Monoclonal antibodies in
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
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
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.