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Antitumor Activity of Intraperitoneal Immunotoxins in a Nude Mouse Model of Human Malignant Mesothelioma¹

Department of Medicine (Oncology), University of Massachusetts Medical Center, Worcester, Massachusetts 01605 [T. W. G., C. R.]; Cetus Corporation, Emeryville, California 94608 [L. L. H.]; Bogden Research Laboratories, Worcester, Massachusetts 01605 [D. L., A. B.]; and Dana Farber Cancer Institute and the Department of Pathology, Harvard Medical School [V. R.], Boston, Massachusetts 02115

Immunotoxins directed against human transferrin receptor have been evaluated in a nude mouse model of human malignant mesothelioma. Immunotoxins were constructed by linking ricin A chain to murine monoclonal antibodies reactive with the human transferrin receptor. A chain was obtained either by isolation from the parent toxin or by recombinant DNA techniques. These immunotoxins acted as potent in vitro cytotoxins against human malignant mesothelioma cells (H-MESO-1) (ID₅₀, 2 x 10^-9 M). Cytotoxic potency and kinetics of cell kill were potentiated in vitro by the carboxylic ionophore monensin. For in vivo trials, nude mice were injected i.p. with 6–9 x 10⁶ human malignant mesothelioma cells 24 h prior to the start of i.p. immunotoxin treatments. The survival of tumor-bearing mice was extended by 149–404%, representing a probable cell kill of 2–4 logs. Specificity of this antitransferrin receptor immunotoxin response was confirmed by the ineffectiveness of irrelevant control immunotoxins and blockade of specific immunotoxin action by excess free antibody. Monensin showed limited in vivo potentiation of immunotoxin effect, but a derivative formed by esterification of monensin with linoleic acid gave improved survival times over treatment with immunotoxin alone.

Immunotoxins constructed with ricin A chain have significant tumoricidal activity in this model of regional antitumor therapy. These results may have direct relevance for treatment of i.p. malignancy in clinical settings.

¹ This investigation was supported in part by USPHS Grants R01-CA29039 and R01-CA39748 awarded by the National Cancer Institute, Department of Health and Human Services.

² Scholar of the O'Brien Fund-Leukemia Research Student Fellowship Fund, Inc.

³ To whom requests for reprints should be addressed, at the Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.

Received 1/ 9/87. Revised 5/ 4/87. Accepted 5/22/87.

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