Onartuzumab Overview

Introduction of Onartuzumab

Onartuzumab is a humanized monovalent monoclonal antibody directed against the hepatocyte growth factor receptor (c-Met) with potential antineoplastic activity. This drug was developed by Genentech, Inc. for the treatment of advanced non-small-cell lung cancer, Neoplasms, Glioblastoma, Gastric Cancer, and Colorectal Cancer, among others. Onartuzumab was designed as a monovalent antibody because bivalent antibodies mimic HGF, stimulating MET signaling, whereas monovalent antibodies act as antagonists. Onartuzumab has shown antitumor activity in multiple human tumor xenograft models. Onartuzumab is being clinically evaluated in multiple cancer types, including lung, colon, breast, stomach, and brain. Importantly, a complete response was observed in phase I studies and an overall survival (OS) benefit was observed in a phase II trial in non–small cell lung cancer, where onartuzumab was administered in combination with erlotinib. To address the erlotinib resistance problem, onartuzumab was tested in patients with EGFR-mutant NSCLC. A phase II clinical trial compared treatment with a combination of onartuzumab and erlotinib, versus erlotinib alone. The onartuzumab/erlotinib combo did not show an overall survival advantage for the patients.

Mechanism of Action of Onartuzumab

MET is a transmembrane receptor tyrosine kinase activated by hepatocyte growth factor (HGF) and plays a role in embryonic development and wound healing. Aberrant MET signaling can be driven by autocrine production of HGF, overexpression of MET, and amplification of the MET gene and may be an oncogenic factor in several human malignancies. Overexpression of MET is associated with poor prognosis in non–small-cell lung cancer (NSCLC); high MET gene copy number is linked with reduced overall survival and an increased risk of death after resection. Unselected patients with recurrent NSCLC are often treated with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib, which improves patient outcomes in second-line therapy and in first-line treatment for EGFR mutation–positive NSCLC. However, resistance to EGFR inhibitors frequently develops. MET and EGFR are often co-expressed, and MET can upregulate EGFR ligand expression, possibly providing a mechanism for the development of erlotinib resistance. Furthermore, amplification of the MET gene occurs in lung cancers with acquired resistance to EGFR TKIs, demonstrating the synergy between MET and EGFR signaling. Onartuzumab is a recombinant, fully humanized, monovalent (one-armed) monoclonal antibody produced in Escherichia coli, which binds to the Sema domain on the extracellular part of MET to block HGF binding and may result in cell death in c-Met-expressing tumor cells. The novel monovalent design of onartuzumab, achieved using the “knobs-into-holes” method to minimize formation of the bivalent antibody configuration, prevents MET dimerization—an event that leads to subsequent pathway activation and that occurs with some bivalent anti-c-MET mAbs. The inhibition of HGF-induced MET activation is expected to prevent cancer cell growth, survival, and metastasis. Onartuzumab has shown antitumor activity in multiple human tumor xenograft models.

Fig 1. Mechanism of Action of Onartuzumab

What We Provide

Therapeutic Antibody

Onartuzumab

We provide high-quality Onartuzumab for use in WB, FC, IP, ELISA, Neut, FuncS, IF and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.

For research use only. Not intended for any clinical use.