Clinical experience with gammaglobulins in enhancing radiobioconjugate targeting by reticuloendothelial system blockade

Full text: In Radiobioconjugate therapy as contrast to radiobioconjugate scintigraphy, a real high tumor / non-tumor ratio during targeting is critical, as temporal separation of early and late images will not suffice. Further nonspecific targeting is a waste of the expensive biomoiety, which is deployed in a 20-100 fold higher dose in therapy as contrasted to imaging. Apart from strategies such as pre targeting and use of high affinity biological moieties, it is also logical to seek to reduce nonspecific reticuloendothical system uptake. Based on experimental studies with human tumor xenograft models we used non-specific gamma globulins for reducing reticuloendothelial system uptake, and tried to determine the best schedule for obtaining this. Various regimens were compared in which gamma globulins were administered from periods ranging from 14 days to 2 hrs. prior to administration of radiolabelled antibody, viz 131 labeled anticytokeratin antibody, as well as regimens in which the gamma globulins were administrated after the radiolabelled antibody at time intervals of 1 hrs, 4hrs, 12hrs and 24 hrs. During prior administration regimes the gamma globulin administered was 33 mg (2ml each of 16.5 mg/ml) of human gamma globulins, intramuscular, (BHARGLOB), from the designated day daily till the day of radioimmunotargeting. This preparation was certified free of hepatitis B and HIV virus. During the post administration regimes a single similar intramuscular dose was given. In either mode the percent of the injected dose nonspecifically localized in the RES was estimated by ROI (Region of interest) measurement during serial scanning with a Siemens ZLC 7500 Orbiter. The results were compared with the RES counts when no blocking was used. Pre-administration of gamma globulins was effective in reducing RES localization by a factor of 28-83% but post administration was not effective. Further, earlier the administration was started; greater was the degree of RES blocking achieved. The routine currently adopted in our department is the administration of Bharglob intramuscularly daily starting 14 days prior to the contemplated dates of radioimmunotherapy and continuing for 7 days after therapy. In addition the thyroid is blocked with cold potassium iodide 100 mg thrice daily during the same period but continuing till 15 days after administration of the radiolabelled antibody. The human gammaglobulin administration did not evoke any allergic reaction syndromes. Whether it would affect the occurrence of the human anti mouse antibody response is under study. We conclude that prior prolonged human gamma globulin administration effectively suppresses non-specific RES localization. Apart from radioimmunotherapy this may be worth exploring in all monoclonal antibody therapies. Thus in monoclonal antibody therapy of lymphomas and breast cancer, the effectiveness of the therapy could be considerably enhanced. Preliminary experience with a case of Lymphoma does in fact corroborate this, with achievement of prolonged therapeutic effect as compared to previous administrations, but a formal trial series is now contemplated. (author)