Overexpression of the tyrosine kinase receptor erbB2 is important in the pathogenesis of a variety of neoplasms. Based on this concept, targeted anti-cancer strategies have been designed to selectively eradicate erbB2 overexpressing tumor cells. These strategies have employed either monoclonal antibodies or antibody toxin molecules with specificity for the cell surface erbB2 protein. As an alternative strategy, anti-erbB2 single-chain immunoglobulin (sFv) genes were constructed to direct expression of intracellular anti-erbB2 antibodies. Expression of an endoplasmic reticulum (ER) form of the anti-erbB2 sFv resulted in a profound down-regulation of cell surface erbB2 in an erbB2 overexpressing ovarian carcinoma cell line. In addition, expression of the intracellular antibody resulted in marked inhibition of tumor cell proliferation. Whereas stable transfectants expressing the anti-erbB2 sFv could be derived from non-erbB2 overexpressing cancer cell lines, expression of the intracellular antibody was incompatible with long-term survival of the erbB2 overexpressing tumor cells. The ability to selectively 'knock-out' erbB2 demonstrates that cell surface localization of erbB2 is essential to its ability to induce aberrant cellular proliferation in tumor cells. In addition, the ability to accomplish selective abrogation of oncogenes by virtue of intracellular antibodies suggests a.