A novel GUCY2C-CD3 T cell engaging bispecific construct (PF-07062119) for the treatment of gastrointestinal cancers
Mathur, D., Root, A.R., Bugaj-Gaweda, B. et al.Purpose: Gastrointestinal cancers remain areas of high unmet need despite advances in targeted- and imumunotherapies. Here we demonstrate potent, tumor selective efficacy with PF-07062119, a T-cell engaging CD3-bispecific targeting tumors expressing GUCY2C, which is expressed widely across CRC and other gastrointestinal malignancies. Additionally, to address immune evasion mechanisms, we explore combinations with immune checkpoint blockade agents, and with anti-angiogenesis therapy. Experimental Design: PF-07062119 activity was evaluated in vitro in multiple tumor cell lines, and in vivo in established subcutaneous and orthotopic human CRC xenograft tumors with adoptive transfer of human T cells. Efficacy was also evaluated in mouse syngeneic tumors using human CD3ε transgenic mice. Immunohistochemistry and mass cytometry were performed to demonstrate drug biodistribution, recruitment of activated T cells, and to identify markers of immune evasion. Combination studies were performed with anti-PD-1/PD-L1 and anti-VEGF antibodies. Toxicity and pharmacokinetic studies were done in cynomolgus macaque. Results: We demonstrate that GUCY2C-positive tumors can be targeted with an anti-GUCY2C/anti-CD3ε bispecific, with selective drug biodistribution to tumors. PF-07062119 showed potent T-cell mediated in vitro activity and in vivo efficacy in multiple CRC human xenograft tumor models, including KRAS and BRAF mutant tumors, as well as in the immunocompetent mouse syngeneic tumor model. PF-07062119 activity was further enhanced when combined with anti-PD-1/PD-L-1 treatment or in combination with anti-angiogenic therapy. Toxicity studies in cynomolgus indicated a monitorable and manageable toxicity profile. Conclusion: These data highlight the potential for PF-07062119 to demonstrate efficacy and improve patient outcomes in CRC and other gastrointestinal malignancies.
Mathur, D., Root, A.R., Bugaj-Gaweda, B. et al. "A novel GUCY2C-CD3 T cell engaging bispecific construct (PF-07062119) for the treatment of gastrointestinal cancers" Clinical Cancer Research (2020): DOI: 10.1158/1078-0432.CCR-19-3275