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Prevention of Epstein-Barr Virus-induced Human B-Cell Lymphoma in Severe Combined Immunodeficient Mice Treated with CD3xCD19 Bispecific Antibodies, CD28 Monospecific Antibodies, and Autologous T Cells¹

Klinik 1 für Innere Medizin [H. B., O. M., S. T., D. K., A. E., H. A., J. W., V. D., H. T.] and Institut für Pathologie [J. L.], Universität zu Köln, J.-Stelzmann-Strasse 9, 50924 Köln, Germany

Bispecific CD3 x antitumor antibodies in combination with coactivating CD28 antibodies can induce resting T cells to proliferate and to lyse syngeneic tumor cells (M. Azuma et al., J. Immunol., 150: 2091–2101, 1993; M. Azuma et al., J. Exp. Med., 177: 845–850, 1993). This combination of antibodies may therefore be useful for active immunotherapy of malignant tumors. In this study, we present a preclinical model to evaluate CD3xCD19 bispecific antibodies. We investigated whether bispecific antibodies prevent the development of malignant EBV-induced lymphomas in severe combined immunodeficient (SCID) mice which lack functional B and T lymphocytes (G. C. Bosma et al., Immunogenetics, 29: 54–57, 1989). SCID mice were engrafted (i.p.) with peripheral blood lymphocytes and EBV and treated after 3 days with CD3xCD19 bispecific antibodies and CD28 antibodies. Our data demonstrate that the growth of B cell lymphomas can be prevented in SCID mice by treatment with CD3xCD19 bispecific antibodies and that B-lymphoma-specific T cells can be recruited. In contrast to in vitro experiments, there was no clear effect of CD28 administration which is due to high expression of B7-1 on the transplanted B cells. Lymphoma-bearing mice had elevated titers of interleukin10 in the serum, in contrast to tumor-free animals. As shown by PCR analysis, there was no evidence of dormant B-lymphoma cells in specimens from surviving mice. In the spleen of surviving mice, rearranged human T-cell receptor gene segments were detectable. Furthermore, mice that were initially treated with CD3xCD19 and CD28 antibodies did not develop lymphomas upon rechallenge with EBV-infected mononuclear cells of the same donor, whereas control animals did. Our results obtained from this autologous human B-lymphoma model have implications for the design and evaluation of new immunotherapeutic modalities for the treatment of human B-cell lymphoma with bispecific antibodies.

¹ This study was supported by grants from the Mildred Scheel Stiftung/Deutsche Krebshilfe (W84/91/Te2) and the Dörenkamp-Stiftung and by the Deutsche Forschungsgemeinschaft.

² To whom requests for reprints should be addressed. Phone: 0049-221-478-4488; fax: 0049-221-478-5545; E-mail: Heribert.Bohlen@Medizin.Uni-Koeln.De.

Received 10/ 7/96. Accepted 3/ 1/97.

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