Nuclear Imaging of Met-Expressing Human and Canine Cancer Xenografts with Radiolabeled Monoclonal Antibodies (MetSeekTM)

Abstract

Purpose: Met, an oncogene product and receptor tyrosine kinase, is a keystone molecule for malignant progression in solid human tumors. We are developing Met-directed imaging and therapeutic agents, including anti-Met monoclonal antibodies (MetSeek TM ). In this study, we compared two antibodies, Met5 and Met3, for nuclear imaging of human and canine Metexpressing tumor xenografts in nude mice. Experimental Design: Xenografts representing cancers of three different human tissue origins and metastatic canine prostate cancer were raised s.c. in host athymic nude mice. Animals were injected i.v. with I-125-Met5 or I-125-Met3, posterior total body gamma camera images were acquired for several days postinjection, and quantitative region-of-interest activity analysis was done. Results: PC-3, SK-LMS-1/HGF, and CNE-2 xenografts imaged with I-125-Met5 were compared with PC-3, SK-LMS-1/HGF, and DU145 xenografts imaged with I-125-Met3. Nuclear imaging contrast was qualitatively similar for I-125-Met5 and I-125-Met3 in PC-3 and SK-LMS-1/HGF host mice. However, by region-of-interest analysis, the set of human tumors imaged with I-125-Met3 exhibited a pattern of rapid initial tumor uptake followed by a continuous decline in activity, whereas the set of human tumors imaged with I-125-Met5 showed slow initial uptake, peak tumorassociated activity at 1 day postinjection, and persistence of activity in xenografts for at least 5 days. GN4 canine prostate cancer xenografts were readily imaged with I-125-Met5. Conclusions: We conclude that radioiodinated Met3 and Met5 offer qualitatively similar nuclear images in xenograft-bearing mice, but quantitative considerations indicate that Met5 might be more useful for radioimmunotherapy. Moreover, canine prostate cancer seems to be a suitable model for second-stage preclinical evaluation of Met5.Met, a receptor tyrosine kinase and oncogene product, is a keystone molecule for the initiation and malignant progression of solid neoplasms in humans and in experimental animal models of cancer (1). The myriad sequelae of Met activation, either following interaction with its native ligand hepatocyte growth factor/scatter factor (HGF/SF), with surrogate ligands (2, 3), or through ligand-independent pathways, include cell proliferation, migration, differentiation, and survival. In normal cells, these events are responsible for such phenomena as the epithelial-to-mesenchymal transformation responsible for limb muscle and diaphragm formation, and the formation of ductular glands. In neoplastic cells, these events are recapitulated as tumor formation, invasion, metastasis, and the prevention of apoptosis. Indeed, the plasticity involved in the initial seeding and subsequent growth of tumor metastases-which requires switching cells from an invasive to a proliferative state-can be accounted for in some experimental systems by ligand-dependent activation of Met (4).Virtually any type of solid tumor can express Met and/or its ligand abnormally (by overabundance, mutation, or dysregulation; see...

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

“…With SPECT imaging, human U87-MG tumor-bearing mice could be visualized with 125 I-labeled MET-binding peptides (23). Moreover, 125 I-labeled Met3 and Met5 antibodies were tested in a panel of human and canine cancer xenografts and showed qualitatively similar SPECT images in mice (24). These tumor visualization results became more explicit using the residualizing (intracellularly retained) radionuclide 89 Zr for PET imaging.…”

Hepatocyte Growth Factor and the Hepatocyte Growth Factor Receptor Signalling Complex as Targets in Cancer Therapies

“…Vande Woude’s group 29 has developed a range of anti-Met antibodies for in vivo imaging. In their recent report, tumours were shown to exhibit rapid and sustained uptake of these 125 I-labelled antibodies, permitting detection of in vivo tumours by a total-body gamma camera 29.…”

Design and feasibility study of a single photon emission microscope system for small animal I-125 imaging

“…From these, we conclude that the intensified EMCCD camera should provide an adequate count rate capability for applications outlined in [23]- [25].…”

“…The axis of the cylinder was 2 cm from the aperture. Note that for most applications that we are targeting at [23]- [25], the total activity injected in mouse seldom exceeds 500 μCi and the target-to-background ratio is typically well below 5:1. So this simulation represents a worst case scenario for testing the count rate capability of this system.…”