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Hyperthermia Enhances Localization of ¹¹¹In-labeled Hapten to Bifunctional Antibody in Human Colon Tumor Xenografts¹

Department of Microbiology [D. S. G., K. L. K.], Department of Radiation Sciences, Section of Radiation Oncology [D. S. G., D. R. S.], Department of Pathology [J. D. C.], Loma Linda University/Independent Order of Foresters Cancer Research Laboratory, Loma Linda University School of Medicine, Loma Linda, California 92350

A unique bifunctional antibody (BFA) delivery system was examined for radiolocalization and distribution following hyperthermia (41.5°C, 45 min) of T380h human colon tumor xenografts. The BFA is an F(ab')₂ fragment made by combining two murine monoclonal antibodies with different specificities, one directed against carcinoembryonic antigen (monoclonal antibody CEM 231) and the other (monoclonal antibody CHA 255) against a hapten found on a derivative of ¹¹¹In-labeled benzyl-EDTA (EOTUBE). This BFA is known as CEM/CHA. The CEM/CHA accumulates in carcinoembryonic antigen-expressing tissue and clears from normal tissues prior to administration of the radiolabeled hapten. T380h tumor chunks were injected s.c. into 31 nude mice. Two weeks later mean tumor volume was 352 mm³ and the animals were assigned to one of four groups: (a) CEM/CHA + hyperthermia + ¹¹¹In-EOTUBE; (b) CHA 255 F(ab')₂ + hyperthermia + ¹¹¹In-EOTUBE, and (c and d) treated in the same manner as a and b, respectively, but without heat. The CEM/CHA, CHA 255 F(ab')₂, and ¹¹¹In-labeled hapten were injected i.p. at 14 µg, 7 µg, and 140–200 µCi/mouse, respectively. The hyperthermia was administered 22–24 h after BFA and the radiolabeled hapten was injected 2 h later. Twenty-four h thereafter, the animals were euthanized for testing. A significantly greater percentage of injected radioactivity localized within heated compared to unheated tumors in mice given CEM/CHA and ¹¹¹In-EOTUBE (7.39%/g tumor and 4.46%/tumor versus 2.72%/g tumor and 1.44%/tumor, respectively). The percentage of kidney activity in mice given CHA 255 F(ab')₂ fragments and heat was 57% lower than in the nonheated group when expressed on a per g basis (12.73 and 22.20%, respectively). Microautoradiography showed greater radiolocalization in heated tumors than in nonheated control tumors of comparable size. Semiquantification by immunoperoxidase staining for carcinoembryonic antigen did not reveal similar differences in the amounts of antigen present in tumors from heated and nonheated groups. These findings suggest that hyperthermia could be used to enhance delivery of radiolabeled haptens to prelocalized BFA and, thus, to enhance tumor imaging and therapeutic efficacy.

¹ Supported by the Independent Order of Foresters (The High Court of Southern California and Hawaii, Rancho Cucamonga, CA) and the Departments of Microbiology, Radiation Sciences, and Pathology, Loma Linda University.

² To whom requests for reprints should be addressed.

Received 8/21/90. Accepted 12/17/90.