Pharmacokinetics and biodistribution of 111In- and 177Lu-labeled J591 antibody specific for prostate-specific membrane antigen: prediction of 90Y-J591 radiation dosimetry based on 111In or 177Lu?

Unlabelled: 111In-Labeled antibodies and peptides have been routinely used as chemical and biologic surrogates for 90Y-labeled therapeutic agents. However, recent studies have shown that there are significant differences in biodistribution between 111In- and 90Y-labeled agents. Yttrium and lutetium metals favor the +3 oxidation state, similar to indium, but there are minor differences in the solution and coordination chemistries among these metals. These 3 metals, however, form strong complexes with the macrocyclic chelator, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA). We, therefore, compared the pharmacokinetics and biodistribution of 111In- and 177Lu-labeled J591 antibody. The radiation dosimetry of 90Y-J591 was estimated based on both 111In and 177Lu data to validate the usage of 111In as a chemical and biologic surrogate for 90Y.

Methods: J591 is a deimmunized monoclonal antibody with specificity for the extracellular domain of prostate-specific membrane antigen. In patients with prostate cancer, phase I dose-escalation studies were conducted with 90Y-J591 (n = 29) and 177Lu-J591 (n = 25). Each patient had pharmacokinetics and imaging studies with 111In-J591 (185 MBq/20 mg) over a period of 1 wk and before treatment with 90Y-J591 antibody. In the 177Lu trial, the pharmacokinetics and imaging studies were performed after treatment with the 177Lu-J591 dose (370-2,590 MBq/m2/10 mg/m2) over a 2-wk period after treatment.

Results: Blood and urinary pharmacokinetics were similar for both tracers. Based on biexponential decay, the terminal half-life was 44 +/- 15 h for both tracers. In addition, the total-body retention of radioactivity over a 7-d period was also similar between the 2 isotopes. The percentage uptake in liver was about 20% greater with 111In than with 177Lu. Radiation dosimetry estimates for 90Y-J591 calculated on the basis of 111In or 177Lu data were mostly similar and showed that liver is the critical organ, followed by spleen and kidney. Based on blood radioactivity, the radiation dose (mGy/MBq) to the bone marrow was 3 times higher with 90Y (0.91 +/- 0.43) compared with that with 177Lu (0.32 +/- 0.10).

Conclusion: 111In- and 177Lu-labeled J591 antibodies have similar plasma and whole-body clearance kinetics. The net retention of 111In activity by lung, liver, and spleen is slightly higher compared with that with 177Lu. These results justify using 111In as a chemical and biologic surrogate for 90Y. However, the radiation dose to the liver may be overestimated by about 25% based on 111In data. In addition, the data also suggest that 177Lu may be a potential alternative for estimating the pharmacokinetics and biodistribution of 90Y-labeled radiopharmaceuticals.