Abstract 549: A novel T cell engaging bispecific antibody induces specific and efficacious lysis of small cell lung cancer cells in vitro and potent T cell re-directed anti-tumor activity in vivo
Authors: Hipp Susanne , Voynov Vladimir , Drobits-Handl Barbara , Trapani Francesca , Giragossian Craig , Scheer Justin M. , Adam Paul J. 
Published: August 2019

Abstract
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 T cell engaging bi-specific antibody that can potently re-direct T cells to specifically lyse SCLC cells expressing Delta-like Ligand 3 (DLL3). DLL3 is frequently expressed on the cell surface of neuroendocrine tumors, with no to very little expression in normal tissues, thus making DLL3 an ideal targeting antigen with which to safely re-direct cytolytic T cells to tumor cells. The bi-specific monovalent DLL3/CD3 IgG-like T cell Engager (ITE) is designed to have sustained serum exposure and simultaneously bind to CD3 on T cells and DLL3 on SCLC cells, resulting in formation of the cytolytic synapse. In vitro, unstimulated peripheral blood mononuclear cells (PBMCs) were co-cultured with several DLL3 expressing SCLC cell lines and increasing concentrations of the DLL3/CD3 ITE. The DLL3/CD3 ITE induced potent dose-dependent lysis of SCLC cell lines with EC90 values ranging from 15 to 150 ng/mL, whereas viability of DLL3-negative cells was unaffected, demonstrating the specificity of the DLL3/CD3 ITE for the DLL3 antigen. In addition, the DLL3/CD3 ITE induced DLL3-dependent activation and proliferation of T cells, and granzyme B and cytokine secretion. In vivo anti-tumor activity of the DLL3/CD3 ITE was assessed in NOG mice bearing subcutaneous xenografts of the SHP77 SCLC cell line and reconstituted with human T cells. Complete tumor regressions were observed with a dose of 0.25 mg/kg administered once weekly by i.v. administration, with the onset of activity being observed after the first dose. Consistent with the mode-of-action the DLL3/CD3 ITE led to a profound infiltration of both CD8 and CD4 T cell subsets in the tumors, which correlated with cleaved caspase 3 expression on tumor cells and tumor shrinkage. The inflammatory tumor microenvironment that was created by treatment with the DLL3/CD3 ITE also led to an increase of PD-1 on T cells and PD-L1 on the tumor cells. The DLL3/CD3 ITE shows cross-reactivity to both DLL3 and CD3 of human and cynomolgus monkey origin respectively, thus allowing the assessment of pharmacodynamics, pharmacokinetics, and safety in cynomolgus monkeys. In a single dose study in cynomolgus monkeys, the DLL3/CD3 ITE demonstrated antibody-like pharmacokinetic properties. These pre-clinical data demonstrate that the DLL3/CD3 ITE is a highly potent, efficacious, and DLL3-selective T cell redirecting agent, and supports future clinical development.
Citation Format: Susanne Hipp, Vladimir Voynov, Barbara Drobits-Handl, Francesca Trapani, Craig Giragossian, Justin M. Scheer, Paul J. Adam. A novel T cell engaging bispecific antibody induces specific and efficacious lysis of small cell lung cancer cells in vitro and potent T cell re-directed anti-tumor activity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 549.