Monoclonal antibodies in tumour therapy
While the picture given so far looks pretty bleak, there is hope of improvement. Among several new approaches to tumour therapy, monoclonal antibodies have started to make the most substantial contribution to improving its effectiveness and reducing the severity of side effects.
The use of antibodies is based on the fact that, due to al-tered gene expression patterns, many tumours possess one or more surface proteins that are not found on the healthy cells14. Antibodies that bind to cell surface antigens can in-duce cell destruction in various ways:
1. By activating the complement system. This is a system of serum proteins that will bind to cell surface-bound antibodies and form holes in the cell membrane, thereby killing the cell. A straightforward example of this pro-cess is the destruction of blood cells by the transfusion of blood with incompatible blood type.
2. By activating cytotoxic lymphocytes. This process is called `Antibody-dependent, cell-mediated cytotoxici-ty', often referred to by the acronym ADCC15 and is im-portant in the immune response to virus infection.
3. Sometimes, the target protein itself will respond to the binding of antibodies with some cytotoxic effect. You have probably heard about apoptosis (programmed cell death). This is triggered by specific cell surface recep-tors, and some antibodies can mimic the effect of ago-nists at these receptors.
In addition, toxic activity can be conferred on antibodies by way of conjugating them with toxic agents (such as diph-theria toxin) or short-lived radioisotopes (such as 131I).
The first demonstration that antibodies can be of use in tu-mour therapy actually predates the invention of monoclonal antibodies; however, the uniformity of monoclonal antibod-ies makes them superior for the following reasons:
• They can be selected to be highly specific for one indi-vidual target protein. In contrast, polyclonal antibodies (even if directed against an individual target protein) have a higher potential to cross-react.
• The are standardized. In contrast, polyclonal antibodies will contain a mixture of specificities that will vary with each donor individual.
• In exceptional cases, monoclonal antibodies may be di-rected against a crucial epitope16 that activates a cytotox-ic activity of the target protein.
For technical reasons, monoclonal antibodies initially were purely murine, i.e. derived from mouse cell lines. In clin-ical use, these murine antibodies met with limited success. Reasons for this include
• production of neutralizing human anti-mouse antibod-ies. This led to rapid elimination of the murine anti-bodies.
• inadequate recruitment of immunological effector func-tions. The interaction of murine antibodies with human lymphocytes and complement is less efficient than that of human antibodies.
A big step forward was the invention of `humanized'mono-clonal antibodies, which are hybrids in which a large part of the murine antibody molecules have been replaced by hu-man sequences (obviously by recombinant DNA technolo-gy). In the recent years, the list of such antibodies that have received approval and are being used in practical therapy has grown to some 20 members. Not all of these are actu-ally intended for tumour therapy; other applications include chronic inflammatory diseases such as transplant rejection, Crohn's disease or rheumatoid arthritis. Among those an-tibodies that are being used in cancer therapy, most are di-rected against target antigens that are associated with spe-cific tumour types. For example, the first clinically useful monoclonal anti-tumour antibody (with the poetic name rit-uximab) is directed against CD20, a surface antigen found in B lymphocytes and particularly highly expressed in B-cell lymphomas, which are tumours derived from B lym-phocytes. CD20 is a particularly suitable target antigen, for the following reasons:
• It is highly expressed on the B-cell lymphoma cells, but not on most other cells of the body.
• It remains on the cell surface after binding of the anti-body, so that the antibody can trigger complement and ADCC. In contrast, many other antigens are being shed from the cells or internalized upon antibody binding, which interferes with a targeted cytotoxic action.
• CD20 has a role in apoptosis, and binding of the anti-body stimulates apoptosis. This means that even with-out recruitment of complement or ADCC antibodies can trigger a cytotoxic effect.
It is clear that we will not always be so lucky to find such a great target on our tumour of interest. However, while B-cell lymphomas are among the less widespread (and more tractable) tumours, a more recent breakthrough is the de-velopment of an antibody that is being used in the therapy of breast cancer, which is one of the most common forms of cancer. This antibody (called trastuzumab) binds to human epidermal growth factor receptor 2 (HER2; hence trastuzumab's commercial name `herceptin'). This receptor is overexpressed on breast cancer cells. Intriguingly, HER2 overexpression is particularly pronounced on those cells that express low amounts of steroid hormone receptors, so that trastuzumab is valuable as a complement to steroid hormone antagonists such as mifepristone. Introduction of trastuzumab has resulted in clear-cut improvements of therapy, and the only impediment to its general use is now cost.
As with the traditional types of tumour therapy, the success of antibody therapy is always endangered by the potential emergence of resistant clones. To reduce this risk, antibodies are typically used in combination or alternatingly with other types of agents.
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