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Effector Mechanism in Antitumor Activity of Monoclonal Antibodies Produced against an Ascitic Mouse Mammary Tumor¹

Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya 464 [M. S., T. T., S. N., Y. N.], and Teijin Institute for Biomedical Research, Asahigaoka, Hino, Tokyo 191, [M. S., T. H.], Japan

Therapeutic effects of monoclonal antibodies with different immunoglobulin classes, detecting the same antigenic determinant of tumor specific antigen expressed on ascitic mouse mammary tumor MM46, were examined. With i.v. administration of 2a, 2b, or l antibody we were able to keep a significant proportion of mice tumor free against i.p. inoculation of 5 x 10⁴ MM46 cells with doses as small as 0.5 µg, but with administration of µ, 3, or antibody we were not able to keep mice tumor free with doses up to 5 µg. With 200 µg of antibody, however, an antitumor effect was observed even with µ or 3 antibody, although antibody still showed no effect at all. The therapeutic effect of 2a was further examined in mice challenged with an increasing dose of tumor cells, and a significant effect was demonstrated against 1 x 10⁶ cells with 200 µg of antibody but not against 5 x 10⁶ cells.

To assess the effector cells in antitumor activity of antibody in vivo, a histological examination of the tumor cells treated with each class of antibody was carried out. The tumor treated by 2a antibody revealed a remarkable cell infiltration consisting predominantly of mononuclear cells, whereas those treated by µ, 3, or antibody did not. The tumor cells treated by 1 or 2b antibody showed a moderate cellular reaction. Next, a Winn assay was carried out in athymic C3H/HeN-nu/nu mice using 2a antibody. A significant antitumor effect was observed even in those mice, indicating that T-cells are not predominant effector cells. The role of macrophages was studied in mice treated with two macrophage toxic agents, carrageenan and silica particles. These agents were shown to reduce the antitumor effect of 2a antibody in both Winn assays and therapeutic experiments. Thus, histological examination and the blocking effect of macrophage toxic agents suggested the participation of host macrophages as effector cells in antibody-mediated tumor cell suppression in vivo.

¹ This work was supported in part by a Grant-in-Aid from the Ministry of Health and Welfare for Comprehensive 10-Year Strategy for Cancer Control, a Grant-in-Aid for Cancer Research from the Ministry of Education, Science, and Culture, Japan, and by the Cancer Research Institute Inc., New York, NY.

² To whom requests for reprints should be addressed.

Received 3/25/85. Revised 8/20/85. Revised 12/30/85. Accepted 12/31/85.