PROSTASCINT scan for staging prostate cancer.

I agreed to enter a debate siding against the value of indium-111 (In)-capromab pendetide (Cyt-356) (ProstaScint) imaging with mixed emotions. On the one hand, our group has been involved with the development and application of radioimmune localization (RIL) for many years both experimentally and clinically.1–6 Also, I have had clinical experience with many industry-sponsored urology applications targeting carcinoembryonic antigen, alpha-fetoprotein, and prostatespecific antigen (PSA) over the years. Indeed, I very enthusiastically participated in In-Cyt-356 imaging clinical studies7 and was glad when the test was approved for clinical use. We have performed more than 100 In-Cyt-356 scans at our institution and continue to perform them in selected cases. On the other hand, that very long experience, together with the documented mixed results of clinical RIL in many other cancers,8–10 has given me a level of skepticism that, I hope, will be constructive to this debate. I desperately want to believe in the clinical utility of In-Cyt-356 scanning, but I do not want to be disappointed again. It has long been a dream of investigators to use antibodies against tumor antigens tagged with radioactivity to localize tumors for staging (RIL) and then to use them by attaching the antibodies to more lethal radionuclides (ie, radioimmune therapy) or to other toxic agents for therapy. Over the years, some very successful RIL and radioimmune therapy studies in animals have been completed.11–14 Also, many clinical studies were done most prominently in the solid tumors of the colon, lung, melanoma, breast, and kidney and in the lymphomas.15–19 In general, the past clinical experience in both the commercial and academic worlds has been a cycle of initial enthusiasm and good results, followed by less sanguine data with loss of enthusiasm or silence. Despite these cycles of enthusiasm, much has been learned about RIL and the physiology of antibody targeting of tumors. The field continues to be strong and recently even more invigorated, although tempered with many hard-learned lessons. A complete description of these caveats is beyond the purpose of this commentary; only a few are mentioned here. First, the type of antibody is very important. Mouse monoclonal antibodies have been the mainstay of tumor targeting either as the native immunoglobulin or antibody fragments. These fragments were initially produced by chemical cleavage of the whole molecule, but many are now produced by genetic engineering. One advantage of the antibody fragments is that they provide different pharmacokinetics than the intact antibodies, allowing more precise matching of clearance profiles, tumor uptake, and radiolabel half-life. Unfortunately, most murine antibodies or their fragments cause a host response against the immunoconjugate—the so-called human antimouse antibody response. Accordingly, murine antibodies that have been “humanized” by recombinant engineering technologies are generally the preferred choice today, especially if multiple exposures are anticipated. Unlike most monoclonal antibodies, the 7E11 antibody used in the ProstaScint system infrequently generates a human anti-mouse antibody response and thus the need to humanize this antibody has not been as pressing. Second, the antigen being targeted by the radiolabeled antibody is also of consideration. In general, antibodies that target antigens residing inside the cell or those that are secreted have a disadvantage compared with those that target antigens expressed on the cell surface. If the antigen is inside the cell, targeting most likely will be limited to those tumor areas at which some cell lysis (eg, necrosis), and therefore exposure, occurs. If the antigen is secreted, targeting of intracellular pools of the antigen within the tumor microenvironment may occur, but the likelihood is strong that the antigen in the blood may bind the antibody and greatly confound tumor localization. The ProstaScint 7E11 antibody targets an intracellular epitope From the Department of Urology, University of Washington, Seattle, Washington Reprint requests: Paul H. Lange, M.D., Department of Urology, University of Washington, HSB BB1115, Box 356510, 1959 Northeast Pacific Street, Seattle, WA 98195 Submitted: January 18, 2000, accepted: December 4, 2000 EDITORIAL