Immuno-PET of the hepatocyte growth factor receptor met using the 1-armed antibody onartuzumab

Abstract

The overexpression and overactivation of hepatocyte growth factor receptor (Met) in various cancers has been linked to increased proliferation, progression to metastatic disease, and drug resistance. Developing a PET agent to assess Met expression would aid in the diagnosis and monitoring of responses to Met-targeted therapies. In these studies, onartuzumab, the experimental therapeutic 1-armed monoclonal antibody, was radiolabeled with 76Br or 89Zr and evaluated as an imaging agent in Met-expressing cell lines and mouse xenografts. Methods: 89Zr-desferrioxamine (df)-onartuzumab was synthesized using a df-conjugate; 76Br- onartuzumab was labeled directly. Met-binding studies were performed using the human tumor- derived cell lines MKN-45, SNU-16, and U87-MG, which have relatively high, moderate, and low levels of Met, respectively. Biodistribution and small-animal PET studies were performed in MKN-45 and U87-MG xenografts. Results: 76Br-onartuzumab and 89Zr-df-onartuzumab exhibited specific, high-affinity Met binding (in the nanomolar range) that was concordant with established Met expression levels. In MKN-45 (gastric carcinoma) xenografts, both tracers cleared slowly from nontarget tissues, with the highest uptake in tumor, blood, kidneys, and lungs. 76Br-onartuzumab MKN-45 tumor uptake remained relatively constant from 18 h (5 percentage injected dose per gram of tissue [%ID/g]) to 48 h (3%ID/g) and exhibited tumor-to-muscle ratios ranging from 4:1 to 6:1. In contrast, 89Zr-df-onartuzumab MKN-45 tumor uptake continued to accumulate from 18 h (10%ID/g) to 120 h (23%ID/g), attaining tumor-to-muscle ratios ranging from 20:1 to 27:1. MKN-45 tumors were easily visualized in imaging studies with both tracers at 18 h, but after 48 h 89Zr-dfonartuzumab image quality improved, with at least 2-fold-greater tumor uptake than nontarget tissues. MKN-45 tumor uptake for both tracers correlated significantly with tumor mass and Met expression and was not affected by the presence of plasma shed Met. Conclusion: 89Zr-df-onartuzumab and 76Br-onartuzumab specifically targeted Met in vitro and in vivo; 89Zr-df-onartuzumab achieved higher tumor uptake and tumor-to-muscle ratios than 76Br-onartuzumab at later times, suggesting that 89Zr- dfonartuzumab would be better suited to image Met for diagnostic and prognostic purposes. Copyright © 2012 by the Society of Nuclear Medicine and Molecular Imaging, Inc.