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Augmentation of Antibody Dependent Cell Mediated Cytotoxicity following in Vivo Therapy with Recombinant Interleukin 2¹

Department of Human Oncology, Pediatrics and Medical Genetics, University of Wisconsin, Madison, Wisconsin 53792 [J. A. H., J. S., P. M. S.]; XOMA Corporation, Santa Monica, California 90404 [R. R. R.]; The Scripps Clinic and Research Foundation, La Jolla, California 92037 [B. M. M., R. A. R.]; and Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10021 [N-K. C.]

Monoclonal antibodies (mAB) with tumor specificity are able to enhance the immunological specificity of interleukin 2 (IL-2)-activated lymphokine activated killer (LAK) cells. Antibodies may also be used to broaden the range of tumor types susceptible to immune mediated cytotoxicity by the activated LAK cells. In these studies, mAB with relative tumor specificity were used to target immunologically activated effector cells in an in vitro antibody dependent cell mediated cytotoxicity (ADCC) assay. The mAB included: 3F8 and 14.G2a, which are both specific for neuroblastoma and melanoma and recognize ganglioside GD2, and mAB ING-1, a mouse-human chimeric antibody with constant regions from human IgG1 and kappa chains and variable regions from a mouse mAB that binds to a broad range of human adenocarcinomas. Each of these mAB was able to mediate ADCC with fresh effector cells and antibody binding targets. When peripheral blood mononuclear cells were obtained from cancer patients prior to and following in vivo therapy with interleukin 2, a significant increase was noted in ADCC activity by peripheral blood mononuclear cells obtained following IL-2 therapy. Inclusion of IL-2 in the medium during the cytotoxic assay with mAB further boosted ADCC. The total activity seen was often greater than the sum of the independent LAK activity and standard ADCC activity. The cells responsible for this ADCC had the CD16+ Fc receptor. Combining IL-2 with mAB in clinical tumor therapy may lead to a wider range of tumor types being responsive to immunotherapy and may also enhance the efficacy of therapy by specifically targeting activated effector cells to tumor cells recognized by mAB. Our results provide strong support for the testing of these hypotheses in clinical trials by combining in vivo treatment with IL-2 and mAB able to mediate ADCC.

¹ Supported by NIH Grants CA-33685 and RR-03186 and Contracts CM-87290 and CM-69995 and by American Cancer Society Grant CH-237.

² To whom requests for reprints should be addressed, at K4/454, UWCCC, 600 Highland Avenue, Madison, WI 53792.

Received 1/19/90. Revised 5/11/90.

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