Monoclonal Antibodies as Therapeutic Agents: Advances and Challenges

Abstract

Despite the major advances in conventional forms of treatment (i.e. surgical techniques, radiotherapy and chemotherapy) and improved survival rates, cancer is still the second leading cause of death in developing countries. One major limitation of cytotoxic drugs and radiation in the treatment of cancer patients is their inability to discriminate between malignant and normal tissues. This in turn prevents the delivery of the optimal (therapeutic) dose of such agents to malignant tissues for their eradication. With the advent of hybridoma technology in 1975, it has been possible for the first time to produce large amounts of an antibody (i.e. monoclonal antibody) against any antigens of interest. Since each antibody is highly specific for a particular antigen, this typical feature of the antibodies has resulted in their widespread use in diagnostic kits, medical research (e.g. to unravel the function of the antigen in physiological and pathological conditions), and more recently, for the management of a wide range of human diseases such as autoimmune disease and human cancers. Thanks to recent advances in genetic engineering, the immunogenicity of rodent antibodies was reduced by producing the chimeric or humanized version of such antibodies or by developing the fully human antibodies. In other instances, as intact antibodies are too large for rapid penetration into solid tumours, it has been possible to develop a smaller fragment of such antibodies (e.g. Fab, scFv, VHH) with greater potential for use in cancer imaging and therapy. Depending on the target antigens and the antibody format, monoclonal antibodies can induce their anti-tumour activities by several mechanisms including activation of the host effector cells. To date, several mAbs have been approved for management of human cancers including: anti-EGFR antibody cetuximab and anti-VEGF antibody bevacizumab for treatment of metastatic colorectal cancer, anti-HER-2 antibody trastuzumab for metastatic breast cancer, anti-CD20 antibodies rituximab and ibritumomab tituxetan for non-Hodgkin lymphoma, anti- CD52 antibody alemeutumab for chronic lymphocytic leukaemia, and anti-CD33 antibody gemutuzumab ozogamicin for the treatment of acute myeloid leukaemia patients. Monoclonal antibodies currently account for about 30% of all new drugs in development, with more than 500 antibodies at different stages of clinical trials worldwide. In this review, the characteristic features of some of the therapeutic antibodies and the antigens recognised by such antibodies will be discussed as well as several challenges that need to be addressed in order to facilitate their widespread use as “magic bullets" in the management of human diseases and in particular human cancers.