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. Mol Cancer Ther; 12(11); 2459-71. Ó2013 AACR.

RNA interference targeting hypoxia-inducible factor 1α via a novel multifunctional surfactant attenuates glioma growth in an intracranial mouse model

“…30 Others have used these U87 cells in a xenograft mouse model and found that specific c-MET antagonists cause dose-dependent tumor growth inhibition. 41 Our results show that targeting HIF-1a leads to reduced c-MET protein levels, which corroborates the results of studies that have shown that this also occurs in breast and lung cancer cell lines. 12 It may be that disrupting HIF-1 function in gliomas, and thus c-MET, will not lead to the same invasion and metastasis encountered in anti-VEGF therapy.…”

In Vivo Visualization of MET Tumor Expression and Anticalin Biodistribution with the MET-Specific Anticalin 89Zr-PRS-110 PET Tracer

“…Importantly, anticalins retain the overall fold of lipocalins but exhibit redesigned pharmacologic properties (6). We rationally engineered PRS-110 (Pieris AG), an anticalin with monovalent specificity for MET (binding affinity of 0.6 nmol/L determined by kinetic exclusion assay) (7), which is based on the tear lipocalin scaffold. PRS-110 acts as both a full antagonist of HGF-evoked MET signaling (half maximal inhibitory concentration [IC 50 ] of 35 nmol/L in HUVEC pMet assay) and also a ligand-independent inhibitor of MET-driven tumorigenesis.…”

“…PRS-110 acts as both a full antagonist of HGF-evoked MET signaling (half maximal inhibitory concentration [IC 50 ] of 35 nmol/L in HUVEC pMet assay) and also a ligand-independent inhibitor of MET-driven tumorigenesis. PRS-110 is being developed as a therapeutic and in this form is site-specifically conjugated to a branched 40-kDa polyethyleneglycol (PEG) (2 · 20 kDa PEG) moiety for half-life prolongation (7). PRS-110 also displays many highly desirable properties as an imaging agent.…”

The Apoptosis Repressor with a CARD Domain (ARC) Gene Is a Direct Hypoxia-Inducible Factor 1 Target Gene and Promotes Survival and Proliferation of VHL-Deficient Renal Cancer Cells

“…Caki1 cells are a low-VHL-expressing cell line and form subcutaneous (s.c.) tumors with long periods of latency and do not metastasize. We used Caki1 cells, which we also used in our in vitro work, for in vivo studies, since they are low-VHL-expressing cells and are frequently used by others for animal studies of RCC (36)(37)(38). We injected Caki1 cells stably transduced with shGFP, shARC no.…”