Abstract 2953: CS5006: A novel integrin β4-targeted antibody-drug conjugate (ADC) with robust antitumor activity in preclinical studies
Authors: Chuan Wang, Yamin Wang, Xinling Zhang, Ning Zhang, Yilin Huo, Yongwang Li, Xuelian Liu, Mengyao Zhu, Jingyu Sun, Yongli Yang, Yuxin Qian, Xueqin Dai, Fei Ma, Yi Sun, Jianxin Yang
Journal: Cancer Research (2025)

Abstract Background: The integrins are a family of cell surface receptors existing as heterodimers formed with one α subunit and one β subunit, and there are 24 heterodimers identified so far. These receptors play diverse roles in cellular adhesion, motility, and cytokinesis. Integrin β4 (ITGB4), also known as CD104, binds to integrin α6 (ITGA6) to form α6β4 integrin heterodimer that is recognized as a ligand of laminin and plays a critical role in strengthening and stabilizing the skin. The cytoplasmic tail of ITGB4 contains approximately 1000 amino acids which is longer than any other integrin β subunit. ITGB4 interacts with and plays important roles in multiple tumor-promoting signaling pathways including ErbB2, PI3K, FAK/AKT, and c-MET, and has been frequently reported as a potential prognostic and predictive marker in various cancers. Methods &amp; Results: Utilizing our proprietary AI-based target identification platform, ITGB4 was identified as a promising therapeutic target for multiple malignancies. Immunohistochemistry (IHC) staining confirmed high ITGB4 expression in tumor tissues from patients with colorectal carcinoma (CRC), non-small cell lung cancer (NSCLC), squamous carcinoma of head and neck (SCCHN) and esophageal squamous cell carcinoma (ESCC). CS5006, an ITGB4-targeted ADC, comprises a humanized anti-ITGB4 antibody, a proprietary CSL linker, and the well-validated topoisomerase 1 inhibitor exatecan (EXd). The plasma-stable, hydrophilic, beta-glucuronide CSL linker enables effectively tumor-selective toxin release. Both CS5006 and the humanized ITGB4-targeted antibody H86.2 exhibited selective binding to ITGB4 with high affinity, and triggered rapid, high-level internalization. In vitro cytotoxicity assays demonstrated CS5006’s potent, target-dependent killing of ITGB4-expressing tumor cell lines. CS5006 also showed robust in vivo antitumor activity in CDX models originated from multiple cancer types, with minimal effective dose (MED) of 5 mg/kg. Pilot toxicity studies in non-human primate demonstrated a favorable safety and pharmacokinetics (PK) profile of CS5006. Conclusion: CS5006 is a novel ITGB4-targeted ADC with robust preclinical efficacy and a favorable safety and PK profile. These findings support further IND-enabling and clinical evaluation of CS5006 as a promising ADC therapy for various advanced solid tumors. Citation Format: Chuan Wang, Yamin Wang, Xinling Zhang, Ning Zhang, Yilin Huo, Yongwang Li, Xuelian Liu, Mengyao Zhu, Jingyu Sun, Yongli Yang, Yuxin Qian, Xueqin Dai, Fei Ma, Yi Sun, Jianxin Yang. CS5006: A novel integrin β4-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 2953.