Abstract 1821: Preclinical efficacy and safety of CS5006, a novel integrin β4-targeting antibody-drug conjugate with a topoisomerase 1 inhibitor payload.

Abstract Background: Integrin β4 (ITGB4) is highly expressed in colorectal carcinoma (CRC), non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), esophageal squamous cell carcinoma (ESCC), and other solid tumors. CS5006 is a novel ITGB4-targeting antibody-drug conjugate (ADC) composed of an ITGB4-specific humanized IgG1 antibody (H86.2) conjugated to the clinically validated exatecan (Exa) payload via a highly stable, hydrophilic tandem-cleavage CSL linker, with a drug-to-antibody (DAR) value of 4. Methods: The potency of CS5006 was evaluated in viability assays across a panel of cancer cell lines with varied ITGB4 expression levels. Its antitumor efficacy was evaluated in cell-derived xenograft (CDX) mouse models. ITGB4 expression level on tumor cell lines applied in vitro and in vivo studies was determined by quantitative flow cytometry and immunohistochemistry (IHC) assays. Its NHP safety and pharmacokinetics (PK) were assessed at three dose levels including 10, 30, 50 mg/kg. The physical stability under accelerated conditions (40°C for 2 weeks and freeze-thaw for 5 cycles) was assessed by SEC-HPLC for purity and by RP-HPLC for DAR value. Results: CS5006 demonstrated potent, target-dependent killing of ITGB4-positive cancer cell lines with potency positively correlating with antigen expression levels (nanomolar range IC50 against high-expressing cells). A single 10 mg/kg dose of CS5006 induced tumor regression across all 9 CDX models, representing NSCLC (n=4), CRC, SCCHN, urothelial carcinoma (UC), gastric cancer (GC) and breast cancer (BC). In a repeat-dose toxicity study, CS5006 was well tolerated in cynomolgus monkeys during the study. Systemic exposure of the ADC was comparable to the total antibody, and increased dose-proportionally, suggesting CS5006’s remarkable circulating stability. CS5006 exhibited excellent developability, maintaining stable after five freeze-thaw cycles and after 2 weeks at 40°C. Conclusions: CS5006 demonstrates high potency, robust antitumor activity, a manageable safety profile, and excellent developability in preclinical studies, supporting its clinical translation. An IND application for CS5006 is planned for H2 2026 to support clinical development in patients with advanced solid tumors. Citation Format: Chuan Wang, Xinling Zhang, Ning Zhang, Yamin Wang, Yongwang Li, Mengyao Zhu, Xuelian Liu, Yaxin Chen, Yuxin Qian, Yongli Yang, Jingyu Sun, Fei Ma, Jianxin Yang. Preclinical efficacy and safety of CS5006, a novel integrin β4-targeting antibody-drug conjugate with a topoisomerase 1 inhibitor payload 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 1821.