Abstract 6735: E-cM-Topi, a potent EGFR-cMET bispecific antibody drug conjugate, with superior anti-tumor effect in non-small-cell lung cancer (NSCLC)

Abstract EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are standard clinical treatment for NSCLC patients with activating EGFR mutations. However, both intrinsic and acquired resistance to EGFR-TKIs limited their long-term efficacy, posing a significant unmet medical need. The protein overexpression of c-MET has been observed in 5-22% of EGFR-TKIs resistant NSCLC patients. Therefore, a bispecific ADC targeting EGFR and c-MET will shed a light on the management for EGFR-TKI resistance. E-cM-Topi is an EGFR and cMET bispecific ADC, consisting of a Fc-silenced EGFR-cMET bispecific antibody, a cleavable linker and a topoisomerase I inhibitor payload (Topi) with superior bystander effect. The binding affinities to EGFR and c-MET 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 to EGFR was adjusted to be weaker than that to c-MET, thereby enhancing the selectivity for EGFR-cMET-co-expressing tumors while minimizing the toxicity on normal tissues. E-cM-Topi demonstrated strong EGFR/cMET-dependent growth inhibition in various NSCLC cell lines. In HCC827 and EBC-1 xenograft models, E-cM-Topi inhibited tumor growth in a dose-dependent manner. Tumor regression was observed at a single dose of 4.5 mg/kg and sustained till day 35 in HCC827 model and day 20 in EBC-1 model. In addition, E-cM-Topi showed good human plasma stability and favorable cyno PK profile. Less than 0.5% of payload was released in human plasma after a 14-day incubation. Half-life of E-cM-Topi was more than 3 days in cyno monkey. In summary, by fine-tuning the EGFR-cMET bispecific antibody affinity and incorporating a superior bystander effect of payload, E-cM-Topi represents a best-in-class potential. It holds promise as an effective treatment option for EGFR-TKI resistant NSCLC patients. Citation Format: Huihui Chen, Le Sun, Bing Hu, Zhiping Zhao, Ziheng Liu, Guangbao Qiu, Dongmei Bai, Ying Li, Ziwei Ren, Ting Zhang, Xin Ye, Lingfeng You, Zhendong Xue, Yuchang Mao, Huaixin Dang, Shuyu Cai, Jun Feng, Min Hu, Feng He. E-cM-Topi, a potent EGFR-cMET bispecific antibody drug conjugate, with superior anti-tumor effect in non-small-cell lung cancer (NSCLC) [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 6735.