Bispecific antibodies reactive with the multidrug-resistance-related glycoprotein and CD3 induce lysis of multidrug-resistant tumor cells
Corresponding Author
J. van Dijk
Department of Pathology, State University Leiden, P.O. Box 9603, 2300 RC Leiden, The Netherlands
Department of Pathology, State University Leiden, P.O. Box 9603, 2300 RC Leiden, The NetherlandsSearch for more papers by this authorT. Tsuruo
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Kami-lkebukuro, Toshima-ku, Tokyo 170, Japan
Search for more papers by this authorD. M. Segal
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Search for more papers by this authorR. L. H. Bolhuis
Department of Immunology, the Dr. Daniel den Hoed Cancer Center, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands
Search for more papers by this authorR. Colognola
Department of Pathology, State University Leiden, P.O. Box 9603, 2300 RC Leiden, The Netherlands
Search for more papers by this authorR. J. van de Griendleuren
Department of Pathology, State University Leiden, P.O. Box 9603, 2300 RC Leiden, The Netherlands
Search for more papers by this authorG. J. Fleuren
Department of Pathology, State University Leiden, P.O. Box 9603, 2300 RC Leiden, The Netherlands
Search for more papers by this authorS. O. Warnaar
Department of Pathology, State University Leiden, P.O. Box 9603, 2300 RC Leiden, The Netherlands
Search for more papers by this authorCorresponding Author
J. van Dijk
Department of Pathology, State University Leiden, P.O. Box 9603, 2300 RC Leiden, The Netherlands
Department of Pathology, State University Leiden, P.O. Box 9603, 2300 RC Leiden, The NetherlandsSearch for more papers by this authorT. Tsuruo
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Kami-lkebukuro, Toshima-ku, Tokyo 170, Japan
Search for more papers by this authorD. M. Segal
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Search for more papers by this authorR. L. H. Bolhuis
Department of Immunology, the Dr. Daniel den Hoed Cancer Center, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands
Search for more papers by this authorR. Colognola
Department of Pathology, State University Leiden, P.O. Box 9603, 2300 RC Leiden, The Netherlands
Search for more papers by this authorR. J. van de Griendleuren
Department of Pathology, State University Leiden, P.O. Box 9603, 2300 RC Leiden, The Netherlands
Search for more papers by this authorG. J. Fleuren
Department of Pathology, State University Leiden, P.O. Box 9603, 2300 RC Leiden, The Netherlands
Search for more papers by this authorS. O. Warnaar
Department of Pathology, State University Leiden, P.O. Box 9603, 2300 RC Leiden, The Netherlands
Search for more papers by this authorAbstract
We describe the lysis of multidrug-resistant (MDR) tumor cells by various lymphocytic effector cells, retargeted with bispecific antibodies (heteroconjugates). The Ab-hetero-conjugate used was prepared by chemically cross-linking the OKT3 monoclonal antibody (MAb) reactive with CD3 antigen on T lymphocytes, with the MRKI6 MAb, which recognizes the MDR-associated P-glycoprotein. Cloned TCRαβCD3+ T lymphocytes, OKT3-activated peripheral-blood mononuclear cells and peripheral-blood mononuclear blood lymphocytes, stimulated with allogeneic irradiated cells in a mixed lymphocyte culture, could be induced to lyse MDR ovarian tumor cells in the presence of Ab-heteroconjugate CD3/MRKI6, whereas the drug-sensitive parental tumor cells lacking the P-glycoprotein were not lysed by these retargeted effector cells. Cloned TCRγδ5/CD3+ T lymphocytes showed a high MHC-unrestricted lysis of MDR tumor cells. Addition of Ab-heteroconjugate CD3/MRKI6 could therefore not enhance target-cell lysis. Melanoma tumor cells transfected with the mdr-l gene which codes for the P-glycoprotein were also efficiently lysed by Ab-heteroconjugate retargeted cloned TCRαβ/CD3+ T cells. Tumor cell lines derived from organs known to express the P-glycoprotein also were lysable by the retargeted effector cells.
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