BCG015：一种靶向TM4SF5用于治疗肝细胞癌的首创抗体药物偶联物

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, and patients with HCC respond poorly to current therapies. Currently, no antibody-drug conjugate (ADC) has been approved or is in late-stage clinical development for the treatment of HCC. To address this unmet medical need, Biocytogen developed a novel ADC targeting TM4SF5 for HCC treatment. Results: TM4SF5 expression was detected in 70% of HCC patient samples, with limited expression in normal tissues. Target abundance studies in HCC cell lines revealed TM4SF5 protein levels comparable to or higher than those of other HCC-associated tumor antigens. TM4SF5 demonstrated internalization activities in HCC cell lines.The lead anti-TM4SF5 mAb generated from Biocytogen's RenLite ® transgenic mice exhibited high affinity, good specificity, strong cancer cell binding, and efficient internalization in vitro . It also demonstrated excellent physicochemical properties and stability under accelerated and stress conditions.BCG015, the BLD1102-conjugated ADC, showed potent and TM4SF5-dependent tumor growth inhibition activity in HCC cell lines. In vivo , BCG015 exhibited significant antitumor efficacy across multiple HCC CDX and PDX models with TM4SF5 expression. In four CDX models, BCG015 demonstrated comparable or superior efficacy compared to ADCs targeting other HCC-associated antigens. Preliminary safety studies in canine and cynomolgus monkey models are ongoing. Conclusion: BCG015 represents a novel, first-in-class ADC targeting TM4SF5 with strong preclinical efficacy. These findings highlight its potential as a promising therapeutic option for HCC patients with TM4SF5 expression, addressing a significant unmet need in liver cancer treatment.