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Bispecific Antibody-dependent Cellular Cytotoxicity of HER2/neu-overexpressing Tumor Cells by Fc Receptor Type I-expressing Effector Cells¹

Medarex, Inc., Annandale, New Jersey 08801 [T. K., R. F. G., A. M., Y. M. D.], and Departments of Microbiology [P. K. W., M. W. F.], Physiology [P. M. G.], and Medicine [J. F., M. W. F.], Dartmouth Medical School, Lebanon, New Hampshire 03756

A bispecific antibody, MDX-H210, was developed to target cytotoxic effector cells expressing Fc receptor type I (FcRI, CD64) to HER2/neu-overexpressing tumor cells. HER2/neu is an appropriate target for immunotherapy due to the high level of expression of this proto-oncogene in a variety of malignancies. The expression of FcRI is limited primarily to cytotoxic immune cells, including monocytes, macrophages, and cytokine-activated polymorphonuclear (PMN) cells. Therefore, tumor cells bound with MDX-H210 can be selectively recognized by effector cells with cytotoxic potential. MDX-H210 was prepared by chemical conjugation of Fab' fragments derived from the HER2/neu-specific monoclonal antibody, 520C9, and the FcRI-specific monoclonal antibody, H22. This bispecific molecule demonstrated specific, dose-dependent, and saturable binding to both HER2/neu- and FcRI-expressing cells. A solid-phase immunoassay that demonstrated simultaneous and specific binding to both antigens was used to confirm the bispecific nature of MDX-H210. Monocytes and PMN cells mediated MDX-H210-dependent lysis of HER2/neu-overexpressing cell lines derived from breast, ovarian, and lung carcinomas. IFN- treatment of monocytes enhanced antibody-dependent cellular cytotoxicity, whereas IFN- and granulocyte colony-stimulating factor were required for PMN cell-mediated tumor cell lysis. In addition, MDX-H210 elicited tumor necrosis factor- secretion from monocytes when cultured in the presence of HER2/neu-positive target cells. These in vitro data suggest that targeting tumor cells to FcRI with MDX-H210 may be an effective treatment for malignancies that overexpress HER2/neu. The in vivo cytotoxic potential of MDX-H210 may be enhanced by combination therapy with the cytokines granulocyte colony-stimulating factor and IFN-, which up-regulate FcRI expression on cytotoxic effector cells.

¹ This work was supported in part by Autoimmunity & Connective Tissue Biology Program Grant T32 AR-07576 (to P. K. W.).

² To whom requests for reprints should be addressed, at Medarex, Inc., 1545 Route 22 East, Annandale, NJ 08801. Phone: (908) 713-6010; Fax: (908) 713-6013.

Received 3/11/97. Accepted 7/11/97.

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