Pharmacokinetics and Biodistribution of (86)Y-Trastuzumab for (90)Y dosimetry in an ovarian carcinoma model: correlative MicroPET and MRI.
Preclinical biodistribution and pharmacokinetics of investigational radiopharmaceuticals are typically obtained by longitudinal animal studies. These have required the sacrifice of multiple animals at each time point. Advances in small-animal imaging have made it possible to evaluate the biodistribution of radiopharmaceuticals across time in individual animals, in vivo. MicroPET and MRI-based preclinical biodistribution and localization data were obtained and used to assess the therapeutic potential of (90)Y-trastuzumab monoclonal antibody (mAb) (anti-HER2/neu) against ovarian carcinoma.


METHODS
Female nude mice were inoculated intraperitoneally with 5.10(6) ovarian carcinoma cells (SKOV3). Fourteen days after inoculation, 12-18 MBq (86)Y-labeled trastuzumab mAb was injected intraperitoneally. Tumor-free mice, injected with (86)Y-trastuzumab, and tumor-bearing mice injected with labeled, irrelevant mAb or (86)Y-trastuzumab + 100-fold excess unlabeled trastuzumab were used as controls. Eight microPET studies per animal were collected over 72 h. Standard and background images were collected for calibration. MicroPET images were registered with MR images acquired on a 1.5-T whole-body MR scanner. For selected time points, 4.7-T small-animal MR images were also obtained. Images were analyzed and registered using software developed in-house. At completion of imaging, suspected tumor lesions were dissected for histopathologic confirmation. Blood, excised normal organs, and tumor nodules were measured by gamma-counting. Tissue uptake was expressed relative to the blood concentration (percentage of injected activity per gram of tissue [%IA/g]/%IA/g blood). (86)Y-Trastuzumab pharmacokinetics were used to perform (90)Y-trastuzumab dosimetry.


RESULTS
Intraperitoneal injection of mAb led to rapid blood-pool uptake (5-9 h) followed by tumor localization (26-32 h), as confirmed by registered MR images. Tumor uptake was greatest for (86)Y-trastuzumab (7 +/- 1); excess unlabeled trastuzumab yielded a 70% reduction. Tumor uptake for the irrelevant mAb was 0.4 +/- 0.1. The concentration in normal organs relative to blood ranged from 0 to 1.4 across all studies, with maximum uptake in spleen. The absorbed dose to the kidneys was 0.31 Gy/MBq (90)Y-trastuzumab. The liver received 0.48 Gy/MBq, and the spleen received 0.56 Gy/MBq. Absorbed dose to tumors varied from 0.10 Gy/MBq for radius = 0.1 mm to 3.7 Gy/MBq for radius = 5 mm.


CONCLUSIONS
For all injected compounds, the relative microPET image intensity of the tumor matched the subsequently determined (86)Y uptake. Coregistration with MR images confirmed the position of (86)Y uptake relative to various organs. Radiolabeled trastuzumab mAb was shown to localize to sites of disease with minimal normal organ uptake. Dosimetry calculations showed a strong dependence on tumor size. These results demonstrate the usefulness of combined microPET and MRI for the evaluation of novel therapeutics.
Palm
Stig
S
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. palms@mskcc.org
Enmon
Richard M
RM
Matei
Cornelia
C
Kolbert
Katherine S
KS
Xu
Su
S
Zanzonico
Pat B
PB
Finn
Ronald L
RL
Koutcher
Jason A
JA
Larson
Steven M
SM
Sgouros
George
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D011874:Radiometry / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013382:Subtraction Technique; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods*; D000068878:Trastuzumab; D014915:Whole-Body Counting; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; D000068878:Trastuzumab