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An Antigen Immunologically Related to the External Domain of gp185 is Shed from Nude Mouse Tumors Overexpressing the c-erbB-2 (HER-2/neu) Oncogene

Department of Immunology, Berlex Biosciences Inc., Alameda, California 94501

An antigen, immunologically related to the external domain of the c-erbB-2 (HER-2/neu) protein, was found shed into the serum of nude mice bearing tumors that overexpress the c-erbB-2 protein (gp185). Utilizing paired combinations from a panel of monoclonal antibodies (TAbs 250–265), with specificity for extracellular epitopes of gp185, an immunora-diometric assay was developed to quantitate this shed antigen. The immunoradiometric assay detected membrane-bound and soluble gp185 as well as a soluble derivative corresponding in sequence to the extracellular domain of gp185 (designated gp75). This recombinantly expressed gp75 was immunoaffinity purified and used to generate a standard curve from which serum samples were quantitated. Increases in antigen levels measured in the sera of tumor-bearing nude mice correlated with both overexpression of the c-erbB-2 protein and increased tumor volume. Positive sera were obtained from mice given implants of NIH3T3 cells transfected with c-erbB-2 complementary DNA (NIH3T3_t), or ovarian (SK-OV-3) or breast (MDA-MB-361) tumor cell lines overexpressing the c-erbB-2 protein. In mice bearing NIH3T3_t tumors, increases in tumor volume from 80 to 9000 mm³ resulted in levels of shed antigen from 8 to >1000 ng/ml gp75 equivalents. Sera from mice with c-erbB-2-negative tumors or tumors overexpressing the epidermal growth factor receptor were negative in the assay. This assay, and the quantitation of shed antigen levels, may have diagnostic or monitoring utility in cancers, such as breast and ovarian, in which the c-erbB-2 protein is overexpressed.

¹ To whom requests for reprints should be addressed, at Department of Immunology, Berlex Biosciences, 1501 Harbor Bay Parkway, Alameda, CA 94501.

² Current address: Microgenics Corp., 2380 Bisso Lane, Concord, CA 94520.

³ Current address: Howard Hughes Medical Institute, Department of Microbiology and Immunology, UCSF, San Francisco, CA 94143.

Received 12/18/89. Accepted 3/ 4/91.

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