Abstract 2954: CS5007: A novel EGFR and HER3 dual-targeted antibody-drug conjugate (ADC) with potent antitumor activity in preclinical studies

Abstract 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) has been shown associated with advanced diseases. EGFR has been clinically validated as a therapeutic target for ADC. For instance, MRG003, an EGFR-targeted ADC, has shown encouraging clinical outcomes in NPC and HNSCC. HER3, another HER family member, is overexpressed in 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 for ADC. Additionally, BL-B01D1, an EGFR/HER3 bispecific ADC, has shown encouraging phase 1 data in advanced cancers. CS5007 is designed to be a potential best-in-class, dual-targeted ADC with 1) fully functional EGFR/HER3 targeted arms to tackle tumor heterogeneity; 2) a proprietary, hydrophilic and stable beta-glucuronide linker to ensure mAb-like PK profile and tumor selective cleavage; and 3) a clinically validated, potent and well-tolerated topoisomerase 1 inhibitor exatecan (EXd). Methods & results: CS5007 demonstrated high-affinity binding (single digit nM) to EGFR single-positive (A431), HER3 single-positive (SW620), and EGFR/HER3 double-positive (BxPC3, FaDu) tumor cells, comparable to its naked bispecific antibody. CS5007 also triggered high-rate internalization on these cells, resulting in efficient cell killing, thus posing the potential to address tumor heterogeneity by targeting tumor cells expressing either or both of EGFR and HER3. In the in vivo studies using CDX models, CS5007 demonstrated robust, antigen-dependent tumor growth inhibition across a range of EGFR and HER3 expression levels. Its efficacy was comparable or superior to the control ADCs composed of the same bispecific antibody with GGFG-DXd and to the monospecific (targeting EGFR or HER3) ADCs bearing GGFG-DXd. CS5007 was well tolerated in rodent with maximum tolerated dose (MTD) at 200 mg/kg and demonstrated a mAb-like PK profile. Its stability in circulation was confirmed in the human/cynomolgus monkey serum incubation assays. In pilot cynomolgus monkey studies, CS5007 was well tolerated at 30 mg/kg administered three times with two weeks interval, with toxicokinetic data confirming its excellent circulating stability. Conclusion: CS5007 is a promising dual-targeted ADC that demonstrates potent antitumor efficacy with a favorable safety and PK profile. These preclinical findings support its further IND-enabling studies and clinical investigations for the treatment of various advanced solid tumors. Citation Format: Chuan Wang, Yamin Wang, Ning Zhang, Xinling Zhang, Yongwang Li, Yuxin Qian, Yongli Yang, Mengyao Zhu, Xuelian Liu, Yaxin Chen, Fei Ma, Yi Sun, Jianxin Yang. CS5007: A novel EGFR and HER3 dual-targeted antibody-drug conjugate (ADC) with potent 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 2954.