Abstract
| Language | English |
|---|---|
| Pages | 2459-2571 |
| Number of pages | 13 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 12 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 2013 |
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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, 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 journal › Article
TY - JOUR
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.
AB - 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.
U2 - 10.1158/1535-7163.MCT-13-0318
DO - 10.1158/1535-7163.MCT-13-0318
M3 - Article
VL - 12
SP - 2459
EP - 2571
JO - Molecular Cancer Therapeutics
T2 - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 11
ER -