Abstract
Purpose
We investigated influences of pretargeting variables, tumor location, and radionuclides in pretargeted radioimmunotherapy (PRIT) as well as estimated tumor absorbed doses.
Methods
LS-174T human colonic carcinoma cells expressing carcinoembryonic antigen (CEA) were inoculated in nude mice. Biodistribution of a bispecific anti-CEA x anti-hapten antibody, TF2, and of a TF2-pretargeted peptide was assessed and a multi-compartment pharmacokinetic model was devised. Tissue absorbed doses were calculated for 131I, 177Lu, 90Y, 211At, and 213Bi using realistic specific activities.
Results
Under conditions optimized for tumor imaging (10:1 TF2 to peptide molar ratio, interval time 15–24 h), tumor uptake reached ∼9 ID/g in subcutaneous tumors at 2 h with very low accretion in normal tissues (tumor to blood ratio >20:1 after 2 h). For a low dose of peptide (0.04 nmol), 211At is predicted to deliver a high absorbed dose to tumors [41.5 Gy considering a relative biologic effect (RBE) of 5], kidneys being dose-limiting. 90Y and 213Bi would also deliver high absorbed doses to tumor (18.6 for 90Y and 26.5 Gy for 213Bi, taking RBE into account, for 0.1 nmol) and acceptable absorbed doses to kidneys. With hepatic metastases, a twofold higher tumor absorbed dose is expected. Owing to the low activities measured in blood, the bone marrow absorbed dose is expected to be without significant toxicity.
Conclusion
Pretargeting achieves high tumor uptake and higher tumor to background ratios compared to direct RIT. Short-lived radionuclides are predicted to deliver high tumor absorbed doses especially 211At, with kidneys being the dose-limiting organ. 177Lu and 131I should be considered for repeated injections.
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Acknowledgments
We thank Robert M. Sharkey, Ph.D., for critical review of this manuscript. We are grateful to William McBride, Ph.D., for providing the peptides, and Chien-Hsing Chang, Ph.D., and Edmund A. Rossi, Ph.D., for the TF2 construct.
Financial support
This work was carried out with the financial support of the European Commission FP7 Collaborative Project program, contract TARCC n HEALTH-F2-2007-201962.
Conflicts of interest
D.M. Goldenberg is employed by or has financial interest in Immunomedics, Inc., and/or IBC Pharmaceuticals, Inc. The other authors declare that they have no conflicts of interest.
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Frampas, E., Maurel, C., Remaud-Le Saëc, P. et al. Pretargeted radioimmunotherapy of colorectal cancer metastases: models and pharmacokinetics predict influence of the physical and radiochemical properties of the radionuclide. Eur J Nucl Med Mol Imaging 38, 2153–2164 (2011). https://doi.org/10.1007/s00259-011-1903-0
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DOI: https://doi.org/10.1007/s00259-011-1903-0