Panoply™ Human GUCY2C Over-expressing Stable Cell Line

Despite advances in targeted and immunotherapies, significant unmet medical needs remain in gastrointestinal cancers. Here, researchers demonstrated the potent, tumor-selective efficacy of PF-07062119, a T cell-directed CD3 bispecific antibody that targets tumors expressing guanylate cyclase C (GUCY2C), which is widely expressed in colorectal cancer and other gastrointestinal malignancies. Furthermore, to address mechanisms of immune escape, researchers explored its combination with immune checkpoint inhibitors and anti-angiogenic therapies. The study demonstrated that GUCY2C-positive tumors can be targeted with an anti-GUCY2C/anti-CD3ϵ bispecific antibody, with selective tumor biodistribution. PF-07062119 demonstrated potent T cell-mediated activity in vitro and in vivo efficacy in multiple human colorectal cancer xenograft models, including KRAS- and BRAF-mutant tumors, as well as in immunocompetent mouse syngeneic tumor models. PF-07062119's activity was further enhanced when combined with anti-PD-1/PD-L1 therapy or anti-angiogenic therapy. Toxicity studies in cynomolgus monkeys demonstrated a manageable and manageable toxicity profile. These data highlight the potential of PF-07062119 to demonstrate efficacy and improve patient outcomes in colorectal cancer and other gastrointestinal malignancies.

PF-07062119 was shown to bind to the surface of human T cells and GUCY2C overexpressing HCT116 tumor cells, but not to GUCY2C-negative HCT116 cells (Figure 1A). To understand the range of GUCY2C expression that triggers T cell-mediated cytotoxicity, cell surface receptor density was quantified across a panel of colorectal tumor cell lines. Receptor densities ranged from 875 to 8,067 receptors per cell (Figure 1B). Treatment of these cells with PF-07062119 and human T cells demonstrated dose-dependent and GUCY2C expression-dependent cytotoxicity, as measured by tumor cell survival (Figure 1C). Consistent with the cytotoxicity assay results, supernatants collected from these cytotoxicity assays demonstrated IFNγ release in a PF-07062119-dose-dependent manner (Figure 1D). No changes in tumor viability or IFNγ release were observed in GUCY2C-negative HCT116 cells, confirming that GUCY2C expression is required for the induction of PF-07062119-mediated T cell effector functions.

Figure 1. PF-07062119 demonstrates in vitro CTL-mediated killing in GUCY2C-positive tumor cells. (Mathur D, et al., 2020)