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 (6Suppl): Abstract nr 3146.