Anti-P-glycoprotein Antibody C219 Cross-reactivity With c-erbB2 Protein: Diagnostic and Clinical Implications
Authors: H. S. L. Chan, V. Ling
Journal: JNCI Journal of the National Cancer Institute (1997)

It has been more than two decades since the discovery of P-glycoprotein, the prototype of the transmembrane multidrug resistance transporters. The expression of P-glycoprotein in normal and malignant tissues has been studied extensively. Because many drug-resistant or poor-prognosis cancers overexpress the MDR1 gene, which encodes P-glycoprotein, a number of clinical correlative studies have been conducted. Many, but not all, of these studies reported that overexpression of P-glycoprotein was associated with an adverse chemotherapeutic outcome, whereas low expression or undetectable P-glycoprotein was associated with good prognosis (1,2), in keeping with the proposed function of P-glycoprotein as a drug efflux ‘‘pump’’ that expels anticancer drugs from resistant cancer cells (3). The results of these clinical correlative studies in various cancer types have spurred ongoing trials that attempt to modulate P-glycoprotein function in vivo with different inhibitors (4). Thus far, because such trials have not conclusively ‘‘reversed’’ the adverse outcome of Pglycoprotein-expressing cancers, there has been a resurgence of interest in examining whether the disparate results of different clinical correlative studies of various cancer types can be attributed to differences in the diagnostic tools, experimental reagents, and methodology used or in the criteria applied for the interpretation of results. These deliberations led to a North American and European consensus conference involving 15 institutions—the 1994 ‘‘St. Jude Methods to Detect Pglycoprotein-Associated MDR [i.e., multidrug resistance] Workshop’’—at which recommendations were forged and published (5) to guide future clinical research on multidrug resistance. Relevant to the increased awareness of potential problems in detecting P-glycoprotein, Liu et al. (6) report in this issue of the Journal that the monoclonal antibody C219 cross-reacts with the c-erbB2 protein (also known as p185 c-erbB2 ) because it contains a peptide sequence that is homologous to the C219 epitope of P-glycoprotein. The implication of this finding is that immunologic detection of P-glycoprotein with the C219 antibody may be confounded by the overexpression of c-erbB2 protein in clinical and research tumor samples. Briefly, these investigators found, by means of immunoblot and immunohistochemical analysis, that the C219 antibody (Signet Laboratories, Inc., Dedham, MA) cross-reacts with p185 c-erbB2 , whereas the monoclonal anti-p185 c-erbB2 antibody, c-neu-Ab3 (Oncogene Science, Inc., Uniondale, NY), does not recognize Pglycoprotein. Comparison of peptide sequences revealed that the C219 antibody recognizes an epitope in P-glycoprotein that shares sequence homology with p185 c-erbB2 . Enzyme-linked immunosorbent assays also demonstrated that the C219 antibody recognizes synthetic peptides derived from the C219 epitope in P-glycoprotein as well as from the C219 epitope-homologous region in p185 c-erbB2 . Their finding is consistent with the con