
AU  - Oberg, Hans Heinrich
AU  - Gerard, Pierre Emmanuel
AU  - Wesch, Daniela
AU  - Peipp, Matthias
AU  - Prigent, Julie
TI  - 1005 BiXAb® MAIT Engagers: solving the problems of classical T-cell engagers in the treatment of solid tumors
AID  - 10.1136/jitc-2023-SITC2023.1005
DP  - 2023 Nov 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - A1113--A1113
VI  - 11
IP  - Suppl 1
4099  - http://jitc.bmj.com/content/11/Suppl_1/A1113.short
4100  - http://jitc.bmj.com/content/11/Suppl_1/A1113.full
SO  - J Immunother Cancer2023 Nov 01; 11
AB  - Background Mucosal-Associated Invariant T cells (MAITs) are an abundant subset of non-conventional T-cells with potent cytotoxic capacity that are resident in many tissues and solid tumors. T-cell redirection is a clinically validated approach in 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 Biomunex has generated bispecific antibodies that bind this MAIT semi-invariant TCR (iTCR) and a tumor associated antigen (HER2) to generate BiXAb® MAIT engagers.Methods Using the Biomunex proprietary BiXAb® platform, bispecific, tetravalent antibodies were generated that target the MAIT iTCR and the HER2 receptor. Binding to proteins and cellular targets was demonstrated by ELISA, DUAL ELISA and FACS. MAIT-cell activation, proliferation and degranulation was followed by gating on MAIT cells within a purified CD8 cell population. Tumor cell lines (varying [HER2]) were co-cultured with MAIT cells and the BiXAb®s in several cytotoxic assays (evaluated by Chromium release). Cytokine release was assessed by Legend Plex assays or ELISA. Cytotoxicity of tumor-resident MAITs was determined from freshly isolated ovarian cancer samples and patient derived 3D organoids were used to assess cytotoxicty and infiltration of peripheral MAITs (The Hub organoids).Results The BiXAb® MAIT engager efficiently binds both target proteins with similar affinities to the parental Mabs (and binds simultaneously). The MAIT engager binds the MAIT iTCR 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. At low effector to target ratios (E:T = 2:1), MAIT cells efficiently kill engaged cancer cells (80% cytotoxicity in 18 hrs) with a potency similar to that of a classical TCE (in clinical development). The MAIT engager did not activate the regulatory T cells or other CD4/CD8 subsets. In addition, using PBMCs, total cytokine release was 1000 fold less with the MAIT engager compared to the classical TCE. Ex vivo cytotoxicity of tumor-resident MAIT cells using freshly isolated ovarian tumor material and MAIT engager-mediated cytotoxicity of patient derived organoids (Colorectal cancer) will be shown.Conclusions The tissue/tumor abundance and potent cytotoxic capability of MAIT cells and the specificity of MAIT engagers (no activation of CD4s/Tregs: reduced CRS and immunosuppression) strongly support the contention that MAIT engagers would have a major, durable response in the treatment of solid tumors.