Abstract 4751: CS5005: A novel SSTR2-targeted antibody-drug conjugate (ADC) with robust antitumor activity in preclinical studies

Abstract Background: Somatostatin receptor 2 (SSTR2) is overexpressed in neuroendocrine tumors (NETs) and small cell lung cancer (SCLC). SSTR2-targeted treatment options for NETs include somatostatin analogs and radionuclide conjugates (RDCs). In SCLC, SSTR2-targeted therapies, including RAZ101 (225Ac bearing RDC), PEN221 (peptide drug conjugate) etc., have shown encouraging clinical results. Unfortunately, such therapies with peptide (SSA analogs like octreotide) suffer from short half-lives and high toxicities due to poor selectivity. Moreover, RDCs are often restricted by limited availability. To tackle these, a highly selective and potent antibody against SSTR2 could offer a promising therapeutic alternative. Here, we present CS5005, a novel SSTR2-targeted ADC developed to treat SSTR2-positive tumors, including NETs and SCLC. Methods: SSTR2-targeted antibodies were generated from immunized mice, followed with rounds of screening, maturation and humanization. The lead antibody of CS5005 was selected based on the binding, internalization capacity, and selectivity for SSTR2. CS5005 is composed of our lead SSTR2-targeted humanized antibody, a proprietary CSL linker and a well-validated topoisomerase 1 inhibitor exatecan (EXd). The plasma-stable, hydrophilic, beta-glucuronide CSL linker enables effectively tumor-selective toxin release. The antitumor activity of CS5005 was evaluated in vitro and in vivo using cell line-derived xenograft (CDX) models originated from multiple carcinomas. Tolerability and PK were assessed in rodents and cynomolgus monkeys. Results: The lead humanized SSTR2-targeted antibody, 221.3.1, demonstrated high-affinity binding to SSTR2-positive cells (e.g. SSTR2-overexpressing HEK, H524, and H446) and high-rate internalization on tumor cells. Importantly, 221.3.1 selectively bound SSTR2 without cross-reactivity to other somatostatin receptors. 221.3.1’s cross-species recognition of SSTR2 supported the selection of cynomolgus monkey for nonclinical toxicology studies. CS5005 retained the antibody features of binding affinity, internalization and selectivity, showing excellent in vitro stability in serum incubation assays and a mAb-like PK profile in the in vivo rodent studies. In vitro cytotoxicity assays confirmed the ability of CS5005 to induce effective, target-dependent killing of SSTR2-expressing tumor cells. CS5005 also demonstrated robust in vivo antitumor activity in CDX models originated from multiple carcinomas, with minimal effective dose (MED) of 5 mg/kg. Pilot toxicity studies in non-human primates demonstrated a favorable tolerability and PK profile of CS5005. Conclusion: CS5005 represents a promising SSTR2-targeted ADC for the treatment of advanced solid tumors. The preclinical findings support further IND-enabling studies and clinical investigations of CS5005 as a novel therapeutical option. Citation Format: Chuan Wang, Xinling Zhang, Ning Zhang, Yamin Wang, Yongwang Li, Xuelian Liu, Mengyao Zhu, Yuxin Qian, Yongli Yang, Jingyu Sun, Xueqin Dai, Fei Ma, Yi Sun, Jianxin Yang. CS5005: A novel SSTR2-targeted antibody-drug conjugate (ADC) with robust antitumor activity in preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4751.