Therapy with unlabeled and 131I-labeled pan-B-cell monoclonal antibodies in nude mice bearing Raji Burkitt's lymphoma xenografts.
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 microCi 131I-labeled MB-1 (IgG1) was compared to treatment with unlabeled MB-1 or 300 microCi 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 microCi 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 microCi 131I-labeled anti-B1 produced a 64% reduction in mean tumor size, while 300 microCi 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-B1 (an IgG2a MoAb which in vitro studies showed to be capable of antibody-dependent cellular cytotoxicity) also had a substantial antitumor effect. Indeed, 300 microCi 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 microCi in another experiment did not produce a significant difference in tumor regression compared to a 300-microCi 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Buchsbaum
D J
DJ
Department of Radiation Oncology, University of Alabama, Birmingham 35233.
Wahl
R L
RL
Normolle
D P
DP
Kaminski
M S
MS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity; D002051:Burkitt Lymphoma / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology / Q000627:therapeutic use*; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D007958:Leukocyte Count / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016499:Radioimmunotherapy / Q000379:methods*; D011879:Radiotherapy Dosage; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes