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

Shane A. Olwill, C Joffroy, H Gille, E Vigna, G Matschiner, A Allersdorfer, B Lunde, Jakub Jaworski, James Burrows, C Chiriaco, H Christian, M Hulsmeyer, S Trentmann, K Jensen, Andreas Hohlbaum, L Audoly

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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.
LanguageEnglish
Pages2459-2571
Number of pages13
JournalMolecular Cancer Therapeutics
Volume12
Issue number11
DOIs
Publication statusPublished - Nov 2013

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

Cite this

Olwill, Shane A. ; Joffroy, C ; Gille, H ; Vigna, E ; Matschiner, G ; Allersdorfer, A ; Lunde, B ; Jaworski, Jakub ; Burrows, James ; Chiriaco, C ; Christian, H ; Hulsmeyer, M ; Trentmann, S ; Jensen, K ; Hohlbaum, Andreas ; Audoly, L. / 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. 2459-2571.
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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.",
author = "Olwill, {Shane A.} and C Joffroy and H Gille and E Vigna and G Matschiner and A Allersdorfer and B Lunde and Jakub Jaworski and James Burrows and C Chiriaco and H Christian and M Hulsmeyer and S Trentmann and K Jensen and Andreas Hohlbaum and L Audoly",
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Olwill, SA, Joffroy, C, Gille, H, Vigna, E, Matschiner, G, Allersdorfer, A, Lunde, B, Jaworski, J, Burrows, J, Chiriaco, C, Christian, H, Hulsmeyer, M, Trentmann, S, Jensen, K, Hohlbaum, A & 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. 2459-2571. https://doi.org/10.1158/1535-7163.MCT-13-0318

A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity. / Olwill, Shane A.; Joffroy, C; Gille, H; Vigna, E; Matschiner, G; Allersdorfer, A; Lunde, B; Jaworski, Jakub; Burrows, James; Chiriaco, C; Christian, H; Hulsmeyer, M; Trentmann, S; Jensen, K; Hohlbaum, Andreas; Audoly, L.

In: Molecular Cancer Therapeutics, Vol. 12, No. 11, 11.2013, p. 2459-2571.

Research output: Contribution to journalArticle

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T1 - A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity

AU - Olwill, Shane A.

AU - Joffroy, C

AU - Gille, H

AU - Vigna, E

AU - Matschiner, G

AU - Allersdorfer, A

AU - Lunde, B

AU - Jaworski, Jakub

AU - Burrows, James

AU - Chiriaco, C

AU - Christian, H

AU - Hulsmeyer, M

AU - Trentmann, S

AU - Jensen, K

AU - Hohlbaum, Andreas

AU - Audoly, L

PY - 2013/11

Y1 - 2013/11

N2 - 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.

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