title: Anti-c-Met monoclonal antibody ABT-700 breaks oncogene addiction in tumors with MET amplification.
abstract: BACKGROUND
  c-Met is the receptor tyrosine kinase for hepatocyte growth factor (HGF) encoded by the MET proto-oncogene. Aberrant activation of c-Met resulting from MET amplification and c-Met overexpression is associated with poor clinical outcome in multiple malignancies underscoring the importance of c-Met signaling in cancer progression. Several c-Met inhibitors have advanced to the clinic; however, the development of inhibitory c-Met-directed therapeutic antibodies has been hampered by inherent agonistic activity.
  
  
  METHODS
  We generated and tested a bivalent anti-c-Met monoclonal antibody ABT-700 in vitro for binding potency and antagonistic activity and in vivo for antitumor efficacy in human tumor xenografts. Human cancer cell lines and gastric cancer tissue microarrays were examined for MET amplification by fluorescence in situ hybridization (FISH).
  
  
  RESULTS
  ABT-700 exhibits a distinctive ability to block both HGF-independent constitutive c-Met signaling and HGF-dependent activation of c-Met. Cancer cells addicted to the constitutively activated c-Met signaling driven by MET amplification undergo apoptosis upon exposure to ABT-700. ABT-700 induces tumor regression and tumor growth delay in preclinical tumor models of gastric and lung cancers harboring amplified MET. ABT-700 in combination with chemotherapeutics also shows additive antitumor effect. Amplification of MET in human cancer tissues can be identified by FISH.
  
  
  CONCLUSIONS
  The preclinical attributes of ABT-700 in blocking c-Met signaling, inducing apoptosis and suppressing tumor growth in cancers with amplified MET provide rationale for examining its potential clinical utility for the treatment of cancers harboring MET amplification.
authors.affiliation: AbbVie, North Chicago, IL, USA. jieyi.wang@abbvie.com.|AbbVie Biotherapeutics, 1500 Seaport Blvd., Redwood City, CA, 94063, USA. jieyi.wang@abbvie.com.
authors.forename: Jieyi
authors.initials: J
authors.lastname: Wang
authors.affiliation: IRPF, Centre d'Immunologie Pierre Fabre 5, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France. liliane.Goetsch@pierre-fabre.com.
authors.forename: Liliane
authors.initials: L
authors.lastname: Goetsch
authors.affiliation: AbbVie, North Chicago, IL, USA. lora.tucker@abbvie.com.
authors.forename: Lora
authors.initials: L
authors.lastname: Tucker
authors.affiliation: AbbVie, North Chicago, IL, USA. cindy.zhang@abbvie.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: IRPF, Centre d'Immunologie Pierre Fabre 5, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France. alexandra.gonzalez@pierre-fabre.com.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gonzalez
authors.affiliation: AbbVie, North Chicago, IL, USA. kedar.vaidya@abbvie.com.
authors.forename: Kedar S
authors.initials: KS
authors.lastname: Vaidya
authors.affiliation: AbbVie, North Chicago, IL, USA. andy.oleksijew@abbvie.com.
authors.forename: Anatol
authors.initials: A
authors.lastname: Oleksijew
authors.affiliation: AbbVie, North Chicago, IL, USA. Erwin.Boghaert@abbvie.com.
authors.forename: Erwin
authors.initials: E
authors.lastname: Boghaert
authors.affiliation: Abbott Molecular, Des Plaines, IL, USA. Minghao.song@abbott.com.
authors.forename: Minghao
authors.initials: M
authors.lastname: Song
authors.affiliation: Abbott Molecular, Des Plaines, IL, USA. irina.sokolova@abbott.com.
authors.forename: Irina
authors.initials: I
authors.lastname: Sokolova
authors.affiliation: Abbott Molecular, Des Plaines, IL, USA. ekaterina.pestova@abbott.com.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Pestova
authors.affiliation: AbbVie, North Chicago, IL, USA. mark.g.anderson@abbvie.com.
authors.forename: Mark
authors.initials: M
authors.lastname: Anderson
authors.affiliation: AbbVie, North Chicago, IL, USA. bill.pappano@abbvie.com.
authors.forename: William N
authors.initials: WN
authors.lastname: Pappano
authors.affiliation: AbbVie, North Chicago, IL, USA. peter.ansell@abbvie.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Ansell
authors.affiliation: AbbVie, North Chicago, IL, USA. anahita.bhathena@abbvie.com.
authors.forename: Anahita
authors.initials: A
authors.lastname: Bhathena
authors.affiliation: AbbVie Biotherapeutics, 1500 Seaport Blvd., Redwood City, CA, 94063, USA. louie.naumovski@abbvie.com.
authors.forename: Louie
authors.initials: L
authors.lastname: Naumovski
authors.affiliation: IRPF, Centre d'Immunologie Pierre Fabre 5, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France. nathalie.corvaia@pierre-fabre.com.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Corvaia
authors.affiliation: AbbVie, North Chicago, IL, USA. ed.reilly@abbvie.com.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Reilly
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005784:Gene Amplification; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met