Abstract 2630: MRG008: A novel EGFR and 5T4 bispecific antibody-drug conjugate (ADC) with potent antitumor activity in preclinical studies.

Abstract Background: Non-small cell lung cancer (NSCLC) is one of the most challenging cancers with unmet medical needs. EGFR (also known as HER1) is an epidermal growth factor receptor with tyrosine kinase activity implicated in both tumorigenesis and tumor progression, and its validity as a therapeutic target for ADC has been clinically confirmed, as exemplified by our approved drug MRG003. Trophoblast glycoprotein, also known as 5T4, is an oncofetal cell surface antigen widely expressed across multiple cancer types. 5T4 expression levels correlate with disease stage and portend poor clinical outcomes. Notably, EGFR and 5T4 are highly co-expressed in most NSCLC patients, while 5T4 exhibits moderate-to-high expression in subsets with low or absent EGFR. Targeting 5T4 thus effectively overcomes the therapeutic limitation of insufficient EGFR expression in this patient population. MRG008 is a bispecific ADC targeting both EGFR and 5T4, comprising an Fc-silenced bispecific antibody, a cleavable linker, and a topoisomerase I inhibitor payload (Topi) with a superior bystander effect. This differentiated design holds promise for broadening the therapeutic scope in NSCLC patients. Methods: The biological activity and safety profile of MRG008 were investigated in a series of preclinical studies, including (1) binding ability to 5T4 and EGFR by ELISA, Flow cytometry and Biacore; (2) internalization rate in single- and dual- target-expressing cancer cells evaluated by pHAb Reactive Dye labeling; (3) in vitro cytotoxicity against single- and dual-target-expressing cancer cells; (4) anti-tumor activity evaluated in NSCLC cell line-derived xenograft (CDX) and NSCLC patient-derived xenograft (PDX) mouse models; (5) plasma stability evaluated in human and cynomolgus monkey plasma; (6) an exploratory pharmacokinetic (PK) study in cynomolgus monkey. Results: MRG008 exhibited comparable binding activity to that of the respective parental monoclonal antibody ADC targeting 5T4 or EGFR. Rapid internalization of MRG008 was observed in both EGFR/5T4 single-expressing and EGFR/5T4 dual-expressing cancer cells. MRG008 demonstrated potent in vitro cytotoxic activity, comparable to that of its parental monoclonal antibody ADCs. MRG008 exhibited robust tumor growth inhibition in NSCLC CDX and PDX mouse models with varying levels of 5T4 and EGFR expression. Additionally, MRG008 showed favorable stability in human plasma and a desirable PK profile in cynomolgus monkeys. Conclusion: MRG008 is a promising dual-targeted ADC with potent anti-tumor efficacy for the treatment of NSCLC. These preclinical findings provide a strong rationale for advancing MRG008 into IND-enabling and clinical studies. Citation Format: Yuanyuan Yang, Zhijian Cai, Deliang Li, Shoujia Liu, Wenci Gong. MRG008: A novel EGFR and 5T4 bispecific antibody-drug conjugate (ADC) with potent antitumor activity in preclinical studies 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 2630.