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Background Mucosal-Associated Invariant T-cells (MAITs), resident in tissues, blood and tumors, are an abundant subset of non-conventional T-cells with potent cytotoxic capacity. Classical T-cell engagers (TCE) bind the epsilon chain of the TCR leading to activation of all T-cells with associated problems of cytokine release syndrome and regulatory T-cell activation. Biomunex has generated a series of bispecific antibodies that bind the invariant TCR alpha chain of MAIT cells and tumor antigens to generate MAIT engagers.Methods The Biomunex proprietary BiXAb platform provides multiple possibilities to produce bispecific, tetravalent antibodies that target the MAIT iTCR and a series of adequate tumor antigens (e.g. HER2, GPC-3, Mesothelin, CEA etc) demonstrating the flexibility and utility of the platform. MAIT cell activation, proliferation and degranulation were followed by FACS profiling. Tumor cell lines were co-cultured with MAIT cells and the BiXAbs in several cytotoxic assays (Chromium release and FACS). Cytokine release was assessed by Legend Plex assays or ELISA. MAIT engager-mediated cytotoxic activity of tumor-resident MAITs was determined in freshly isolated ovarian cancer samples by impedance measurements and MAIT cell infiltration/cytotoxicity in patient derived 3D organoids was measured by luminescence.Results MAIT engagers induced rapid activation, proliferation and degranulation of MAIT cells leading to efficient killing of the engaged cancer cells. The HER-2 directed MAIT engager (BMX-A) had the same potency when compared to an equivalent CD3 TCE. BMX-A did not activate the other CD4/CD8 subsets which resulted in a 1000X reduction in IL-6 release from PBMCs compared to a classical CD3 TCE. Additionally, the CD3 TCE induced regulatory T-cell activation, proliferation and IL-10 release whilst BMX-A had no impact on this T-cell subset. In freshly isolated and dissociated ovarian tumor biopsies, the addition of BMX-A induced tumor resident MAIT cells to proliferate and serial kill 90% of the human tumor at a starting E:T ratio of 1:200.Conclusions MAIT engagers induce potent cytotoxicity of cancer cells and induce tumor resident MAIT cells to kill cancer cells from patient derived biopsies. MAIT engagers do not activate CD4 T-cells and hence have a stronger safety profile, as judged by a 1000X decrease in IL-6 compared to classical TCEs. In addition, MAIT engagers do not activate regulatory T-cells and so will not increase local immunosuppression in the tumor microenvironment. Taken together, MAIT engagers are expected to increase the efficacy ratio with a significantly improved safety profile and large therapeutic window for the treatment of solid tumors.