Targeting tumor cells
Introduction
The advent of human or humanized antibodies has revolutionized the therapeutic use of monoclonal antibodies in humans [1]. There was a long period between the original reports of Milstein et al. [2] documenting the development of monoclonal antibodies and the breakthroughs in humanization [3•] or in the production of fully human antibodies [4•], using genetically altered mice or other technologies, which have led to the increased attention that these possibilities offer for the production of therapeutic antibodies. Some of the successes in the use of therapeutic antibodies are in autoimmune disease — for example, the use of infliximab (Remicade®, Centocor) for treating Crohn’s disease and rheumatoid arthritis [5] — but by far the most popular therapeutic area for the use of monoclonal antibodies has been in cancer. Here, we will review recent progress in this area.
A key development has been the extensive use of gene arrays that has allowed the identification of cell-surface molecules specifically expressed in tumor cells. A pioneering step in this area was the development of Herceptin® (see below), an antibody that targets the breast antigen, human epidermal growth factor receptor 2 (Her-2) 6.•, 7.. Importantly, this antibody also has another key characteristic: it is able to act on its own (a so-called ‘naked antibody’) without the need for conjugation to other toxic molecules. Her-2, moreover, also exhibits another common feature of therapeutic tumor targets: it is present only in a subset of breast cancer patients [7]. The latter feature is more likely to be the rule rather than the exception because at the molecular level, cancer is heterogeneous [8•]. While this heterogeneity will eventually aid us in establishing better diagnoses and treatments for patients, in the meantime it is likely to result in further work necessary to define such subgroups of patients. In turn, the identification of these disease subtypes will improve the diagnosis and treatment of cancer patients. However, for the time being, it is necessary to keep this heterogeneity in mind when considering highly specific new therapeutics. Furthermore, recent advances point to an important role for chemokines, integrins and other adhesion molecules in metastasis. Understanding the molecular mechanisms that regulate metastasis is also critical in order to identify future targets of importance in cancer. Here, we will review both the advances and successes in this area, key research questions and some of the challenges that lie ahead.
Section snippets
The case for small molecules: Imatinib mesylate
Imatinib mesylate (STI-571/Gleevec® [US]/Glivec® [non-US], Novartis) is a small-molecule inhibitor of three tyrosine kinases, Bcr-Abl, c-kit and the platelet-derived growth factor receptor (PDGFR). c-Abl expression is linked to the Philadelphia chromosome [9], which is present in chronic myelogenous leukemia (CML) [10]. c-kit is the receptor for the cytokine stem cell factor (SCF) [11], or kit ligand. The expression of c-kit on cells usually means that SCF can act either as a growth factor (on
The case for antibodies: Herceptin®, Rituxan®
While Imatinib is one of the best examples of a specific small molecule targeting a cancer, much more interest has been generated for the use of antibodies that target specific molecules expressed by tumor cells. The reason for this increased attention is that there are now several examples of effective antibodies to treat various cancers. Two such examples are Herceptin® (Trastuzumab, Genentech) and Rituxan® (Rituximib; IDEC Pharmaceuticals Corporation). Herceptin® targets the Her-2 antigen
Antibody–drug conjugates
Cell-surface molecules that exhibit high specificity for tumor cells are easier to find [16]. Often, little is known about the function of these highly specific cell-surface molecules; for this reason, the development of antibodies against these targets might not result in the impairment of tumor progression or survival. The specificity of these molecules instead can be used to turn these antibodies into a highly specific way of delivering toxins. Popular toxins that have been used in this way
Other issues in the development of tumor therapeutics
There are several issues that bear great importance in the development and use of specific cancer therapeutics. Some of these are the discussed below.
Conclusions
There is little doubt that we are entering a period of exponential growth in the development of highly specific and effective anti-cancer drugs. Most of these initially are going to be antibodies, although, as the example of Imatinib shows, small molecules will also be successful. The latter class of drugs has the limitation of being likely to target only certain molecular families that are more amenable for small-molecule discovery (i.e. G-protein-coupled receptors, ion channels, etc.).
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
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