Therapy with Unlabeled and 1311-labeled Pan-B-Cell Monoclonal Antibodies in Nude Mice Bearing Raji Burkitt's Lymphoma Xenografts 1

Clinical trials of radioimmunotherapy (RIT) of lymphoma have produced frequent tumor regressions and remissions, but it has been difficult to determine to what extent these tumor responses have been due to antibody-specific targeted radiation, nontargeted radiation, and/or cytotoxicity mediated by the carrier monoclonal antibody (MoAb). In this report, RIT was studied in athymic nude mice bearing s.c. Raji human Burkitt's lymphoma xenografts using two different pan-B-cell MoAbs, MB-1 (anti-CD37) and anti-B1 (anti-CD20), which differ in isotype (and thus the potential for interaction with host effector mechanisms) and isotype-matched control antibodies either in the unlabeled state or labeled with t3q. When a single i.p. injection of 300 ~Ci t3q-labeled MB-1 (IgG1) was compared to treatment with unlabeled MB-1 or 300 ~Ci ~3q-labeled MYS control IgGl MoAb, an antibody-specific targeted radiation effect of RIT was seen. ~311-1abeled MB-1 produced a 44 4. 19% (SEM) reduction in tumor size at 3 weeks posttreatment, while unlabeled MB-1 or 300 ~Ci 13q-labeled MYS control IgG1 antibody treatment resulted in continued tumor growth over this period of time. In vitro studies demonstrated that MB-1 was incapable of mediating antibody-dependent cellular cytotoxicity using Raji tumor cell targets and human peripheral blood mononuclear cells. Similar to the MB-1 studies, treatment with 300 ~tCi 13q-labeled anti-B1 produced a 64% reduction in mean tumor size, while 300 ~Ci of control antibody resulted in a 58% increase in tumor size over the same 3-week period. In contrast to MB-I, however, unlabeled anti-B1 (an IgG2a MoAb which in vitro studies showed to be capable of antibodydependent cellular cytotoxicity) also had a substantial antitumor effect. Indeed, 300 ~Ci 1311-labeled anti-B1 and unlabeled anti-B1 treatment (using an equivalent amount of total protein in the treatment dose) produced a similar specific reduction in tumor size. Increasing the radionuclide dose of anti-Bl to 450 #Ci in another experiment did not produce a significant difference in tumor regression compared to a 300~Ci dose. These results suggest that the antitumor effects of t3q-labeled anti-B1 treatment were dominated by antibody-mediated cytotoxicity mechanisms, such that an antibody-specific targeted radiation effect could not be distinguished. In contrast, antibody-specific targeting of radiation was the dominant mechanism of tumor killing with ~3q-labeled MB-I. These results underscore the importance of investigating non-radiation-related antibody effects as well as radiation effects in ongoing lymphoma RIT trials with pan-B-cell antibodies.