hOA-DN30 is a one-armed humanized antibody with the following features:
- Highly target Specific
- A unique mechanism of action
An efficient weapon for therapy
Preventing the “flare” effect
A unique mechanism of action
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.
Conventional antibodies directed against MET receptors display a dual paradox activity. From one side simply block ligand binding, by competing with HGF. From the other side, display agonist activity by inducing receptor dimerization. METIS strategy was to obtain a pure antagonist antibody converting, by molecular engineering, a divalent antibody to its monovalent (one-arm) form.
A ten years long research effort yielded an antibody (hOA-DN30) with a unique mechanism of action:
This cascade of events translates into powerful inhibition of HGF/MET mediated biological activities such as growth, migration and prevention of apoptosis (cellular death).
* 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
Highly target specific
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).
MET is powerful oncogene driving ‘invasive’ growth. The latter is a complex biological phenomenon controlling cell-cell interaction, growth, migration and tissue invasion. The movie shows the dramatic effect of switching on and off the MET oncogene on cancer liver cells.
In vitro studies
The hOA-DN30 antibody has tremendous efficacy on cancer sustained by the MET oncogene. The figure displays the results obtained by testing in vitro multiple human cell lines transformed by amplification of the MET oncogene. The response to the antibody is highly specific.
In vivo studies
The hOA-DN30 antibody has powerful therapeutic activity in vivo dramatically reducing tumor burden of different humaned tumors xenografted in mice. The antibody was administered i.v at the indicated dose. The antibody was totally devoid of non-specific toxicity.
Preventing the “Flare” effect
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.
hOA-DN30 antibody: an invasive diagnostic tool
Cancers respond to target therapy only when the specific oncogenic lesion is identified. Novel technologies allow identification of oncogene lesion by sequencing DNA extracted from bioptic samples or blood, procedures some how cumbersome and expensive.
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)
|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|