hOA-DN30

A unique mechanism of actions

* A Disintegrin and metalloproteinase domain-containing protein 10 – specific protease that cleaves membrane proteins at the cell surface.
** Intramembrane protease that specifically cleaves single-pass transmembrane proteins within the transmembrane domain; Figure adapted from Petrelli, A. et al., Proc. Natl. Acad Sci. US: 2006, 28, 5090-5095

hOA-DN30 exerts a therapeutic effect via a unique mechanism of action, different compared to all other MET antibodies currently in clinical or in pre-clinical evaluation.

Most of the antibodies directed to MET receptors display an agonist activity, simply blocking ligand binding. METIS strategy was to obtain a pure antagonist antibody converting, by molecular engineering, a divalent agonistic antibody to its monovalent (one-arm) form.

hOA-DN30 is able to:

  • physically remove MET receptors from the cancer cell surface (‘SHEDDING”), by activating specific surface metalloproteases of the ADAM family
  • to generate a soluble 130-kDa ectodomain (‘‘DECOY) able to compete for ligand (HGF) binding
  • as well as to bind intact MET receptors still present on the cell surface

This cascade of events translates into inhibition of HGF/MET mediated biological activities.

Highly target specific

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  • hOA-DN30 exerts pure antagonistic activity

  • hOA-DN30 binds to the extracellular portion of the MET receptor at sub-nanomolar affinity and is selective for MET

An efficient weapon for therapy

Activation of MET in liver stem cells results in ‘anchorage-independent’ growth and aggressive invasion of the extracellular matrix.

Inactivation of MET is followed by growth arrest and dramatic cell death by apoptosis (see video).

In vitro studies

The in vitro biological activity of hOA-DN30 was assessed on multiple human tumor cell lines and on MET-amplified patients derived cancer cells.

hOA-DN30 is considerably more effective in inhibiting cell proliferation on cancer cells with MET gene amplification than on cells presenting normal levels of MET.

In vivo studies

The in vivo antitumor efficacy was evaluated on different human xenograft cancer models and patients-derived tumor cells (xenopatients, PDX) by intravenous administration of hOA-DN30 or vehicle.

invitro
Dose-dipendent tumor growth inhibition on MET amplified human Gastric Carcinoma (GTL-16)
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hOA-DN30 exerts long-lasting antitumor effect with a significantly reduced tumor growth at well tolerated doses and a wide therapeutic window.

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Preventing the "flare" effect

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Left panel: The green color indicates MET receptors on the cell surface, and the red indicates phosphoMET (activated MET).

Right panel: The graph shows the number of cells in the S-phase (DNA replication) of the cell cycle.

(Pupo E, et al. Cancer Res. 2016; 76:5019–29)

Treatment with MET inhibitors blocks MET endocytosis, causing a local increase in the number of receptors at the plasma membrane level (green in the 2nd column below).

Upon inhibitor washout, the receptor is readily re-activated (red in the 3rd column below). An adverse event observed frequently in clinical settings after drug discontinuation.

Notably, treatment with hOA-DN30 antibody that induces shedding of the receptor at the cell surface level (last column below) substantially prevents this rebound (‘Flare’) effect, providing a rationale for combining or alternate mechanistically different types of MET-targeted therapies.

Non invasive diagnostic tools

sequential

Expression of the MET oncogene by human gastric cancer cells transplanted in a nude mouse. The MET protein is revealed by 89Zr-labeled DN30 antibody (Perk et al., Eur J Nucl Med Mol Imaging. 2008; 35:1857–1867)

Cancers respond to target therapy only when the specific oncogenic lesion is identified. Novel technologies allowed identification of oncogene lesion by DNA sequencing – in bioptic samples – a panel of suspected oncogenes (Oncocarta) or the entire genome (Next-Generation Sequencing).

As an effective non-invasive alternative, the hOA-DN30 antibody is an excellent tool to identify MET amplification by imaging technology and can be used as a biomarker to identify responsive patients (e.g. those displaying gene amplification)

Potential market

In a significant number of cancers, MET behaves as a driver gene that is required for the onset and progression of the disease.

Those cancers appear to be dependent on (or addicted to) MET signaling for their growth and survival.

(Comoglio PM, Trusolino L, Boccaccio C. Nat Rev Cancer. 2018 Jun;18(6):341-358).

Tumor type TOTAL patients Patients in EU Patients in Italy TOTAL incidence of MET alterations TOTAL patients with MET alterations Patients with MET alterations in EU Patients with MET alterations in Italy
Lung 1.800.000 448.000 37.000 7% 126.000 31.360 2.590
Gastroesophageal 1.400.00 215.000 14.000 5% 70.000 10.750 700
Colorectal Cancer 1.400.000 471.000 48.000 1% 14.000 4.710 480
210.000 46.820 3.770