PROPOSAL FOR TRANSLATIONAL ANALYSIS AND DEVELOPMENT OF CLINICAL RADIOLABELED IMMUNOGLOBULIN THERAPY

Background and purpose: Radiolabeled immunoglobulin therapy (RIT) can be a selective, effective, low-toxicity outpatient cancer therapy. A c onsensus on the best approach for the preclinical and clinical develop ment of RIT reagents needs to be developed. We report the M.D. Anderso n Cancer Center prior experience in translating RIT from laboratory to clinic for the treatment of Hodgkin's disease and propose a flow diag ram for the development of RIT for other malignancies. Material and me thods: Three different animal models are described: nude mice bearing human tumor xenografts, normal beagle dogs, and normal rhesus monkeys. We produced and purified antibodies and prepared chelate-immunoconjug ates reactive with six different human rumor-associated antigens. The Igs used were derived from rabbits, mice, and humans (human-derived RI T reagents being less immunogenic in human patients). Eighty patients with refractory Hodgkin's disease were treated with radiolabeled antif erritin. Results: We recommend a two-injection scheme using, (1) an in dium-111-labeled radioimmunoconjugate for diagnosis, pharmacokinetic s tudies, and dosimetry, and (2) a yttrium-90-labeled radioimmunoconjuga te for therapy. The animal models provide useful data on tumor targeti ng, radiotoxicology, and undesirable biodistributions. A 70% response rate is obtained in patients with advanced recurrent Hodgkin's disease . More extensive preclinical testing allows for safer and more effecti ve clinical RIT studies. Conclusions: We recommend, (1) preclinical op timization of chelation chemistry, Ig size, Ig origin, route of admini stration, and fractionation, (2) new clinical Phase I-III studies more appropriate for RIT development than the classical Phase I-III studie s used for the development of chemotherapeutic agents, and (3) more ex tensive preclinical testing of RIT reagents.