RC108（一种靶向c-Met的ADC）相比Teliso-V在cMet高表达与HGF依赖性肿瘤细胞之间表现出差异性细胞毒性，提示其潜在的安全性优势

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.