HRA00129-C004, a Novel c-Met Antibody-Drug Conjugate (ADC), Exerts Encouraging Anti-Tumor Activities and Favorable Safety Profiles

Abstract 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 essential for tumor growth and metastasis, making it a prime target for antibody drug conjugates (ADCs). In this study, we developed a new ADC, HRA00129-C004, which consists of a specifically designed humanized anti-c-Met monoclonal antibody conjugated to a potent topoisomerase I (Topo I) inhibitor through a cleavable linker. We systematically assessed the pharmacological 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, 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 anti-tumor activities in both cell line-derived 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 strong bystander effect. It is currently being investigated in a Phase I clinical trial for patients with advanced solid tumors.