title: A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity.
abstract: Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be "fit for purpose" for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients.
authors.affiliation: Corresponding Authors: Shane A. Olwill, Pieris AG, Lise-Meitner-Strasse 30, 85354 Freising, Germany. olwill@pieris-ag.com.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Olwill
authors.forename: Christian
authors.initials: C
authors.lastname: Joffroy
authors.forename: Hendrik
authors.initials: H
authors.lastname: Gille
authors.forename: Elisa
authors.initials: E
authors.lastname: Vigna
authors.forename: Gabriele
authors.initials: G
authors.lastname: Matschiner
authors.forename: Andrea
authors.initials: A
authors.lastname: Allersdorfer
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Lunde
authors.forename: Jakub
authors.initials: J
authors.lastname: Jaworski
authors.forename: James F
authors.initials: JF
authors.lastname: Burrows
authors.forename: Cristina
authors.initials: C
authors.lastname: Chiriaco
authors.forename: Hans Jürgen
authors.initials: HJ
authors.lastname: Christian
authors.forename: Martin
authors.initials: M
authors.lastname: Hülsmeyer
authors.forename: Stefan
authors.initials: S
authors.lastname: Trentmann
authors.forename: Kristian
authors.initials: K
authors.lastname: Jensen
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Hohlbaum
authors.forename: Laurent
authors.initials: L
authors.lastname: Audoly
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D016466:CHO Cells; D045744:Cell Line, Tumor; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D018604:Epitope Mapping; D005260:Female; D019073:HT29 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008024:Ligands; D054834:Lipocalins / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011506:Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D008024:Ligands; D054834:Lipocalins; C000588668:PRS-110; D047428:Protein Kinase Inhibitors; D011506:Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met