Proof of concept of immuno-PET molecular imaging of met using 76Br- and 89Zr-labeled MetMAb.

Abstract

10632 Background: Oncogenic signaling via the hepatocyte growth factor (HGF)/Met pathway promotes tumor cell proliferation, migration, invasion and survival. High levels of Met are poorly prognostic for multiple cancer subtypes, including non small-cell lung cancer (NSCLC) and pancreatic cancer. MetMAb is a monovalent monoclonal antibody that binds Met and blocks activation by HGF. Recent Phase II clinical studies show that the combination of MetMAb with erlotinib in 2nd-3rd line NSCLC significantly prolongs overall survival in patients whose archive tumor samples display high levels of Met. We investigated the feasibility of identifying diagnostically positive tumors in mouse xenografts by non-invasive immuno-PET imaging using either 76Br- or 89Zr -labeled MetMAb. Methods: MetMab was labeled directly with 76Br or conjugated with bifunctional chelator based on desferrioxamine B (Df-Bz-SCN) to form Df-MetMAb (1:1) for labeling with 89Zr. Met binding affinities of both forms of radiolabeled MetMab were determined using cultured cells. Biodistribution and imaging studies were done in mice bearing NCI-H441 (NSCLC), MKN-45 (gastric), U-87 MG (glioblastoma) or KP4 (pancreatic) xenografts at various time points. Plasma and tumor samples were taken to determine shed Met and tumor Met levels, respectively. Results: 76Br-MetMAb and 89Zr-Df-MetMAb retained nM binding affinity for human Met. Imaging and biodistribution studies showed rapid uptake and slow clearance of both tracers specifically in tumor xenografts. MKN-45 tumor uptake of 76Br-MetMAb correlated with tumor mass, Met abundance, and phosphoMet content. 76Br-MetMAb biodistribution was independent of plasma shed Met level, suggesting that plasma Met will not affect tumor imaging sensitivity. Tumor-to-muscle intensity ratio and signal stability values were also good for both tracers, and both robustly identified xenografts with high levels of Met, whereas 89Zr-Df-MetMAb was clearly superior for imaging the lower Met abundance U-87 MG xenografts. Conclusions: Radiolabeled MetMAb displays several promising features and warrants further development as an immuno-PET reagent to non-invasively image Met in vivo for diagnostic and prognostic endpoints.