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Anti-c-Met monoclonal antibody ABT-700 breaks oncogene addiction in tumors with MET amplification.
Wang, Jieyi; Goetsch, Liliane; Tucker, Lora; Zhang, Qian; Gonzalez, Alexandra; Vaidya, Kedar S; Oleksijew, Anatol; Boghaert, Erwin; Song, Minghao; Sokolova, Irina; Pestova, Ekaterina; Anderson, Mark; Pappano, William N; Ansell, Peter; Bhathena, Anahita; Naumovski, Louie; Corvaia, Nathalie; Reilly, Edward B.
Afiliación
  • Wang J; AbbVie, North Chicago, IL, USA. jieyi.wang@abbvie.com.
  • Goetsch L; AbbVie Biotherapeutics, 1500 Seaport Blvd., Redwood City, CA, 94063, USA. jieyi.wang@abbvie.com.
  • Tucker L; IRPF, Centre d'Immunologie Pierre Fabre 5, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France. liliane.Goetsch@pierre-fabre.com.
  • Zhang Q; AbbVie, North Chicago, IL, USA. lora.tucker@abbvie.com.
  • Gonzalez A; AbbVie, North Chicago, IL, USA. cindy.zhang@abbvie.com.
  • Vaidya KS; IRPF, Centre d'Immunologie Pierre Fabre 5, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France. alexandra.gonzalez@pierre-fabre.com.
  • Oleksijew A; AbbVie, North Chicago, IL, USA. kedar.vaidya@abbvie.com.
  • Boghaert E; AbbVie, North Chicago, IL, USA. andy.oleksijew@abbvie.com.
  • Song M; AbbVie, North Chicago, IL, USA. Erwin.Boghaert@abbvie.com.
  • Sokolova I; Abbott Molecular, Des Plaines, IL, USA. Minghao.song@abbott.com.
  • Pestova E; Abbott Molecular, Des Plaines, IL, USA. irina.sokolova@abbott.com.
  • Anderson M; Abbott Molecular, Des Plaines, IL, USA. ekaterina.pestova@abbott.com.
  • Pappano WN; AbbVie, North Chicago, IL, USA. mark.g.anderson@abbvie.com.
  • Ansell P; AbbVie, North Chicago, IL, USA. bill.pappano@abbvie.com.
  • Bhathena A; AbbVie, North Chicago, IL, USA. peter.ansell@abbvie.com.
  • Naumovski L; AbbVie, North Chicago, IL, USA. anahita.bhathena@abbvie.com.
  • Corvaia N; AbbVie Biotherapeutics, 1500 Seaport Blvd., Redwood City, CA, 94063, USA. louie.naumovski@abbvie.com.
  • Reilly EB; IRPF, Centre d'Immunologie Pierre Fabre 5, Av Napoléon III, F-74164, Saint-Julien-en-Genevois, France. nathalie.corvaia@pierre-fabre.com.
BMC Cancer ; 16: 105, 2016 Feb 16.
Article en En | MEDLINE | ID: mdl-26879245
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.

METHOD:

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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas c-met / Anticuerpos Monoclonales / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: BMC Cancer Asunto de la revista: NEOPLASIAS Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas c-met / Anticuerpos Monoclonales / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: BMC Cancer Asunto de la revista: NEOPLASIAS Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos