MAIT衔接器：规避Treg抑制以在实体瘤中实现更强的活性

MAIT engagers are part of the immune cell engager drug modality and specifically target Mucosal Associated Invariant T cells (MAITs) via their unique T cell receptor (TCR) and tether them to cancer cells, via a tumor antigen, to elicit MAIT-mediated cell death. MAIT cells are an abundant cytotoxic subset of non-conventional T cells that are present in blood and all major organs and are particularly enriched in barrier tissues. Classical CD3 engagers activate all T cell subsets, including the regulatory T-cell (T-regs) population whose activation in the tumor microenvironment (TME) will dampen the intended cytotoxicity of the CD8 cytotoxic T cells and will limit CD3 engager efficacy. Unlike CD3 engagers, MAIT engagers only activate MAIT cells and do not cause increased immune suppression via T-reg activation or cytokine release syndrome (CRS) via general CD4 T cell activation. MAIT engagers were generated using Biomunex's proprietary bispecific, tetravalent antibody platform, BiXAb. MAIT-cell activation, proliferation, degranulation and cytotoxicity assays were established in co-culture between tumor cells, immune cell subsets (CD8 or PBMCs) and BiXAb MAIT engagers. Analysis of activation, degranulation and proliferation was followed by FACs whilst cytotoxicity was assessed by chromium release. Regulatory T cells were enriched from PBMCs and used in co-culture assays to assess CD8 T cell repression as judged by IL-2 release. General cytokine release was measured by Legend Plex or ELISA. Cytotoxicity of tumor-resident MAITs, from fresh patient samples, was determined by impedance measurements. In vivo efficacy studies were performed in humanized mouse models by co-injection of CD8s, cancer cells and the MAIT engager. MAIT engagers are as potent as classical CD3 engagers in terms of activation, degranulation, proliferation and cytotoxicity towards cancer cells. However, in co-culture assays of cancer cells and PBMCs, CD3 engagers induce large quantities of cytokines, especially IL-6 which is known to initiate CRS whilst MAIT engagers induced similar levels to control antibodies suggesting greater safety. CD3 engagers induced Treg activation proliferation and release of IL-10 in a dose dependent manner and induced Treg suppression of CD8 activation. MAIT engagers had no impact on Treg biology and increased immune suppression. Ex vivo cytotoxicity of tumor-resident MAIT cells using dissociated Ovarian cancer samples at “real E:T ratios” showed that MAITs in human tumors can respond to MAIT engagers, proliferate and eliminate tumor cells. In vivo efficacy studies showed that MAIT engagers can control human tumors in mice models of cancer. MAIT engagers are as potent as CD3 engagers but have a significantly improved safety profile. More importantly, they do not cause Treg activation which can dampen T-cell cytotoxicity in the TME and are expected to show greater efficacy in the clinic for the treatment of solid tumors.