A Bispecific DLL3/CD3 IgG-like T-cell Antibody induces anti-tumor responses in Small Cell Lung Cancer

Purpose: Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy resistant recurrence in the majority of patients. To effectively treat SCLC we have developed a unique and novel IgG-like T-cell engaging bispecific antibody (ITE) that potently re-directs T-cells to specifically lyse SCLC cells expressing Delta-like ligand 3 (DLL3), an antigen that is frequently expressed on the cell surface of SCLC cells, with no to very little detectable expression in normal tissues. Experimental Design: The anti-tumor activity and mode of action of DLL3/CD3 ITE was evaluated in vitro using SCLC cell lines and primary human effector cells and in vivo in a SCLC xenograft model reconstituted with human CD3+ T-cells. Results: Selective binding of DLL3/CD3 ITE to DLL3-positive tumor cells and T-cells induces formation of an immunological synapse resulting in tumor cell lysis and activation of T-cells. In a human T-cell engrafted xenograft model, the DLL3/CD3 ITE leads to an increase in infiltration of T-cells into the tumor tissue resulting in apoptosis of the tumor cells and tumor regression. Consistent with the mode of action, the DLL3/CD3 ITE treatment led to upregulation of PD-1, PD-L1, and LAG-3. Conclusion: This study highlights the ability of the DLL3/CD3 ITE to induce strictly DLL3-dependent T-cell re-directed lysis of tumor cells and recruitment of T-cells into non-inflamed tumor tissues leading to tumor regression in a pre-clinical in vivo model. These data support clinical testing of the DLL3/CD3 ITE in SCLC patients.