the progression of diseases such as arthritis; results using antibody therapy have been
encouraging. Monoclonal antibodies can also be used to reduce the numbers of
specific cell typesin vivoby binding to surface markers on them. The binding of the
antibody to the cells alerts the immune system and causes the cells to be cleared from
circulation. Chimeric (formed from two sources) mouse/human monoclonal antibodies
consisting of mouse variable regions and human constant regions which are specific
to the B cell markerCD20have been used successfully for the treatment of systemic
lupus erythematosus. This disease is characterised by the development of aberrant
B cells secreting autoantibodies which cause a number of immune phenomena. The
decrease in circulating B cells reduces the number producing the autoantibodies and
alleviates some of the symptoms.
Agonistic(causing upregulation of a biological system) monoclonal antibodies are
therapeutic antibodies which have the ability to influence living cellsin vivo. They
upregulate cellular systems by binding tosurface receptor molecules. Normally, cell
receptors are stimulated briefly by their ligand (substance that binds to them) and the
resulting upregulation is also brief. Agonistic monoclonal antibodies bind to the
receptor molecule and mimic their ligand, but have the capacity to remain in place
for much longer than the natural molecule. This is due to the fact that the cell finds it
much more difficult to clear the antibody than it would the natural ligand. The action
of agonistic antibodies is incredibly powerful as the internal system cascades that can
be generated are potentially catastrophic for both the cell and the organism. Their use
has been mainly restricted to induction ofapoptosis(programmed cell death) in
cancer cells and only where a known unique cellular receptor is being stimulated.
There are a number of therapeutic inhibitory antibodies available and all of them
downregulate cellular systems by blocking the binding of antigen to receptor. They
behave ascompetitive analoguesto the inhibitor and have a longdwell time(the time
they remain bound) on the receptor increasing their potency. They may block the
binding of hormones, cytokines and other cellular messengers. They have been used
successfully for the management of some hormone-dependent tumours such as breast
cancer and also for the downregulation of the immune system to help prevent
rejection after organ transplantation.
These therapeutic antibody types need to be carefully engineered to make them
effective as treatment agents. The avidity and affinity of the antibodies is critical to
their therapeutic efficacy as their specific binding ability is critical to their length and
specificity of action. Additionally, they must not appear as ‘foreign’ to the immune
system or they will be rapidly cleared by the body. Often, the original monoclonal
antibody will have been derived using a mouse system and as a result is a murine
antibody. These antibodies can be humanised by engineering the cells, retaining the
murine binding site and replacing the constant region genes with human ones. The
resulting antibody escapes immune surveillance but retain their effective binding
capacity. Natural antibodies may remain in the circulation for up to 6 weeks but
engineered antibodies survive a much shorter time. The shortened survival time is due
to thehumanisationwhich still leaves a degree of murine antibody visible to the
immune system. Each engineered, therapeutic antibody has a different half-lifein vivo
and this factor is of great importance when baseline dosage is being established. All of298 Immunochemical techniques