High-Dose Radioimmunotherapy and Extracorporeal Depletion in A Syngeneic Rat Tumor Model

Sammanfattning: ABSTRACT Radioimmunotherapy (RIT) consists of using monoclonal antibodies (mAbs) recognizing tumor-selective antigens, as carriers of cytotoxic radionuclides to tumor tissue. RIT has been effective in lymphoma but less successful in solid tumors. mAbs slowly diffuse from the vasculature into and through solid tumors, resulting in slow, limited accretion of antibodies. The outcome is a low tumor-to-normal tissue (T/N) activity ratio. Hence high activities (MBq) for therapy are needed to achieve sufficient tumor dose. The dose-limiting factor is myelotoxicity caused mainly by slow clearance of mAbs from the circulation. Methods: Extracorporeal depletion of radioactivity in blood is one strategy to increase T/N ratios and reduce toxicity . Extracorporeal affinity adsorption treatment (ECAT) is based on the biotin-avidin system utilizing the high-affinity interaction between avidin and biotin. Antibodies are radiolabeled and biotinylated using a trifunctional protein reagent. By passing whole blood extracorporeally through a column coated with avidin, radioimmunoconjugates are adsorbed in the column and eliminated from the circulation. Aim: To investigate and optimize ECAT in an imunocompetent syngeneic rat tumor model. Results: We established a suitable model for evaluation of the toxicity-reducing potential of ECAT, strategies to increase administered activities, and for the comparison of different radionuclides. In addition we developed a new technique for gaining blood access via the tail which requires no surgery, causes minimal stress to the animals and allows several animals to be studied simultaneously. ECAT reduces myelotoxicity associated with RIT. The timing of ECAT influences the duration and degree of bone marrow recovery and toxicity-reducing effect. The maximal tolerable dose of 177Lu- or 90Y-labeled RIC can be increased 2.0 or 1.5 times, respectively. ECAT is efficient as a means of removing biotinylated antibodies in a two-step pretargeting therapy concept, and would probably also be efficient as a clearing step in pretargeting strategies employing streptavidin-conjugated mAbs followed by the administration of radiolabelled biotin. Our rat tumor model with the tumor cell line used is not optimal for the evaluation of the therapeutic effect of high-dose RIT in combination with ECAT because of the favorable radiation “sensitivity” ratio of rats, which results in efficient tumor therapy even without ECAT. RIT with 90Y and 177Lu seems not to be effective on microscopic cancer disease due to the radiation energy being deposited outside the tumor cell cluster.