Experimental studies on enhancing radioimmunolocalisation using reticuloendothelial system blockade

Full text: One of the major problems limiting radiobioconjugate therapy is the small fraction of the injected dose of radiopharmaceutical that localizes in the tumour. As regards radiolabelled antibodies the Fc moiety of the intact immunoglobulin is believed to mediate nonspecific localization in the reticuloendothelial system (RES) through galactosyl receptors. Attempts to overcome this have included degalactosylation of the antibodies as well as using immunoglobulin constructs devoid of Fc, but the tumour dwell time of these was inadequate for delivering an adequate therapy dose. The use of Fab 3 constructs devoid of Fc, but with higher molecular weight, and also of pre-targeting using either avidin biotin interaction or bi-specific anti chelate antibodies are other methods to reduce non-specific targeting. Another approach that we have considered is blocking the reticuloendothelial system, which can be theoretically done either by particles or by large molecular weight moieties. After creating experimental tumour models in mice, using cell lines or human tumour xenografts, different agents were evaluated to achieve RES blocking: particles of India Ink; unlabelled human immunoglobulins, dextran, polygeline and hydroxyethyl starch preparations. The latter 3 are commercially available as plasma expanders used in the therapy of shock etc. They were administered in quantities of the order of 1 mg each 4 or 24 hrs. prior to the intravenous administration of 50 micrograms of a murine immunoglobulin M3 after radiolabeling the latter with either 99mTc or 131-I prepared by the Mather modified techniques of Schwarz and the Iodogen method respectively. The RES take was measured by organ counting after sacrificing the animal prior to region of interest counting by imaging on a SIEMENS gamma camera. The particulate India ink was ineffective in altering nonspecific radiolabelled antibody uptake. All the other agents were effective, particularly when administered 24 hrs. prior to the radiolabeled antibody. The most efficacious agent was nonspecific gammaglobulin. Dextran was difficult to inject by reason of high viscosity. However radiolabelled gamma globulin did not decrease radiolabelled peptide liver uptake in parallel experiments with a Tc labeled peptide (to be reported separately). It is possible that the nonspecific gamma globulins are more effective because of their closely mimicking chemical nature to radiolabelled antibodies. Being extensively used in clinical practice for many indications, it appears reasonable to exploit them for reticuloendothelial blocking in radioimmuno therapy. It would also appear logical to explore the best route and schedule of gamma globulin administration in clinical studies rather than with the tiny mouse. Possible extensions of this for enhancing the delivery of even non-radiolabelled antibodies to target are possible, for example during monoclonal antibody therapy of lymphomas and breast cancers. (author)