Pretargeted radioimmunotherapy of colorectal cancer metastases: models and pharmacokinetics predict influence of the physical and radiochemical properties of the radionuclide

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 I-131, Lu-177, Y-90, At-211, and Bi-213 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 similar to 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), At-211 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. Y-90 and Bi-213 would also deliver high absorbed doses to tumor (18.6 for Y-90 and 26.5 Gy for Bi-213, 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 At-211, with kidneys being the dose-limiting organ. Lu-177 and I-131 should be considered for repeated injections.