Three-step radioimmunotherapy with yttrium-90 biotin: dosimetry and pharmacokinetics in cancer patients

A three-step avidin-biotin approach has been applied as a pretargeting syst em in radioimmunotherapy (RIT) as an alternative to conventional RIT with d irectly labelled monoclonal antibodies (MoAbs). Although dosimetric and tox icity studies following conventional RIT have been reported? these aspects have not previously been evaluated in a three-step RIT protocol. This repor t presents the results of pharmacokinetic and dosimetric studies performed in 24 patients with different tumours. Special consideration was given to t he dose delivered to the red marrow and to the haematological toxicity. The possible additive dose to red marrow due to the release of unbound yttrium -90 was investigated. The protocol consisted in the injection of biotinylat ed MoAbs (first step) followed 1 day later by the combined administration o f avidin and streptavidin (second step). After 24 h, biotin radiolabelled w ith 1.85-2.97 GBq/m(2) of Y-90 was injected (third step). Two different che lating agents, DTPA and DOTA, coupled to biotin, were used in these studies . Indium-111 biotin was used as a tracer of Y-90 to follow the biodistribut ion during therapy. Serial blood samples and complete urine collection were obtained over 3 days. Whole-body and single-photon emission tomography ima ges were acquired at 1, 16, 24 and 40 h after injection. The sequence of im ages was used to extrapolate Y-90-biotin time-activity curves. Numerical fi tting and compartmental modelling were used to calculate the residence time values (tau) for critical organs and tumour, and results were compared; th e absorbed doses were estimated using the MIRDOSE3.1 software. The residenc e times obtained by the numerical and compartmental models showed no releva nt differences (<10%); the compartmental model seemed to be more appropriat e, giving a more accurate representation of the exchange between organs. Th e mean value for the tau in blood was 2.0+/-1.1 h; the mean urinary excreti on in the first 24 h was 82.5%+/-10.8%. Without considering any contributio n of free Y-90, kidneys, liver, bladder and red marrow mean absorbed doses were 1.62+/-1.14, 0.27+/-0.23, 3.61+/-0.70 and 0.11+/-0.05 mGy/MBq, respect ively; the effective dose was 0.32+/-0.06 mSv/MBq, while the dose to the tu mour ranged from 0.62 to 15.05 mGy/MBq. The amount of free Y-90 released af ter the injection proved to be negligible in the case of Y-90-DPTA-DOTA-bio tin, but noteworthy in the case of Y-90-DTPA-biotin (mean value: 5.6%+/-2.5 % of injected dose), giving an additive dose to red marrow of 0.18+/-0.08 m Gy per MBq of injected Y-90-DTPA-biotin. Small fractions of free Y-90 origi nating from incomplete radiolabelling can contribute significantly to the r ed marrow dose (3.26 mGy per MBq of free Y-90) and may explain some of the high levels of haematological toxicity observed. These results indicate tha t pretargeted three-step RIT allows the administraton of high Y-90 activiti es capable of delivering a high dose to the tumour and sparing red marrow a nd other normal organs. Although Y-90-biotin clears rapidly from circulatio n, the use of DOTA-biotin conjugate for a stable chelation of Y-90 is stron gly recommended, considering that small amounts of free Y-90 contribute sig nificantly in increasing the red marrow dose.