This technology consists of highly specific rabbit monoclonal antibodies reactive with phosphorylated tyrosine located at amino acid 1235 in the human MET sequence. Binding to this pYl235 residue is independent of the phosphorylation of other tyrosines in the vicinity (1230 and 1234), does not cross-react with these nearby phosphotyrosine residues, and does not occur when Y1235 is unphosphorylated.
The receptor tyrosine kinase MET is an important drug target for treatment of various diseases including diseases mediated by dysregulated cell proliferation (e.g., cancer). A key event involved in MET activation and/or signaling is phosphorylation at the Y1235 position. However, MET activation and/or signaling is difficult to assess due to the lack of specific binding reagents that detect phosphorylation at Y1235 of MET without cross-reacting with one or more other phosphorylation sites. Inventors from NCI’s DCTD have developed an invention that enables specific quantitation of the phosphorylation status of the 1235-tyrosine residue, which is a key post-translational modification that activates MET receptor signaling. Specific pY1235 measurement will have many useful applications including (but not limited to): 1) pharmacodynamic assessments of the molecular response of the MET receptor to inhibitors, proving target engagement, providing evidence for mechanism-of-action, developing optimized dosing schedules, and enabling proof-of-concept; 2) comparison of potency of multiple MET inhibitors in preclinical and clinical studies to identify best in class agent; 3) identifying patients with activated MET status - a more discriminating measurement of MET-dependency of tumors than current genomic measurements – as a diagnostic test for selecting the ideal group of patients for treatment with MET inhibitor(s); and 4) test and confirm hypothesis of MET activation in preclinical and clinical studies to develop combinations of MET inhibitors and other agents targeting cancers.
Researchers at the NCI seek licensing and/or co-development research collaborations to commercialize and develop a companion diagnostic for selective MET inhibitors.
- Reagent to quantify the activation of the MET pathway
- Companion diagnostic tool for selective MET inhibitors
- Diagnostic tool for induced activation of the MET pathway by other therapeutics
- This invention differs from existing antibodies directed at MET in that the antibody binds specifically to phosphorylated MET Y1235 and measures the level of MET kinase activation
- Can be used to measure the pharmacodynamic and molecular target response to candidate MET inhibitors to inform and guide drug development and clinical trials
Apurva Srivastava (NCI), Thomas D. Pfister (NCI), Mario Antonio Navas (NCI), Ralph E. Parchment (NCI), James H. Doroshow (NCI)
Srivastava AK, et al. Pharmacodynamic Response of the MET/HGF Receptor to Small-Molecule Tyrosine Kinase Inhibitors Examined with Validated, Fit-for-Clinic Immunoassays. [PMID 27001313]
- U.S. Provisional: U.S. Provisional Patent Application Number 62/309,920, Filed 17 Mar 2016