title: ABBV-399, a c-Met Antibody-Drug Conjugate that Targets BothMET-Amplified and c-Met-Overexpressing Tumors, Irrespective ofMETPathway Dependence.
abstract: Purpose:Despite the importance of theMEToncogene 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 withMETamplification 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 amplifiedMETand 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 amplifiedMETcell 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 onMETsignaling. 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: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Jieyi
authors: J
authors: Wang
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Mark G
authors: MG
authors: Anderson
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Anatol
authors: A
authors: Oleksijew
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Kedar S
authors: KS
authors: Vaidya
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Erwin R
authors: ER
authors: Boghaert
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Lora
authors: L
authors: Tucker
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Qian
authors: Q
authors: Zhang
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Edward K
authors: EK
authors: Han
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Joann P
authors: JP
authors: Palma
authors: AbbVie Biotherapeutics Research, Redwood City, California.
authors: Louie
authors: L
authors: Naumovski
authors: AbbVie, Oncology Discovery, North Chicago, Illinois. ed.reilly@abbvie.com.
authors: Edward B
authors: EB
authors: Reilly
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C000626235:telisotuzumab vedotin; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met