Abstract 2931: RC108, a c-Met-targeting ADC, exhibits differential cytotoxicity between cMet-high and HGF-dependent tumor cells compared with Teliso-V, suggesting a potential safety advantage.

Abstract Telisotuzumab vedotin (Teliso-V) is the first c-MET-targeting ADC approved by FDA in May 2025 for the treatment of locally advanced or metastatic non-squamous NSCLC with high c-MET protein expression in patients who have received prior systemic therapy. Aberrant c-MET signaling is frequently observed in lung cancer and many other malignancies. Both c-MET overexpression and its ligand HGF contribute to hyperactivated c-MET signaling, promoting tumor proliferation, metastasis, and therapeutic resistance. Consequently, c-MET-targeted therapies employing various modalities have been actively pursued. RC108 is a novel c-MET-targeting ADC developed by RemeGen. It comprises a humanized antibody linked via a cleavable valine-citrulline/PABC linker to the cytotoxic payload monomethyl auristatin E (MMAE). Comparative in vitro studies were performed to evaluate RC108 versus Teliso-V, focusing on binding characteristics and cytotoxicity profiles. Both antibodies recognize distinct epitopes (bins) on the c-MET protein, and although their antigen-binding affinities and cell-binding properties are broadly comparable, RC108 exhibits faster and more efficient endocytosis than Teliso-V. For cytotoxicity assessment, a panel of cancer cell lines-particularly lung carcinoma cells-was characterized for c-MET signaling status using Western blotting to distinguish HGF-dependent versus HGF-independent (c-MET overexpression-driven) activation. The results revealed a clear pattern that RC108 demonstrated equal or superior potency to Teliso-V in c-MET-overexpressing tumor cells, but showed markedly weaker cytotoxicity in HGF-dependent cells. Although the underlying mechanism is under further investigation, clinical observations with RC108 support the hypothesis that this differential activity may confer a potential safety advantage. Since HGF-dependent c-MET signaling is commonly utilized by normal tissues in physiological repair and homeostasis, the lower cytotoxicity of RC108 in HGF-driven cells may indicate reduced interference with normal tissue signaling while maintaining strong activity against tumors driven by c-MET overexpression. Clinically, RC108 has shown a favorable and manageable safety profile in early monotherapy trials, characterized by a low incidence of TRAEs. In contrast, Teliso-V exhibited notable toxicity in earlier studies, with a relatively high discontinuation rate due to TRAEs. Importantly, RC108 was associated with low rates of peripheral neuropathy, a markedly lower incidence of interstitial lung disease (ILD), and no observed ocular toxicity. In summary, RC108 is a c-MET-targeted ADC with distinct properties to be recognized in further studies and may have potentially improved safety margin. Citation Format: Jiayue Geng, Zhanjiao Yu, Haiqing Zhong, Qingbo Wang, Xiao Lv, Tongyu Xiao, Kailin Wang, Xiaoping Zhang, Xiaoli He, Lili Wang, Ying Jiang, Jianing Liu, Yinghao Xin, Jianmin Fang, Yuanhao Li. RC108, a c-Met-targeting ADC, exhibits differential cytotoxicity between cMet-high and HGF-dependent tumor cells compared with Teliso-V, suggesting a potential safety advantage [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 2931.