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.

• Authors: Jieyi Wang, Mark G Anderson, Anatol Oleksijew, Kedar S Vaidya, Erwin R Boghaert, Lora Tucker, Qian Zhang, Edward K Han, Joann P Palma, Louie Naumovski, Edward B Reilly
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 4 Pg. 992-1000 (Feb 15 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 27573171 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• telisotuzumab vedotin
• MET protein, human
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, adverse effects)
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• MCF-7 Cells
• Mice
• Neoplasms (drug therapy, genetics, immunology, pathology)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, genetics)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays