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Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama 35233, [D. J. B.], Departments of Internal Medicine [R. L. W., M. S. K.] and Radiology [R. L. W.], Medical School, and Department of Biostatistics [D. P. N.], School of Public Health, University of Michigan, Ann Arbor, Michigan 48109
2 To whom requests for reprints should be addressed, at Department of Radiation Oncology, University of Alabama at Birmingham, 619 South 19th Street, Birmingham, AL 35233-6832.
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 131I. When a single i.p. injection of 300 µCi 131I-labeled MB-1 (IgG1) was compared to treatment with unlabeled MB-1 or 300 µCi 131I-labeled MYS control IgG1 MoAb, an antibody-specific targeted radiation effect of RIT was seen. 131I-labeled MB-1 produced a 44 ± 19% (SEM) reduction in tumor size at 3 weeks posttreatment, while unlabeled MB-1 or 300 µCi 131I-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 µCi 131I-labeled anti-BI produced a 64% reduction in mean tumor size, while 300 µCi of control antibody resulted in a 58% increase in tumor size over the same 3-week period. In contrast to MB-1, however, unlabeled anti-BI (an IgG2a MoAb which in vitro studies showed to be capable of antibody-dependent cellular cytotoxicity) also had a substantial antitumor effect. Indeed, 300 µCi 131I-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-B1 to 450 µCi in another experiment did not produce a significant difference in tumor regression compared to a 300-µCi dose.
These results suggest that the antitumor effects of 131I-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 131I-labeled MB-1. 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.
1 This investigation was supported by National Cancer Institute Grants P01 CA42768 and R01 CA43368.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 10/29/91. Accepted 9/24/92.
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