CYT X300：一种新型EGFR x 泛gamma delta T细胞衔接器，用于治疗实体瘤

CD3 T cell engagers (TCEs) are an emerging immunotherapeutic modality, with multiple approvals for haematological cancers. However, the successful application of CD3 TCEs in solid tumors has been much more limited, largely due to the broad activation of all CD3 positive cells with these agents and the paucity of tumor associated antigens (TAAs) with tumor restricted expression profiles. Together, this often leads to unacceptable toxicity resulting from healthy tissue damage and/or dose-limiting cytokine release syndrome (CRS) from broad T cell activation. Cytospire's approach to enabling TCE development for many well-validated TAAs is to activate specific subsets of cytotoxic immune cells that can distinguish between malignant and non-malignant cells and which also produce lower levels of CRS-causing cytokines. Gamma delta (gammadelta) T cells are a promising class of cells that act at the nexus of innate and adaptive immunity. gammadeltaT cells drive potent anti-cancer activity, while utilising a plethora of functionally redundant stress markers (such as ULBPs, MICA, MICB) to discriminate tumor from healthy cells. Due to this biology, gammadelta TCEs are considered to have great potential as effector cells for next generation TCEs. To date, clinical-stage gammadelta TCEs have leveraged a blood-resident (Vdelta2) subset of gammadeltaT cells. However, there is a growing literature showing that favourable patient outcomes in a range of solid tumors are driven by tissue/tumor resident gammadeltaT cells (Vdelta1 and Vdelta3 cells), elevating these as essential cells to leverage with novel gammadelta TCEs. Here, we present the preclinical characterisation of CYT X300, a novel pan-gammadelta TCE that targets EGFR, a broadly expressed, clinically validated TAA on solid tumor cells. CYT X300 incorporates a novel antibody binder to an epitope present on all gammadeltaT cells including the tissue/tumor resident Vdelta1 and Vdelta3 cells, coupled with a clinically validated anti-EGFR antibody domain and a silenced Fc domain. CYT X300 activates all subsets of gammadeltaT cells and induces proliferation of these effector cells. CYT X300 drives potent killing of cancer cells with EC50s in the picomolar range across a range of EGFR expression levels. In vivo , CYT X300 has robust anti-tumor activity in two murine cancer models, and ex vivo potently activates primary gammadeltaT cells from non-small cell lung cancer (NSCLC) patient tumor samples. Crucially, CYT X300 does not induce killing of primary, EGFR-positive healthy cells nor excessive production of cytokines such as IL-6 and TNFalpha that are known to drive CRS. Studies in non-human primates have shown that CYT X300 is very well tolerated and does not induce the severe toxicities that have been a hallmark of EGFR x CD3 engagers. Based on these data, CYT X300 is currently being advanced through IND-enabling preclinical studies and GMP manufacturing. A first-in-human clinical study is being planned to evaluate CYT X300 as a treatment for a range of EGFR-positive solid tumors including colorectal, head and neck and non-small cell lung cancers.