Blood Pharmacokinetics of Various Monoclonal Antibodies Labeled with a New Trifunctional Chelating Reagent for Simultaneous Conjugation with 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid and Biotin before Radiolabeling

Abstract

Purpose: Knowledge of the blood pharmacokinetics of monoclonal antibodies is crucial in deciding the optimal time for starting the administration of a “clearing agent” or using a “clearing device.” The primary purpose was to investigate whether the pharmacokinetics of various antibodies labeled with the same chelator and 111In differed significantly after i.v. injection in immunocompetent rats. A new trifunctional chelator called “1033” containing a biotin and a radiometal chelation moiety is introduced, making it possible to use only one conjugation procedure for the antibody. Experimental Design: Sixty-five non–tumor-bearing rats were included and divided into four groups (I-IV). The blood pharmacokinetics was investigated for rituximab, BR96, and trastuzumab labeled with 1033 and 111In (I-III). The whole-body activity and activity uptake in muscle, liver, and kidney, which might explain differences in the early pharmacokinetics in blood, were also measured. hMN14 labeled with another chelator [1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)], but with the same radionuclide (111In-biotin-DOTA-hMN14), was studied (IV). The blood pharmacokinetics from another 15 tumor-bearing rats was compared with those of non–tumor-bearing rats (III) by injection of 111In-1033-BR96. Results: No statistical difference was detected between the groups regarding the blood pharmacokinetics of rituximab, BR96, or trastuzumab. The pharmacokinetics and biodistribution of 111In-biotin-DOTA-hMN14 exhibited a clear difference compared with others. There were no significant differences in the blood pharmacokinetics of 111In-1033-BR96 between tumor-bearing rats and non–tumor-bearing rats. Conclusions: Different antibodies labeled with the trifunctional chelator 1033 and 111In did not exhibit different blood pharmacokinetics, which means that the pharmacokinetics could be predicted irrespective of the IgG1 antibody chosen. A small tumor burden did not change the pharmacokinetics of the radioimmunoconjugates.

Use of Monte Carlo simulations with a realistic rat phantom for examining the correlation between hematopoietic system response and red marrow absorbed dose in Brown Norway rats undergoing radionuclide therapy with177Lu- and90Y-BR96 mAbs

“…In addition, we presented a novel method for a quantitative correlation between the reduction of the peripheral white blood cell and platelet concentrations as a function of the absorbed dose to the red marrow. When reviewing the raw data from the previously described kinetic study by Wang et al, 15 the RMBLR was shown to increase with time post injection (Fig. 1).…”

“…The dosimetry calculations were based on recently published kinetic data extracted from dissected animals and blood samples using 111 In-labeled 1033-BR-96 antibodies. 15 Tissue samples from muscle, kidney, liver, spleen, bowel, lymph nodes, lung, bone marrow, tumor, ventricle, and pancreas were collected from three animals at each time point-1.5, 8, 24, 48, and 96 h post injection-and measured in a well-type gamma counter (LKB, Finland) to calculate the percentage of injected activity per gram (%IA/g). Imaging from a planar scintillation camera (General Electric Maxi Camera 535, Milwaukee, WI) was performed prior to dissection to determine total body activity and used for determination of the activity in the remainder.…”

“…In this present study, absorbed doses were calculated based on the aforementioned kinetic study 15 and the activity escalation study, 1 and the reduced MTDs from the follow-up study. 16 The %IA/g of each organ was multiplied by the organ weight of the original Roby and the Brown Norway-Roby 250 g (average weight of rats in kinetic study) virtual rat phantoms in order to obtain the fraction of administered activity within the organs.…”

Choosing the optimal fit function: Comparison of the Akaike information criterion and the F‐test

“…If the data of the patients could be described by common kinetic parameters this would possibly allow using a simplified method for dosimetry in radionuclide therapy. 4,5 The smaller the differences among the patients, the better the fit will be with shared parameters. For the model consisting of two exponential functions ͑four parameters͒ all 16 combinations of shared or nonshared parameters were investigated, i.e., 16 different models were examined.…”

“…This may be of interest, for example, in radionuclide therapy, because equal kinetic parameters would possibly allow using a simplified method for dosimetry. 4,5 Different criteria exist to choose the best model ͓e.g., F-test, 6 Imbimbos I P proposed in the pharmacokinetic context, 7 the AIC, 8 and the Bayesian information criterion 9 ͑BIC͔͒. In the following investigation we concentrate on the commonly used F-test and the corrected Akaike information criterion ͑AICc͒, which is a modification of the AIC recommended for small sample sizes in comparison to the number of model parameters.…”