Quantitative PET imaging of Met-expressing human cancer xenografts with 89Zr-labelled monoclonal antibody DN30
- 560 Downloads
Targeting the c-Met receptor with monoclonal antibodies (MAbs) is an appealing approach for cancer diagnosis and treatment because this receptor plays a prominent role in tumour invasion and metastasis. Positron emission tomography (PET) might be a powerful tool for guidance of therapy with anti-Met MAbs like the recently described MAb DN30 because it allows accurate quantitative imaging of tumour targeting (immuno-PET). We considered the potential of PET with either 89Zr-labelled (residualising radionuclide) or 124I-labelled (non-residualising radionuclide) DN30 for imaging of Met-expressing tumours.
Materials and methods
The biodistribution of co-injected 89Zr-DN30 and iodine-labelled DN30 was compared in nude mice bearing either the human gastric cancer line GLT-16 (high Met expression) or the head-and-neck cancer line FaDu (low Met expression). PET images were acquired in both xenograft models up to 4 days post-injection (p.i.) and used for quantification of tumour uptake.
Biodistribution studies in GTL-16-tumour-bearing mice revealed that 89Zr-DN30 achieved much higher tumour uptake levels than iodine-labelled DN30 (e.g. 19.6%ID/g vs 5.3%ID/g, 5 days p.i.), while blood levels were similar, indicating internalisation of DN30. Therefore, 89Zr-DN30 was selected for PET imaging of GLT-16-bearing mice. Tumours as small as 11 mg were readily visualised with immuno-PET. A distinctive lower 89Zr uptake was observed in FaDu compared to GTL-16 xenografts (e.g. 7.8%ID/g vs 18.1%ID/g, 3 days p.i.). Nevertheless, FaDu xenografts were also clearly visualised with 89Zr-DN30 immuno-PET. An excellent correlation was found between PET-image-derived 89Zr tumour uptake and ex-vivo-assessed 89Zr tumour uptake (R 2 = 0.98).
The long-lived positron emitter 89Zr seems attractive for PET-guided development of therapeutic anti-c-Met MAbs.
KeywordsMet receptor Immuno-PET Molecular imaging DN30 Zirconium-89
This project was financially supported by the Dutch Technology Foundation (grant VBC.6120) and by the Associazione Italiana per la Ricerca sul Cancro. We thank the technical staff of BV Cyclotron and the Radionuclide Center for supplying and processing of 89Zr, Floris van Velden for PET analyses and Otto Hoekstra for providing PET imaging facilities and for reviewing the manuscript.
- 13.Divgi CR, Pandit-Taskar N, Jungbluth AA, Reuter VE, Gonen M, Ruan S, et al. Preoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: a phase I trial. Lancet Oncol 2007;8:304–10.PubMedCrossRefGoogle Scholar
- 18.Perk LR, Visser GWM, Vosjan MJWD, Stigter-van Walsum M, Tijink BM, Leemans CR, et al. 89Zr as a PET surrogate radioisotope for scouting biodistribution of the therapeutic radiometals 90Y and 177Lu in tumor-bearing nude mice after coupling to the internalizing antibody cetuximab. J Nucl Med 2005;46:1898–906.PubMedGoogle Scholar
- 19.Borjesson PKE, Jauw YWS, Boellaard R, De Bree R, Comans EFI, Roos JC, et al. Performance of immuno-positron emission tomography with zirconium-89-labeled chimeric monoclonal antibody U36 in the detection of lymph node metastases in head and neck cancer patients. Clin Cancer Res 2006;12:2133–40.PubMedCrossRefGoogle Scholar
- 33.Dijkers E, Lub-de Hooge MN, Kosterink JG, Jager PL, Brouwers AH, Perk LR, et al. Characterization of 89Zr-trastuzumab for clinical HER2 immunoPET imaging. J Clin Oncol 2007;25(Suppl 1):3508.Google Scholar
- 35.Perk LR, Visser GWM, Budde M, Vosjan MJWD, Jurek P, Kiefer GE, et al. Facile radiolabeling of monoclonal antibodies and other proteins with zirconium-89 or gallium-68 for PET imaging using p-isothiocyanatobenzyl-desferrioxamine. Nat Protoc 2008. DOI 10.1038/nprot.2008.22.