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Radiotherapy in Mice with Yttrium-90-labeled Anti-Ly1 Monoclonal Antibody: Therapy of the T Cell Lymphoma EL4¹

Department of Therapeutic Radiology, Section on Experimental Cancer Immunology [H. S., D. J. B., P. E., D. A. V.], and Department of Pediatrics, Division of Bone Marrow Transplantation, and Institute of Human Genetics [B. R. B.], University of Minnesota Hospital and Clinic, Minneapolis, Minnesota 55455, and Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109 [D. J. B.]

Yttrium-90 is a potent ß-emitting radionuclide with potential for therapy of lymphoma. A monoclonal antibody against Ly1, the murine homologue of human CD5, was labeled with ⁹⁰Y and found to selectively bind to Ly1-positive, radiation-sensitive, EL4 mouse lymphoma cells. When tested in this aggressive model of T cell lymphoma, in vivo studies in C57BL/6 mice showed that a single 140-µCi i.p. dose of ⁹⁰Y-anti-Ly1, given 1 day after i.v. injection of a lethal dose of EL4 cells, resulted in significant but transient improvement in survival. Protection was selective, since a ⁹⁰Y-labeled irrelevant control antibody did not prolong survival. Biodistribution studies showed that protection was likely limited by inadequate localization of labeled antibody to tumor. Importantly, labeled anti-Ly1 specifically localized in the immunological tissue (spleen and thymus) and lowered the WBC count, perhaps limiting the tolerated dose. Myelosuppression, which is considered one of the major side effects associated with ⁹⁰Y usage, was not a lethal complication, since WBC counts recovered in mice given a 140-µCi dose of ⁹⁰Y-anti-Ly1 without EL4 cells and 100% of these animals survived. The maximum tolerated dose was less than 200 µCi. Despite the high localization of ⁹⁰Y-anti-Ly1 in spleen, splenectomies of tumor-injected mice did not improve the antitumor efficacy of radiolabeled antibody. Further evidence for inadequate delivery of radionuclide to tumor was shown when external total-body irradiation was given to mice given injections of a lethal dose of EL4 tumor cells. Comparison of internal and external irradiation studies indicated that the partially protective effect of 140 µCi ⁹⁰Y-anti-Ly1 was equivalent to external radiation of only 100–200 cGy. Because this model reflects the current clinical limitations of radiolabeled antibodies for therapy, including partial antitumor efficacy, delivery of labeled anti-T cell antibodies to the immune system, and low maximum tolerated dose, the model may be useful for examining strategies which could increase the tolerated dose and therapeutic efficacy.

¹ This work was supported in part by United States Public Health Service Grants R01-CA31618, R01-CA36725, R01-CA43368, K08-AM1509, P01-CA21737, R23-AI19254, RFP N01-AI-85002, and T32-CA09445 awarded by the National Cancer Institute, DHHS; American Cancer Society Grant IM-502; Minnesota Medical Foundation; and the Children's Cancer Research Fund. D. A. V. is a Leukemia Society of America Scholar. H. S. was supported in part by a fellowship from the Rotary Foundation. This is Center for Experimental Transplantation and Cancer Research manuscript number 59. This study was presented at the Fifth International Conference on Monoclonal Antibody Immunoconjugates for Cancer, March 15–17, 1990, in San Diego, CA.

² To whom requests for reprints should be addressed, at Box 367 UMHC, 420 Delaware Street S.E., Minneapolis, MN 55455.

Received 9/10/90. Accepted 1/24/91.

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