Abstract 3146: HRA00130-C004, a novel anti-DLL3 ADC with bystander effect, high DAR and favorable safety profiles

Abstract Small Cell Lung Cancer (SCLC) is a highly aggressive neuroendocrine tumor, accounting for ~15% of all new lung cancer cases1. It is estimated that there are 250,000 new SCLC cases and at least 200,000 deaths globally each year2. SCLC exhibits high recurrence after first-line treatment, poor response to subsequent therapies, and rare survival3. Lacking of recommended treatments for prolonging survival remains a problem over decades4. DLL3 is an inhibitory ligand of the Notch receptor. It binds to its Notch receptor through a cis-interaction, thus, mediates inhibition of Notch pathway to facilitate neuroendocrine tumorigenesis5. DLL3 is highly upregulated and aberrantly expressed on the cell surface in SCLC and other high-grade neuroendocrine tumors with limited expression in normal tissues6.Here we presented a DLL3-directed ADC, HRA00130-C004, which features a differentiated topoisomerase I inhibitor payload DXh conjugated via a cleavable linker to a humanized IgG1 antibody. HRA00130-C004 strongly inhibited the proliferation of cell lines with different DLL3 expression. In the bystander killing assays, HRA00130-C004 was able to kill both DMS53 cells (DLL3 over-expressed) and U-2OS (DLL3-negative) cells when they are co-cultured. The in vivo treatment of HRA00130-C004 resulted in a dramatic and sustained inhibition of tumor growth in H1184 (DLL3 high) and DMS53 (DLL3 low) xenograft models. No obvious weight loss was observed during the experiment. Furthermore, HRA00130-C004 demonstrated a favorable PK profile and satisfactory molecular integrity in rats with 3mg/kg dosing and cynomolgus monkeys with 10 mg/kg dosing. The exposure of total antibody and intact ADC was consistent. Moreover, HRA00130-C004 was well tolerated in rats and cynomolgus monkeys with no related adverse findings, which indicated its favorable safety profiles. In summary, taking advantage of Hengrui’s DXh platform, HRA00130-C004 has demonstrated great potency and good safety profiles. These data support the future clinical development of HRA00130-C004. 1.CA Cancer J. Clin., 2018, 68, 7; 2.J. Natl. Compr. Cancer Netw. 2018, 16, 1171; 3.Mol. Ther. Oncolytics, 2021, 20, 470; 4.Journal of Cancer, 2022, 13, 2945; 5.Cellular Oncology, 2019, 42, 261; 6.Journal of Hematology and Oncology 2019, 12, 61; Citation Format: Qingqing Yao, Changding Xue, Zhibin Xu, Lingfeng You, Zhendong Xue, Yuchang Mao, Sophie Lin, Jun Feng, Zhe Zhang, Xin Ye, Min Hu, Feng He. HRA00130-C004, a novel anti-DLL3 ADC with bystander effect, high DAR and favorable safety profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3146.