Zr-Desferrioxamine -isothiocyanatobenzyl-anti-hepatocyte growth factor receptor 1-armed antibody onartuzumab

MET is a proto-oncogene protein, also known as c-Met or hepatocyte growth factor (HGF) receptor (HGFR) (1). MET is a membrane receptor with tyrosine kinase activity that is essential for embryonic development and wound healing. MET is normally expressed by stem cells, progenitor cells, and cells of epithelial origin, whereas expression of HGF, which is the only known ligand of MET, is restricted to cells of mesenchymal origin. Upon HGF stimulation, MET induces several biological responses that lead to invasive growth (2). Abnormal MET activation in cancer correlates with poor prognosis because deregulated MET triggers tumor growth, induces angiogenesis, and activates metastasis (3). MET and HGF are overexpressed in many types of human malignancies, including kidney, liver, stomach, breast, and brain cancers (2, 4, 5). Inhibition of MET function has been shown to inhibit pathological angiogenesis as well as tumor growth and metastasis (6). On the other hand, targeting HGF instead of the HGF receptor may also be beneficial to patients by blocking binding of HGF to MET. Monoclonal antibody DN30 (150 kDa) is directed against the extracellular domain of MET, with a of 2.64 nM (6). Inhibition of HGFR function with DN30 has been shown to inhibit pathological angiogenesis as well as tumor growth and metastasis. Perk et al. (7) prepared Zr--succinyldesferrioxamine-DN30 (Zr-DN30) for imaging MET expression in tumors, showing tumor accumulation corresponding to MET expression levels. However, DN30 is a partial agonist with partial biological responses. Onartuzumab is a MET-selective humanized 1-armed monoclonal antibody (100 kDa) with anti-proliferation, anti-angiogenic, and pro-apoptotic properties against tumor growth in mouse tumor models (8). Onartuzumab is a pure antagonist with monovalent binding to MET. For use with positron emission tomography (PET), onartuzumab was conjugated with the bifunctional chelate -isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS) and labeled with Zr to form Zr-Df-onartuzumab for imaging MET expression in tumors (9).