HRA00129-C004, a Novel c-Met Antibody-Drug Conjugate, Exerts Encouraging Antitumor Activities and Favorable Safety...

The c-Met receptor tyrosine kinase, encoded by the MET proto-oncogene, plays a critical role in embryogenesis, tissue regeneration, and carcinogenesis. It is predominantly expressed in neoplastic cells and is essential for tumor growth and metastasis, making it a prime target for antibody-drug conjugates (ADC). In this study, we developed a new ADC, HRA00129-C004, which consists of a specifically designed humanized anti-c-Met mAb conjugated to a potent topoisomerase I inhibitor through a cleavable linker. We systematically assessed the pharmacologic properties, pharmacokinetics, and safety profiles of HRA00129-C004 in a series of preclinical models. Our studies demonstrated that HRA00129-C004 selectively binds to c-Met proteins, is internalized into lysosomes, and releases its payload. This process leads to DNA damage and apoptosis in multiple c-Met-expressing cancer cell lines and exhibits strong antitumor activities in both cell line- and patient-derived xenografts. Furthermore, HRA00129-C004 showed stability in circulation and had a favorable safety profile in cynomolgus monkeys. In summary, HRA00129-C004 is a superior c-Met ADC with relatively low affinity to c-Met, efficient internalization, and a strong bystander effect. It is currently being investigated in a phase I clinical trial for patients with advanced solid tumors.