Monoclonal antibody therapy of human cancer: Taking the HER2 protooncogene to the clinic

Abstract

The HER2 protooncogene encodes a 185-kDa transmembrane protein (p185HER2) with extensive homology to the epidermal growth factor (EGF) receptor. Clinical and experimental evidence supports a role for overexpression of the HER2 protooncogene in the progression of human breast, ovarian, and non-small cell lung carcinoma. These data also support the hypothesis that p185HER2 present on the surface of overexpressing tumor cells may be a good target for receptor-targeted therapeutics. The anti-p185HER2 murine monoclonal antibody (muMAb) 4D5 is one of over 100 monoclonals that was derived following immunization of mice with cells overexpressing p185HER2. The monoclonal antibody is directed at the extracellular (ligand binding) domain of this receptor tyrosine kinase and presumably has its effect as a result of modulating receptor function. In vitro assays have shown that muMAb 4D5 can specifically inhibit the growth of tumor cells only when they overexpress the HER2 protooncogene. MuMAb 4D5 has also been shown to enhance the TNF-alpha sensitivity of breast tumor cells that overexpress this protooncogene. Relevant to its clinical application, muMAb 4D5 may enhance the sensitivity of p185HER2-overexpressing tumor cells to cisplatin, a chemotherapeutic drug often used in the treatment of ovarian cancer. In vivo assays with a nude mouse model have shown that the monoclonal antibody can localize at the tumor site and can inhibit the growth of human tumor xenografts which overexpress p185HER2. Modulation of p185HER2 activity by muMAb 4D5 can therefore reverse many of the properties associated with tumor progression mediated by this putative growth factor receptor. Together with the demonstrated activity of muMAb 4D5 in nude mouse models, these results support the clinical application of muMAb 4D5 for therapy of human cancers characterized by the overexpression of p185HER2.

Targeting the function of the HER2 oncogene in human cancer therapeutics

“…The mAb 4D5 was selected among a panel of mouse anti-HER2 antibodies at Genentech Inc. (South San Francisco, CA, USA) for development because of its antitumor effects in vitro and in mouse models (Hudziak et al, 1989;Shepard et al, 1991). Mouse mAb 4D5 was humanized for clinical use yielding several humanized variants.…”

Signal‐Transduction Therapy

“…Antibodies against the extracellular domain have had better success in preventing EGFR-driven (Mendelsohn et al 1992;Naramura et al, 1993;Fan et al, 1993) or Her-2-driven (Drebin et al, 1985(Drebin et al, , 1986Stancovski et al, 1991;Shepard et al, 1991 ;Harwerth et al, 1993;Kern et al, 1993;Lewis et al, 1993) tumor growth. Thus Her-2 and EGFR antibodies are currently in clinical trials.…”

Large‐scale N‐glycoproteome map of rat brain tissue: Simultaneous characterization of insoluble and soluble protein fractions

“…Glycoproteins are involved in various molecular and cellular mechanisms, including development, growth, communication, and especially in cancer progression. Some glycoproteins have been successfully applied in clinical treatment or diagnosis, such as Her2/neu for breast cancer, CA125 for ovarian cancer, and prostate-specific antigen for prostate cancer [1,2].…”

“…However, many glycoproteins with important biological functions are of low abundance, as above-mentioned CA125 and prostate-specific antigen [1][2][3][4]. When further treated with enzyme, the glycopeptides are only 2-5% in the digests.…”