Immuno-PET of the Hepatocyte Growth Factor Receptor Met Using the 1-Armed Antibody Onartuzumab

Abstract

The over-expression and -activation 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 imaging agent to assess Met expression would aid in diagnosis and monitoring responses to Met-targeted therapies. In these studies Onartuzumab (MetMAb), the experimental therapeutic one-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-df-Onartuzumab was synthesized using a desferrioxamine-Onartuzumab conjugate (df-Onartuzumab); 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 microPET imaging studies were performed in MKN-45 and U87-MG xenografts. Results 76Br-Onartuzumab and 89Zr-df-Onartuzumab exhibited specific, high affinity Met binding (nM) that was concordant with established Met expression levels. In MKN-45 (gastric carcinoma) xenografts, both tracers cleared slowly from non-target tissues with the highest uptakes in tumor, blood, kidney, and lung. 76Br-Onartuzumab MKN-45 tumor uptakes remained relatively constant from 18 h (5%ID/g) to 48 h (3%ID/g) and exhibited tumor: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: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-df-Onartuzumab image quality improved with at least 2 fold greater tumor uptakes compared to non-target tissues. MKN-45 tumor uptakes for both tracers correlated significantly with tumor mass and Met expression, and were not affected by the presence of plasma shed Met. Conclusions 89Zr-df-Onartuzumab and 76Br-Onartuzumab specifically targeted Met in vitro and in vivo; 89Zr-df-Onartuzumab achieved higher tumor uptakes and tumor:muscle ratios than 76Br-Onartuzumab at later times suggesting that 89Zr-df-Onartuzumab would be better suited to image Met for diagnostic and prognostic purposes.

In Vivo Visualization of MET Tumor Expression and Anticalin Biodistribution with the MET-Specific Anticalin 89Zr-PRS-110 PET Tracer

“…The development and quality control of 89 Zr-PRS-110 provided results similar to those previously seen for 89 Zr labeling of non-anti-MET antibodies (19), underscoring the compatibility of anticalins with standard labeling protocols and facilitating their application as radiotracers.…”

c-Met PET Imaging Detects Early-Stage Locoregional Recurrence of Basal-Like Breast Cancer

“…89 Zr-db-/ 76 Brornartuzumab and 89 Zr-PRS-110 were developed and assessed for visualization of c-Met-positive tumors in preclinical models (28,29). Optimal imaging time points were identified to be between 2 and 5 d after tracer administration, thus hampering potential routine clinical use as diagnostic agents.…”

Interrogating Tumor Metabolism and Tumor Microenvironments Using Molecular Positron Emission Tomography Imaging. Theranostic Approaches to Improve Therapeutics

“…There was significant correlation between Br-onartuzumab tumor uptake and tumor c-Met expression levels. In addition, higher tumor uptake was achieved using 89 Br-onartuzumab at later time points and had higher tumor-to-muscle ratios, suggesting that 89 Zr-onartuzumab would be better suited to image c-Met for diagnostic and prognostic purposes (Jagoda et al, 2012).…”

“…A study in non-small cell lung cancer patients whose tumor was positive for c-Met showed that onartuzumab can prolong survival (Surati et al, 2011). Jagoda et al (2012 Zr and evaluated the ability to image c-Met-expressing tumors in mouse xenografts models.…”