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Functional Properties and Effect on Growth Suppression of Human Neuroblastoma Tumors by Isotype Switch Variants of Monoclonal Antiganglioside G_D2 Antibody 14.18¹

Departments of Immunology [K. M., H. M. Y., D. A. C., U. W., D. J. S., R. A. R.] and Basic and Clinical Science [T. J. K.], Scripps Clinic and Research Foundation, La Jolla, California 92037

A complete family of IgG isotype switch variant hybridomas was generated from the anti-G_D2 monoclonal IgG3-producing hybridoma, 14.18, with the aid of the fluorescence-activated cell sorter. The IgG1, IgG2b, and IgG2a monoclonal antibodies (Mabs) produced by respective isotype switch variant hybridomas 14G1, 14G2b, or 14G2a, have binding activities for the biochemically defined G_D2 antigen and G_D2-expressing neuroblastoma target cell lines identical to that of IgG3 Mabs produced by the 14.18 parent cell line. This permitted us to examine the relative in vitro and in vivo cytotoxic capacities of each of the anti-G_D2 antibodies for G_D2-expressing neuroblastoma cells independent of antibody binding affinity or specificity. Mabs produced by 14.18, 14G2a, or 14G2b, but not 14G1, can direct efficient complement-dependent cytotoxicity against neuroblastoma tumor cells in the presence of human complement. Mabs produced by the parent 14.18 or by 14G2a are more efficient in directing antibody-dependent cell-mediated cytotoxicity than Mabs produced by 14G2b, and Mabs of 14G1 are inactive. However, despite these noted in vitro differences, antibodies produced by each member of this switch variant family suppress the growth of human neuroblastoma tumor cells in BALB/c athymic nu/nu mice. These studies suggest that a mechanism(s) other than Fc-directed complement-dependent cytotoxicity or antibody-dependent cell-mediated cytotoxicity may account for the in vivo antitumor effects of these particular antibodies.

¹ Supported in part by NIH Grants CA42508 (R. A. R.), AR33489 (T. J. K.), and CA45726 (D. A. C.) and a Fellowship Support Grant from the Joseph Drown Foundation, Los Angeles, CA. This is Scripps Publication No. 5228-IMM.

² Scholar of the Leukemia Society of America and supported in part by the Scott Helping Hand Fund.

³ Recipient of a Fellowship from the National Cancer Center, Plainview, NY.

⁴ To whom requests for reprints should be addressed, at Department of Immunology, Research Institute of Scripps Clinic, 10666 N. Torrey Pines Road, La Jolla, CA 92037.

Received 9/19/88. Revised 2/14/89. Accepted 2/27/89.

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