A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity

Shane A. Olwill, Christian Joffroy, Hendrik Gille, Elisa Vigna, Gabriele Matschiner, Andrea Allersdorfer, Bradley M. Lunde, Jakub Jaworski, James F. Burrows, Cristina Chiriaco, Hans Jürgen Christian, Martin Hülsmeyer, Stefan Trentmann, Kristian Jensen, Andreas M. Hohlbaum, Laurent Audoly

Research output: Contribution to journalArticle

Abstract

Activation of theMEToncogenic 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 toMETwith 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. Mol Cancer Ther; 12(11); 2459-71.

Original languageEnglish
Pages (from-to)2459-2471
Number of pages13
JournalMolecular Cancer Therapeutics
Volume12
Issue number11
DOIs
Publication statusPublished - Nov 2013

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Ligands
Hepatocyte Growth Factor
Proteins
Neoplasms
Heterografts
Therapeutics
PRS-110
Biological Products
Confocal Microscopy
Phosphorylation
Biopsy
Drug Therapy
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity. / Olwill, Shane A.; Joffroy, Christian; Gille, Hendrik; Vigna, Elisa; Matschiner, Gabriele; Allersdorfer, Andrea; Lunde, Bradley M.; Jaworski, Jakub; Burrows, James F.; Chiriaco, Cristina; Christian, Hans Jürgen; Hülsmeyer, Martin; Trentmann, Stefan; Jensen, Kristian; Hohlbaum, Andreas M.; Audoly, Laurent.

In: Molecular Cancer Therapeutics, Vol. 12, No. 11, 11.2013, p. 2459-2471.

Research output: Contribution to journalArticle

Olwill, SA, Joffroy, C, Gille, H, Vigna, E, Matschiner, G, Allersdorfer, A, Lunde, BM, Jaworski, J, Burrows, JF, Chiriaco, C, Christian, HJ, Hülsmeyer, M, Trentmann, S, Jensen, K, Hohlbaum, AM & Audoly, L 2013, 'A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity', Molecular Cancer Therapeutics, vol. 12, no. 11, pp. 2459-2471. https://doi.org/10.1158/1535-7163
Olwill, Shane A. ; Joffroy, Christian ; Gille, Hendrik ; Vigna, Elisa ; Matschiner, Gabriele ; Allersdorfer, Andrea ; Lunde, Bradley M. ; Jaworski, Jakub ; Burrows, James F. ; Chiriaco, Cristina ; Christian, Hans Jürgen ; Hülsmeyer, Martin ; Trentmann, Stefan ; Jensen, Kristian ; Hohlbaum, Andreas M. ; Audoly, Laurent. / A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 11. pp. 2459-2471.
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AU - Burrows, James F.

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