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Rheumatoid arthritis and the pharmaceutical
industry
Biological medicines for the control of the proliferative
and destructive stages
Despite great research efforts, the NSAIDs and the DMARDs
available are far from ideal and it is clear that the next
major advance is most likely to come from the range of new,
experimental biological medicines. This area is an exciting,
if complex, one for RA research. Several of the targets being
investigated are shown in the illustration on page 20, where
they are numbered 1 to 9.
The proliferative and destructive stages of RA are associated
with cells in the immune system releasing special substances
called cytokines and growth factors into the
blood and tissues. These stimulate unwanted growth of pannus
and synovial tissue. The trigger which starts this off – and
probably perpetuates it in susceptible people – is thought
to be an antigen, possibly arising from an infection.
The antigen acts as a stimulus to immune cells, which then
bind to each other.
Although this is the body’s natural reaction from the immune
system, in people with RA, the harmful substances released
as a result of binding may:
- trigger synovial cells to digest cartilage and bone,
- attract more cells into the joint by making the blood
vessel walls sticky,
- have direct damaging effects on joint tissues.
Scientists have sought to prevent the release of harmful
molecules, block their effects, or inhibit the production
of digestive enzymes that destroy cartilage and bone.
Medicines that block the formation of harmful cytokines
Several companies, including Celltech, Glaxo Wellcome, Merck,
Sharp & Dohme, Novartis, Proteus, SmithKline Beecham and Zeneca,
are investigating medicines to prevent the formation of harmful
cytokines.
Celltech has developed a particular expertise in adapting
animal or human antibodies for use as medicines. One, CDP855,
binds at an early stage of the immune process and could have
potential in several diseases, including RA (Step 1). Zeneca
and Merck Sharp & Dohme also have interests in this area.
Zeneca has identified ZD2315, which is at the pre-clinical
trial stage, as part of a wider programme aimed at developing
treatments for a number of human conditions in which unwanted
immune cell binding is involved. Vaccination with small fragments
of the molecules of some of the proteins involved may induce
natural antibodies that produce much the same effect, but
the results of such studies are not yet known (Step 2).
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antigen A
substance that can stimulate an immune response
monoclonal antibody
A protein made by the immune system and derived from
a single group of cells which recognises only one kind
of antigen
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Other companies have developed compounds acting in a similar
way (Step 3). Glaxo Wellcome has produced a genetically engineered
monoclonal antibody called 4162W94 to block
the CD4 receptor, which plays an important role in the body’s
immune system. It is currently in Phase II clinical trials
in RA but the results are not yet known. At an earlier stage
is a similar inhibitor from Novartis, while SmithKline Beecham
is developing two more such antibodies. One of these, SB-217969,
is in Phase II, while SB-210396 is slightly more advanced
and has reached early Phase III studies. No results are yet
available from these trials, but the value of this approach
in RA should become much clearer before long.
Proteus has developed a novel approach, called NISV, which
may have potential for several diseases, including RA. It
involves small fatty droplets which can be taken up by immune
cells, whose activities are then damped down so that they
produce fewer of the harmful cytokines.
Some work has been done to produce medicines that bind to
the surface of immune cells to stop them being activated (Step
4). The inhibitors are monoclonal antibodies or antibodies
coupled to chemical compounds that would bind to and then
kill activated cells. These approaches are under development
by Roche and Eli Lilly. One compound, DAB486IL-2, has
entered early clinical trials in people with RA who do not
respond to other therapy, with results that are initially
encouraging. Glaxo Wellcome is also studying a monoclonal
antibody, GW353430, which may act in a similar way.
Inhibitors of harmful cytokines
Ideally, a biological medicine would prevent the formation
of potentially damaging substances. However, in many people
with RA, such substances are already present and it is too
late. In this case it is necessary to neutralise them or block
their effects. Two of these harmful substances are interleukin-1
(IL-1) and tumour necrosis factor (TNF) (Steps 5 and
7).
In this area, Celltech has developed a genetically engineered
human antibody, CDP571, that neutralises the effects of TNF.
When given to people who had failed to respond to DMARDs or
who had unacceptable side effects, CDP571 resulted in improvements
in patients’ joints. Notably, they experienced a feeling of
well-being which quickly took effect. More extensive trials
are now planned. Two companies, Amgen-Synergen and Hoechst
Marion Roussel, are developing medicines that act in a similar
way towards IL-1.
Beneficial cytokines
Not all the cytokines released into the joint by the immune
system are harmful. Some may have beneficial effects in RA
by actually protecting the cartilage and bone. Both interleukin-4
(IL-4) and interleukin-10 (IL-10) reduce the release of harmful
substances and stimulate the formation of natural substances
that inhibit IL-1 and TNF. IL-10 also appears able to reduce
the release of enzymes which digest cartilage. Hence efforts
have been made to produce both IL-4 and IL-10 as potential
medicines through genetic engineering (Step 6).
IL-4 has entered clinical trials but to date, the greatest
attention has focused on IL-10, which is being developed by
Schering-Plough. A Phase I trial was completed in Britain
in 1996, with promising results. A Phase II trial has now
started in several countries, including the UK. The results
will add greatly to our understanding of RA and give leads
towards treatment in more aggressive cases.
Inhibitors of enzymes that digest cartilage
The enzymes most frequently involved in the digestion of
cartilage are called the matrix metalloproteinases
(MMPs). One of these, collagenase, attacks the collagen fibres
in cartilage. Collagen is a protein that is the main building
block of cartilage. MMPs are the subject of active research
programmes and several compounds have reached the clinical
trial stage (Step 8). Roche has made a series of collagenase
inhibitors and have selected one, Ro32-3555, now called
trocade, for clinical development. It has been shown
to block the breakdown of cartilage. It may have potential
in the treatment of both RA and osteoarthritis, and the compound
will soon enter clinical trials for RA.
MMP inhibitors are also a particular focus for Chiroscience,
which is investigating a novel chemical type at the early
research and development stage. If successful, these molecules
will help reduce the destructive stage in RA and limit joint
damage, but none is yet generally available.
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