Abstract 5453: E-M ADC, a promising EGFR-MUC1 bispecific antibody drug conjugate, with superior anti-tumor effect in a wide range of tumors

Abstract Mucin 1 (MUC1) is a transmembrane glycoprotein with abundant glycosylation. In normal tissues, MUC1 is present at the apical surface of epithelial cells, while epidermal growth factor receptor (EGFR) is present at the basal surface of epithelial cells. Tumor cells lose apical-basal polarity, leading to even distribution of EGFR and MUC1 on cell surface, a phenomenon that allows EGFR and MUC1 to be spatially close together. And EGFR and MUC1 are highly co-expressed in a variety of tumors, e.g., non-small cell lung cancer (NSCLC), esophageal squamous cell carcinoma (ESCC) and breast cancer (BC), among others. Accordingly, bispecific ADCs targeting EGFR and MUC1 preferentially target dual-expressed tumor cells, reducing the binding to normal tissues, meanwhile conjugating with TOPi, which can improve the efficacy. And the EGFR-MUC1 bispecific ADCs have a wider range of indications and patient populations. E-M-TOPi, a EGFR and MUC1 bispecific ADC, consists of a EGFR-MUC1 bispecific antibody (E-M), a cleavable linker and a topoisomerase I inhibitor. TOPi exhibited potent cytotoxicity with good membrane permeability. The binding affinities of E-M to EGFR and MUC1 were optimized to enhance tumor cell selectivity, increase endocytosis, and improve pharmacokinetics (PK). Considering the wide expression of EGFR in normal tissue, the binding affinity of E-M to EGFR was reduced to be weaker than that to MUC1, thereby enhancing the selectivity for EGFR-MUC1 co-expressing tumors while minimizing the toxicity to normal tissues. E-M-TOPi demonstrated significantly stronger EGFR/MUC1 dependent growth inhibition in various tumor cell lines. In HCC827 and HPAC (different EGFR-MUC1 co-expression levels) xenograft mouse models, E-M-TOPi inhibited tumor growth in a dose-dependent manner. Tumor regression was observed at 6 mg/kg of E-M-TOPi and sustained till day 30 in HCC827 model and day 28 in HPAC model. In addition, E-M-TOPi showed good human plasma stability and favorable cyno PK profile. Less than 0.5% of payload was released into human plasma after a 21-day incubation. Half-life of E-M-TOPi was more than 4 days in cyno monkey. In summary, by fine-tuning the EGFR-MUC1 bispecific antibody affinity and incorporating a superior bystander effect, E-M-TOPi holds the potential to be a best-in-class therapeutic candidate. Citation Format: Ziheng Liu, Le Sun, Bing Hu, Lingfeng You, Xinyu Gao, Jin Shao, Shimeng Liu, Beibei Fu, Ying Li, Manting Zhang, Dandan Xiong, Yan Liu, Guangbao Qiu, Ziwei Ren, Zhendong Xue, Yuchang Mao, Huaixin Dang, Ting Zhang, Xin Ye, Shuyu Cai, Jun Feng, Min Hu, Feng He. E-M ADC, a promising EGFR-MUC1 bispecific antibody drug conjugate, with superior anti-tumor effect in a wide range of tumors [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 5453.