Two phase II trials that were investigating treatment of multiple sclerosis
with altered peptide ligands (APLs) have had to be stopped because of adverse
reactions (Nature Medicine 2000;6:1167 and 1176).
In the first study, Dr Bibiana Bielekova (neuroimmunology branch, National Institute
of Neurological Disorders and Stroke, US) and colleagues developed CGP77116,
an APL of myelin basic protein (MBP), a component of myelin, in the hope that
it would alter relapsing-remitting MS activity in humans. Seven volunteers with
relapsing-remitting MS were given 50mg of CGP77116 subcutaneously weekly but
all but one of the subjects discontinued treatment. Three suffered exacerbations
of their MS, one had a systemic hypersensitivity reaction to the drug and the
remaining three discontinued for other reasons. A further patient was given
a lower dose of CGP77116 but also suffered an adverse reaction. All patients
suffered injection-site reactions.
The authors say that two of the three exacerbations were related to the administration
of APL therapy. The third was not caused by CGP77116, which they say suggests
that not all MS attacks might be caused by the same antigen.
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| A better understanding of autoimmune responses is needed, authors say |
MBP-specific T-cells may still be valid targets for treating MS but a better
understanding of autoimmune diseases in individuals is needed before they can
be used effectively and safely, the authors conclude.
In the second study, Dr Ludwig Kappos (department of neurology, University hospitals,
Basel, Switzerland) and colleagues looked at the effect of an MBP-specific APL
and placebo on magnetic resonance imaging (MRI) scans of the central nervous
system. However, halfway through the study, the trial was stopped because 13
of the 142 patients had had a hypersensitivity reaction. Symptoms included itching,
paraesthesiae, rash and dyspnoea. In addition, one patient suffered a hypotensive
episode and another, syncope. The authors note that, in general, there was no
worsening of MRI scans in patients who had suffered a reaction. They conclude
that APL induces T-cell activity against autoimmune antigens but at the price
of causing hypersensitivity reactions.
In a commentary on the two studies, Drs Claude Genain and Scott Zamvil (department
of neurology, University of California) say that “one should not conclude
that APL therapy is either good or bad”. The observations made in the studies
should stimulate further research into which patients are most likely to benefit
from APL therapy, they say (ibid, p1098).
The aetiology of MS is not understood but animal data suggest that it is an
autoimmune disease mediated by myelin-specific T-cells. Specific therapies for
T-cell autoimmune diseases in animal models have been developed where the target
antigen is known. Thus, there has been a great deal of interest in finding similar
approaches for human autoimmune diseases.
One approach is to use altered peptide ligands. These affect T-cell responses
in one of three ways — by acting either as partial agonists or as antagonists
at T-cell receptors or by inducing the production of T-cells that suppress the
inflammatory response.