TUMOR PRETARGETING FOR RADIOIMMUNO DETECTION AND RADIOIMMUNOTHERAPY

The limited success of the sole use of monoclonal antibodies for cance r detection and treatment has led to the development of multistep meth ods using antibodies in conjunction with low molecular weight agents. For tumor pretargeting, it is important to optimize dose and schedule of relevant agents and to understand barriers to targeted delivery. He re, we address these issues for the anticarcinoembryonic antigen bifun ctional antibody-hapten and the streptavidinylated antibody-biotin sys tems using a recently developed physiologically based pharmacokinetic model, Methods: For baseline conditions of a standard 70-kg man with a 20-g tumor embedded in the liver, the model was used in conjunction w ith the Medical Internal Radiation Dosimetry schema to: estimate absor bed doses in tumor and normal tissues; determine the dose dependence o f effector agent accumulation in tumor; simulate tumor-to-background e ffector agent uptake ratio; and calculate the therapeutic ratio for di fferent antibody forms and radionuclides. Alternative drug administrat ion schemes and variable tumor physiological conditions were considere d. Results: Model simulations showed that I-131-labeled biotin with th e streptavidinylated F(ab')(2) provided the highest therapeutic ratio under the optimized conditions. The simulations also showed that bioti n with the bifunctional streptavidinylated immunoglobulin G provided t he highest tumor-to-liver uptake ratio during the early period, Sensit ivity analysis showed that antibody extravasation was the major factor limiting the accretion of the effector agent in tumor, whereas antige n expression in normal tissues and tumor antigen shedding had little e ffect on the absorbed doses. Conclusion: Tumor pretargeting should pro vide a definite advantage over direct antibody targeting with up to a 200% increase in tumor-to-background ratio in radioimmunodetection and up to a 76% increase in tumor-to-bone marrow therapeutic ratio in rad ioimmunotherapy. Rapid antibody clearance from the bloodstream before effector agent injection is expected to improve the therapeutic ratio marginally (3%-10%). However, continuous plasmapheresis dramatically i ncreased the tumor-to-background ratio by a factor of 10 in RAID and t he tumor-to-bone marrow therapeutic ratio by more than 110% for short- lived radionuclides in RAIT. Apart from drastic measures such as exten ded plasmapheresis, pretargeting selectivity was neither sensitive eno ugh for radioimmunodetection nor effective enough for radioimmunothera py in patients with typical solid tumors even using the optimized prot ocols.