title: LY2875358, a neutralizing and internalizing anti-MET bivalent antibody, inhibits HGF-dependent and HGF-independent MET activation and tumor growth.
abstract: OBJECTIVE
  MET, the receptor for hepatocyte growth factor (HGF), has been implicated in driving tumor proliferation and metastasis. High MET expression is correlated with poor prognosis in multiple cancers. Activation of MET can be induced either by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation or by HGF-dependent autocrine or paracrine mechanisms.
  
  
  RESULTS
  Here, we report on LY2875358, a novel humanized bivalent anti-MET antibody that has high neutralization and internalization activities, resulting in inhibition of both HGF-dependent and HGF-independent MET pathway activation and tumor growth. In contrast to other bivalent MET antibodies, LY2875358 exhibits no functional agonist activity and does not stimulate biologic activities such as cell proliferation, scattering, invasion, tubulogenesis, or apoptosis protection in various HGF-responsive cells and no evidence of inducing proliferation in vivo in a monkey toxicity study. LY2875358 blocks HGF binding to MET and HGF-induced MET phosphorylation and cell proliferation. In contrast to the humanized one-armed 5D5 anti-MET antibody, LY2875358 induces internalization and degradation of MET that inhibits cell proliferation and tumor growth in models where MET is constitutively activated. Moreover, LY2875358 has potent antitumor activity in both HGF-dependent and HGF-independent (MET-amplified) xenograft tumor models. Together, these findings indicate that the mechanism of action of LY2875358 is different from that of the one-armed MET antibody.
  
  
  CONCLUSIONS
  LY2875358 may provide a promising therapeutic strategy for patients whose tumors are driven by both HGF-dependent and HGF-independent MET activation. LY2875358 is currently being investigated in multiple clinical studies.
authors.affiliation: Biotechnology Discovery Research, Liu_Ling@lilly.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.affiliation: Biotechnology Discovery Research.
authors.forename: Wei
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Biotechnology Discovery Research.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wortinger
authors.affiliation: Oncology Discovery Research.
authors.forename: S Betty
authors.initials: SB
authors.lastname: Yan
authors.affiliation: Toxicology.
authors.forename: Paul
authors.initials: P
authors.lastname: Cornwell
authors.affiliation: Oncology Discovery Research.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Peek
authors.affiliation: Oncology Discovery Research.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Stephens
authors.affiliation: Biotechnology Discovery Research.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Tetreault
authors.affiliation: Biotechnology Discovery Research.
authors.forename: Jinqi
authors.initials: J
authors.lastname: Xia
authors.affiliation: Discovery Statistics.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Manro
authors.affiliation: Diagnostic Experimental Pathology.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Credille
authors.affiliation: Diagnostic Experimental Pathology.
authors.forename: Darryl W
authors.initials: DW
authors.lastname: Ballard
authors.affiliation: Drug Disposition.
authors.forename: Patricia
authors.initials: P
authors.lastname: Brown-Augsburger
authors.affiliation: Oncology Medical.
authors.forename: Volker
authors.initials: V
authors.lastname: Wacheck
authors.affiliation: Biotechnology Discovery Research.
authors.forename: Chi-Kin
authors.initials: CK
authors.lastname: Chow
authors.affiliation: Bioproduct Research and Development.
authors.forename: Lihua
authors.initials: L
authors.lastname: Huang
authors.affiliation: Discovery Chemistry Research and Technologies. Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Biotechnology Discovery Research.
authors.forename: Irene
authors.initials: I
authors.lastname: Denning
authors.affiliation: Biotechnology Discovery Research.
authors.forename: Julian
authors.initials: J
authors.lastname: Davies
authors.affiliation: Biotechnology Discovery Research.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Biotechnology Discovery Research.
authors.forename: Peter
authors.initials: P
authors.lastname: Vaillancourt
authors.affiliation: Biotechnology Discovery Research.
authors.forename: Jirong
authors.initials: J
authors.lastname: Lu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D021381:Protein Transport; D059748:Proteolysis; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C000599789:emibetuzumab