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Clinically Effective Monoclonal Antibody 3F8 Mediates Nonoxidative Lysis of Human Neuroectodermal Tumor Cells by Polymorphonuclear Leukocytes¹

Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Most studies of antibody-dependent cellular cytotoxicity (ADCC) by polymorphonuclear leukocytes (PMN) have supported oxidative lytic processes. This may be because the studies used nonhuman or nonneoplastic cells that were highly sensitive to reactive oxygen species or were small enough to be phagocytosed by PMN. We therefore investigated whether oxygen radicals participate in PMN cytotoxicity toward human neuroectodermal solid tumor cells sensitized by 3F8, which is an antiganglioside G_D2 murine IgG3 monoclonal antibody with documented anticancer activity in humans. A 4-h ⁵¹Cr release assay was used to assess tumor cell lysis by hydrogen peroxide, superoxide, and hypochlorite. Nine of 11 G_D2(+) human melanoma and neuroblastoma cell lines had equal or greater resistance to these oxidants as compared to a G_D2(-) human carcinoma line (SKBr1-III) found by others (and confirmed by us) to be significantly more resistant to oxidative lysis than a murine cell line (P388D₁) representative of those commonly used in cytotoxicity assays. To facilitate detection of oxidant-mediated lysis, subsequent studies of 3F8-mediated ADCC used G_D2(+) targets that were relatively sensitive and others that were relatively resistant to oxygen radicals. Normal PMN and PMN obtained from children with chronic granulomatous disease, which do not generate reactive oxygen species, were equally effective in ADCC. Granulocyte-macrophage colony-stimulating factor, which primes oxidative responses of normal but not of chronic granulomatous disease PMN, enhanced ADCC by both kinds of PMN. During ADCC of 3F8-sensitized targets, with or without granulocyte-macrophage colony-stimulating factor, G_D2(-) "innocent bystander" tumor cells (including P388D₁) were not lysed, a finding consistent with unimportant extracellular release of cytotoxic mediators. Finally, antioxidant and antimyeloperoxidase moieties did not block ADCC. We conclude that oxidants are not key factors in 3F8-mediated lysis by PMN of human neuroectodermal tumor cells.

¹ This work was supported by grants from the American Cancer Society (IM521 and CDA90-242), the National Cancer Institute (CA33049), the Robert Steel Foundation, and the Justin Zahn Fund. B. H. K. is a recipient of an American Cancer Society Career Development Award. Presented in part at the 32nd Annual Meeting of the American Society of Hematology, Boston, MA, November 28–December 4, 1990.

² To whom requests for reprints should be addressed, at Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.

Received 4/15/91. Accepted 7/ 8/91.

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