1005 BiXAb® MAIT Engagers: solving the problems of classical T-cell engagers in the treatment of solid tumors

BackgroundMucosal-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.MethodsUsing 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).ResultsThe 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.ConclusionsThe tissue/tumor abundance and potent cytotoxic capability of MAIT cells and the specificity of MAIT