Abstract 1822: Preclinical efficacy and safety of CS5008, a novel SSTR2×DLL3 bispecific antibody-drug conjugate (ADC) with topoisomerase 1 inhibitor payload for small cell lung cancer and neuroendocrine tumors.

Abstract Background: CS5008 is a first-in-class bispecific ADC targeting SSTR2 and DLL3, constructed on CStone's proprietary modular ADC platform. It comprises a bispecific antibody with high affinity for both targets, a proprietary tandem-cleavable β-glucuronide linker (CSL20), and the topoisomerase 1 inhibitor exatecan as payload (drug-to-antibody ratio = 4). CS5008 is designed to overcome tumor heterogeneity in small cell lung cancer (SCLC) and neuroendocrine tumors (NETs) by simultaneously targeting two clinically validated antigens with complementary expression profiles. SSTR2 is a well-established target in neuroendocrine tumors (NETs/NECs). DLL3 is a clinically validated target in SCLC, serving as the target of tarlatamab, a T-cell engager. However, tumor heterogeneity and subtype plasticity often limit the effectiveness of single-target approaches in SCLC. CS5008 is a first-in-class bispecific ADC designed to address this challenge by simultaneously targeting SSTR2 and DLL3. It is constructed on CStone's proprietary modular ADC platform and comprises a bispecific antibody with high affinity for both targets, a proprietary tandem-cleavable β-glucuronide-cathepsin linker (CSL20), and the topoisomerase 1 inhibitor exatecan as payload (drug-to-antibody ratio = 4). Methods: CS5008 was evaluated in vitro for binding affinity, internalization, and cytotoxicity using tumor cell lines with varied SSTR2/DLL3 expression levels. In vivo efficacy was assessed in multiple SCLC xenograft (CDX) models (e.g., H524, H69, H82, H446, COR-L279, SHP77). Pharmacokinetics (PK) and tolerability were studied in rodents and non-human primates, including preliminary toxicology assessments at doses of 30, 45, and 60 mg/kg administered every three weeks (Q3W). Results: CS5008 exhibited nanomolar binding affinity for both DLL3 and SSTR2, both of which were determined by flow cytometry (FACS) on SCLC tumor cells. It induced rapid internalization and potent, antigen-dependent cell killing in SSTR2+/DLL3+ models (e.g., IC50 of 1.54 nM in H524 cells). A single treatment with 10 mg/kg CS5008 achieved significant tumor growth inhibition in all 5 tested SCLC CDX models with different expression level of DLL3 and SSTR2 assessed by FACS, indicating the designated character of CS5005 to overcome the heterogeneity of SCLC. PK profiles in rodents and non-human primates demonstrated CS5008’s high circulating stability. In cynomolgus monkeys, CS5008 was well-tolerated at doses up to 60 mg/kg. Conclusions: CS5008 demonstrated potent antitumor activity against SCLC by dual targeting of SSTR2 and DLL3, effectively addressing heterogeneity. Its favorable preclinical safety and robust PK support further clinical development. An IND application is expected by the end of 2026. Citation Format: Chuan Wang, Yongwang Li, Ning Zhang, Yamin Wang, Xinling Zhang, Xuelian Liu, Yuxin Qian, Hui Dai, Xueqin Dai, Yaxin Chen, Zicong Zheng, Wenjing Xiang, Fei Ma, Jianxin Yang. Preclinical efficacy and safety of CS5008, a novel SSTR2×DLL3 bispecific antibody-drug conjugate (ADC) with topoisomerase 1 inhibitor payload for small cell lung cancer and neuroendocrine tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1822.