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Elimination of Clonogenic Tumor Cells from Human Bone Marrow Using a Combination of Monoclonal Antibody:Ricin A Chain Conjugates¹

Divisions of Tumor Immunology [M. B., P. D. F., L. N., J. R., R. C. B.], Cancer Pharmacology [V. R.], Medicine [R. C. B.], Radiation Therapy [J. G., L. R.], and Pediatric Oncology [J. L.], Dana-Farber Cancer Institute; the Department of Medicine, Brigham and Women's Hospital [L. N., J. R., R. C. B.]; and the Departments of Medicine [L. N., J. R., R. C. B.], Radiation Therapy [J. G.], Pathology [V. R.], and Pediatrics [J. L.], Harvard Medical School, Boston, Massachusetts 02115

Effective autologous bone marrow transplantation for leukemia and lymphoma is likely to depend upon the selective removal in vitro of malignant cells from normal human bone marrow precursors. Highly specific cytotoxic conjugates formed by coupling ricin A chain to monoclonal antibodies might prove useful for the selective elimination of malignant cells. Consequently, ricin A chain conjugates have been prepared with several different murine monoclonal antibodies and tested for their ability to eliminate clonogenic Burkitt's lymphoma cells from an excess of human bone marrow. The most active reagents included an antibody:A chain conjugate which bound to the nonpolymorphic chain of the la molecule and another which reacted with the µ heavy chain of cell surface immunoglobulin. Conjugates formed with anti-common acute lymphoblastic leukemia antigen, anti-M_r 26,000 glycoprotein, and anti-B1 were much less active on these Burkitt's cells, contrasting with results of complement-dependent tumor cell lysis. Tumor cell kill was partially inhibited by the addition of greater than 2 x 10⁶ human bone marrow cells/ml but could be potentiated by increasing the concentration of conjugate or by the addition of 10 mM ammonium chloride. In the presence of ammonium chloride, at least 4 logs of clonogenic tumor cells could be eliminated within 24 h from a 20-fold excess of bone marrow using 10^-7 M ricin A chain linked to one or two different antibodies. Similar treatment of normal human bone marrow temporarily inhibited granulocyte-macrophage colony-forming units (cell) formation but did not compromise establishment of continuous bone marrow cultures. The degree of selective elimination of tumor cells with A chain antibody conjugates was comparable to that achieved with 4-hydroperoxycyclophosphamide or with multiple monoclonal antibodies and complement.

¹ Supported in part by National Cancer Institutes Grants CA 28740 and CA 29039.

² Fellow of the Associazione Italiana per la Ricerca sul Cancro.

³ Fellow of Fondazione A. Villa Rusconi.

⁴ Fellow of the American-Italian Cancer Research Foundation.

⁵ Scholar of the Leukemia Society of America, Inc.

⁶ Scholar of the Leukemia Society of America, Inc. To whom requests for reprints should be addressed, at Box 3843, Duke University Medical Center, Durham, NC 27710.

Received 1/ 2/85. Revised 11/25/85. Accepted 12/ 2/85.