Abstract 2927: CS2011: A novel bispecific antibody targeting EGFR and HER3 that demonstrates promising antitumor activity in preclinical evaluation

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Background: EGFR (also known as HER1) is an epidermal growth factor receptor with tyrosine kinase activity implicated in both tumorigenesis and tumor progression, and its overexpression in approximately 70% of colorectal cancer (CRC), 60% of lung cancers, and over 90% of head and neck squamous cell carcinoma (HNSCC) have been shown associated with advanced diseases. Approved anti-EGFR therapies, including cetuximab, pantitumumab, and necitumumab, are widely used in treating the aforementioned malignancies. Amivantamab, a bispecific antibody targeting EGFR and c-MET, has been approved for treating advanced NSCLC with EGFR mutations. HER3, another member of the HER family, is overexpressed in cancers including CRC and lung cancer. The upregulation of HER3 has been reported in tumors when treated with MAPK/PI3K inhibitors, EGFR TKIs, or hormone therapies. Daiichi’s HER3-ADC, U3-1402, has shown promising clinical results in advanced EGFR-mutant NSCLC, confirming HER3 as a valid therapeutic target. CS2011 is a bispecific antibody composed of a potent anti-EGFR arm and a fully functional anti-HER3 arm. Unlike anti-EGFR, anti-HER2 or anti-HER3 mono-targeting antibodies, CS2011 inhibits almost all functional membrane dimers formed with HER members, and therefore acts as a broad epithelial growth factor signaling blocker to address tumor heterogeneity effectively. Methods & Results: The lead molecule of CS2011, J17, was constructed with monovalent arms targeting EGFR and HER3. J17 showed high binding affinities to EGFR or HER3 respectively and dual binding to EGFR & HER3 concurrently, as assessed by BLI. Our data further demonstrated that J17 possessed single-digit nanomolar affinities to EGFR-positive and/or HER3-positive tumor cells, while demonstrating no binding activity to EGFR/HER3-negative cells. J17 induced faster and deeper internalization compared to anti-EGFR and anti-HER3 mono-targeting antibodies. J17 also effectively inhibited EGFR downstream signaling to levels similar to anti-EGFR antibodies. Furthermore, J17 inhibited NRG1 (HER3 ligand)-induced proliferation of A431 cells. In-vivo studies further demonstrated potent tumor growth inhibition by J17. J17 also demonstrated favorable stability and developability, achieving yields comparable to those of monoclonal antibodies. Pilot pharmacokinetic (PK) and toxicity studies in cynomolgus monkeys suggested a monoclonal antibody-like PK profile and favorable tolerability at 30 mg/kg. Conclusion: CS2011 is a promising bispecific antibody for the treatment of various advanced solid tumors. Current preclinical data support further IND-enabling development and clinical research on CS2011. Citation Format: Chuan Wang, Ning Zhang, Xinling Zhang, Yongwang Li, Yongli Yang, Mengyao Zhu, Yuxin Qian, Jingyu Sun, Xuelian Liu, Fei Ma, Yi Sun, Jianxin Yang. CS2A novel bispecific antibody targeting EGFR and HER3 that demonstrates promising antitumor activity in preclinical evaluation [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 2927.