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.

Prediction of myelotoxicity based on bone marrow radiation-absorbed dose: radioimmunotherapy studies using 90Y- and 177Lu-labeled J591 antibodies specific for prostate-specific membrane antigen.

UNLABELLED: In radioimmunotherapy, myelotoxicity due to bone marrow radiation-absorbed dose is the predominant factor and frequently is the dose-limiting factor that determines the maximum tolerated dose (MTD). With (90)Y- and (131)I-labeled monoclonal antibodies, it has been reported that myelotoxicity cannot be predicted on the basis of the amount of radioactive dose administered or the bone marrow radiation-absorbed dose (BMrad), estimated using blood radioactivity concentration. As part of a phase I dose-escalation study in patients with prostate cancer with (90)Y-DOTA-J591 (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) ((90)Y-J591) and (177)Lu-DOTA-J591 ((177)Lu-J591), we evaluated the potential value of several factors in predicting myelotoxicity. METHODS: Seven groups of patients (n = 28) received 370-2,775 MBq/m(2) (10-75 mCi/m(2)) of (177)Lu-J591 and 5 groups of patients (n = 27) received 185-740 MBq (5-20 mCi/m(2)) of (90)Y-J591. Pharmacokinetics and imaging studies were performed for 1-2 wk after (177)Lu treatment, whereas patients receiving (90)Y had these studies performed with (111)In-DOTA-J591 ((111)In-J591) as a surrogate. The BMrad was estimated based on blood radioactivity concentration. Myelotoxicity consisting of thrombocytopenia or neutropenia was graded 1-4 based on criteria of the National Cancer Institute. RESULTS: Blood pharmacokinetics are similar for both tracers. The radiation dose (mGy/MBq) to the bone marrow was 3 times higher with (90)Y (0.91 +/- 0.43) compared with that with (177)Lu (0.32 +/- 0.10). The MTD was 647.5 MBq/m(2) with (90)Y-J591 and 2,590 MBq/m(2) with (177)Lu-J591. The percentage of patients with myelotoxicity (grade 3-4) increased with increasing doses of (90)Y (r = 0.91) or (177)Lu (r = 0.92). There was a better correlation between the radioactive dose administered and the BMrad with (177)Lu (r = 0.91) compared with that with (90)Y (r = 0.75). In addition, with (177)Lu, the fractional decrease in platelets (FDP) correlates well with both the radioactive dose administered (r = 0.88) and the BMrad (r = 0.86). In contrast, with (90)Y, there was poor correlation between the FDP and the radioactive dose administered (r = 0.20) or the BMrad (r = 0.26). Similar results were also observed with white blood cell toxicity. CONCLUSION: In patients with prostate cancer, myelotoxicity after treatment with (177)Lu-J591 can be predicted on the basis of the amount of radioactive dose administered or the BMrad. The lack of correlation between myelotoxicity and (90)Y-J591 BMrad may be due to several factors. (90)Y-J591 may be less stable in vivo and, as a result, higher amounts of free (90)Y may be localized in the bone. In addition, the cross-fire effect of high-energy beta(-)-particles within the bone and the marrow may deliver radiation dose nonuniformly within the marrow.