ABBV-399, a c-Met Antibody–Drug Conjugate that Targets Both MET–Amplified and c-Met–Overexpressing Tumors, Irrespective of MET Pathway Dependence

Abstract Purpose: Despite the importance of the MET oncogene in many malignancies, clinical strategies targeting c-Met have benefitted only small subsets of patients with tumors driven by signaling through the c-Met pathway, thereby necessitating selection of patients with MET amplification and/or c-Met activation most likely to respond. An ADC targeting c-Met could overcome these limitations with potential as a broad-acting therapeutic. Experimental Design: ADC ABBV-399 was generated with the c-Met–targeting antibody, ABT-700. Antitumor activity was evaluated in cancer cells with overexpressed c-Met or amplified MET and in xenografts including patient-derived xenograft (PDX) models and those refractory to other c-Met inhibitors. The correlation between c-Met expression and sensitivity to ABBV-399 in tumor and normal cell lines was assessed to evaluate the risk of on-target toxicity. Results: A threshold level of c-Met expressed by sensitive tumor but not normal cells is required for significant ABBV-399–mediated killing of tumor cells. Activity extends to c-Met or amplified MET cell line and PDX models where significant tumor growth inhibition and regressions are observed. ABBV-399 inhibits growth of xenograft tumors refractory to other c-Met inhibitors and provides significant therapeutic benefit in combination with standard-of-care chemotherapy. Conclusions: ABBV-399 represents a novel therapeutic strategy to deliver a potent cytotoxin to c-Met–overexpressing tumor cells enabling cell killing regardless of reliance on MET signaling. ABBV-399 has progressed to a phase I study where it has been well tolerated and has produced objective responses in c-Met–expressing non–small cell lung cancer (NSCLC) patients. Clin Cancer Res; 23(4); 992–1000. ©2016 AACR.