Preclinical activity of the DLL3-targeted T cell engager MK-6070 in neuroendocrine prostate cancer.

Neuroendocrine prostate cancer is an aggressive variant of prostate cancer with limited therapeutic options. Delta-like ligand 3 (DLL3) is a cell surface protein and therapeutic target expressed in the vast majority of NEPC tumors. The DLL3-targeted T cell activating construct MK-6070 (formerly called HPN328) binds to both DLL3 on tumor cells and CD3 on T cells, as well as serum albumin to extend half-life. A phase 1/2 trial of MK-6070 is currently underway which includes an NEPC cohort (NCT04471727). Here we report the preclinical activity of MK-6070 in prostate cancer models, showing high specificity and anti-tumor activity in DLL3-expressing NEPC models both in vitro and in vivo, with T cell activation and tumor infiltration of T cells after treatment. MK-6070 also demonstrates anti-tumor activity in mixed tumors, impacting DLL3-negative prostate cancer cells after engagement with surrounding DLL3-expressing tumor cells, supporting a potential bystander effect. Overall, these data demonstrate promising activity of MK-6070 in NEPC preclinical models including heterogeneous tumors, supporting the clinical development of MK-6070.