Abstract 5550: QLS31904: An anti-DLL3/CD3 bispecific antibody for T cell immunotherapy of small cell lung cancer

Abstract

Background: More than 150,000 patients are diagnosed with small cell lung cancer (SCLC) each year in the world. Standard of care for patients at different stages of SCLC includes radiation, etoposide, cisplatin/carboplatin, and atezolizumab. However, relapse is quite common. Therefore, there is a strong need to develop a more effective treatment. Delta-like ligand 3 (DLL3) is a target selectively expressed in SCLC rather than normal tissue. We have developed an anti-DLL3/CD3 bispecific antibody QLS31904 that is engineered to direct and activate T cells through CD3 to kill SCLC cells expressing DLL3. Methods: Tumor cell killing, T cell activation, and cytokine production of QLS31904 in a concentration range were assessed in the presence of SCLC cells and human T cells in vitro. Antitumor activity of QLS31904 was evaluated in SCLC xenograft models, in which NCG mice were co-implanted with SHP-77 and human T cells first, then treated with intraperitoneal QLS31904 or control IgG1AA isotype. The in vivo tumor growth inhibition was assessed. Pharmacokinetic analyses were performed in non-human primates (NHP). The cross-reactivity of QLS31904 with NHP DLL3 and CD3 were established, and the tolerability was also evaluated in NHP model. Results: QLS31904 displayed the anticipated bispecific binding properties and mediated potent and selective lysis of DLL3-positive cancer cell lines through recruitment and activation of human T cells. No cytokine activation was observed with human peripheral blood mononuclear cell alone. In xenograft models, QLS31904 induced significant tumor growth inhibition at doses as low as 20 µg/kg, including complete regression of established tumors. QLS31904 exhibits about 100 hours of T1/2 in NHP, supporting feasibility of weekly dosing. QLS31904 was well tolerated with no related adverse findings up to the highest tested dose (five weekly doses of 10mg/kg) in NHP. Conclusions: QLS31904 has an impressive efficacy and safety profile in the preclinical studies, making it a potentially viable option for DLL3-expressing SCLC in the clinical setting. Citation Format: Liuqing Yang, Ruimei Li, Jiahua Jiang, Hongliang Qian, Hongxiu Ge, Ting Lu, Yan Fang, Jun Liu, Shuyong Zhao. QLS31904: An anti-DLL3/CD3 bispecific antibody for T cell immunotherapy of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5550.

Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer

“…This TCE comprises three chains covalently linked by disulfide bonds: an anti-DLL3-specific fragment antigen-binding (Fab) component, an anti-CD3-directed scFv fragment, and a modified Fc region to support heterodimerization and purification and prevent unwanted Fc receptor binding (Fig. 3E) [58].…”

“…QLS31904 inhibited tumor growth in triple-immunodeficient mice implanted with SHP-77 and human T cells [ 112 ]…”