Quantitative PET imaging of Met-expressing human cancer xenografts with 89Zr-labelled monoclonal antibody DN30.
OBJECTIVE
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 (89)Zr-labelled (residualising radionuclide) or (124)I-labelled (non-residualising radionuclide) DN30 for imaging of Met-expressing tumours.


METHODS
The biodistribution of co-injected (89)Zr-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.


RESULTS
Biodistribution studies in GTL-16-tumour-bearing mice revealed that (89)Zr-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, (89)Zr-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 (89)Zr 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 (89)Zr-DN30 immuno-PET. An excellent correlation was found between PET-image-derived (89)Zr tumour uptake and ex-vivo-assessed (89)Zr tumour uptake (R(2)=0.98).


CONCLUSIONS
The long-lived positron emitter (89)Zr seems attractive for PET-guided development of therapeutic anti-c-Met MAbs.
Perk
Lars R
LR
Department of Otolaryngology-Head and Neck Surgery, VU University Medical Centre, De Boelelaan 1117, P.O. Box 7057, Amsterdam 1007 MB, The Netherlands.
Stigter-van Walsum
Marijke
M
Visser
Gerard W M
GW
Kloet
Reina W
RW
Vosjan
Maria J W D
MJ
Leemans
C René
CR
Giaccone
Giuseppe
G
Albano
Raffaella
R
Comoglio
Paolo M
PM
van Dongen
Guus A M S
GA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met; D011868:Radioisotopes / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D015040:Zirconium / Q000493:pharmacokinetics*
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D011518:Proto-Oncogene Proteins; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D017978:Receptors, Growth Factor; D015040:Zirconium; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met