Monoclonal antibodies targeting cancer: 'magic bullets' or just the trigger?

The Holy Grail of cancer therapy is to develop agents capable of selectively destroying disseminated tumour cells while sparing normal tissues. With this aim, major efforts have been directed at harnessing the exquisite specificity of the immune response. Hybridoma technology has enabled the development of tumour selective monoclonal antibodies (mAbs) [1,2], and the past few years have witnessed the approval by the Food and Drug Administration of the first mAbs for the therapy of cancer: Rituxan (anti-CD20) for non-Hodgkin's lymphoma and Herceptin [anti-(c-erbB-2/HER-2)] for metastatic breast cancer. The purpose of this commentary is to summarise known and recently reported properties of these mAbs and consider whether recent findings might lead to more effective therapies for cancer.Although the earlier detection of breast cancer and improvements in surgery and adjuvant therapy have improved survival rates, there are still around 15,000 deaths in the UK each year and 43,000 in the USA. This is due primarily to the development of drug-resistant metastatic disease. An increasing number of genetic changes have been identified in breast and other cancers, which are now being actively explored for targeted therapy [3]. One of the most exciting new targets is the c-erbB-2/HER-2/neu proto-oncogene, which is expressed in 20-30% of breast and other carcinomas. Clinical observations and laboratory experiments have demonstrated convincingly that, together with the related epidermal growth factor receptor (EGFR), it is causally related to maintenance of the malignant phenotype, functioning as a critical signalling molecule in tumour cell proliferation, motility, angiogenesis and metastasis [4]. The accessibility of c-erbB-2 at the cell surface, low expression on normal adult tissues and relatively homogeneous distribution within 'positive' tumours and their metastases makes it an ideal candidate for immunotherapeutic intervention [5].Initially, attention focused on specificity