Basic Protein May Be Target For Multiple Sclerosis Immunotherapy
Despite these adverse effects, the findings confirm that the targeted peptide
plays a role in the disease and provide valuable information that may help
refine this type of therapy for MS as well as other autoimmune diseases.
Results of the two studies will be published in the October 1, 2000, issue of
Investigators at the National Institutes of Health, Stanford University, and
13 other research centers tested a type of targeted immunotherapy designed to
alter immune reactions to a specific protein, thereby treating the disease
without compromising other immune functions. In this case, the therapy was an
altered version of one segment of a protein called myelin basic protein (MBP).
Therapies using altered peptides of this type are referred to as altered
peptide ligand or APL therapies. MBP is a component of myelin, a fatty substance
that surrounds and insulates nerve fibers. It is released during flare-ups of
relapsing-remitting MS, and it is believed to be one of the proteins which is
attacked by the immune system, causing symptoms of the disease.
Relapsing-remitting MS is marked by periodic increases in brain inflammation
and disease symptoms, interspersed with periods of full or partial recovery.
Previous research suggested that introducing an altered form of MBP into MS
patients might cause the body to react to the normal MBP in a protective way
instead of a harmful way, thereby stopping flare-ups of the disease.
In the first study, researchers led by Roland Martin, M.D., of the National
Institute of Neurological Disorders and Stroke (NINDS) Cellular Immunology
Section tested the therapy in 24 patients with active relapsing-remitting MS.
The study was partially sponsored by Neurocrine Biosciences, Inc., which owns
the rights to this therapy, under a Cooperative Research and Development
Agreement (CRADA). After studying the patientsí normal disease patterns for
six months, the researchers administered 50 mg of APL weekly for up to nine
months while using clinical tests, immunology work-ups, and MRI scans to
carefully monitor the effects of the therapy in patients. Two out of eight
treated patients showed an increase in inflammatory brain lesions that was
linked to the APL therapy by sophisticated studies of their immune cells. One
patient developed a general hypersensitivity reaction and three others
discontinued dosing due to side effects that could not be directly linked to the
Hypersensitivity is a condition in which the body over-reacts to a protein or
other stimulus. After the first seven patients showed adverse effects, the dose
was reduced to 5 mg for the eighth patient. When this patient also showed an
increase in MS lesions that seemed to be related to therapy, the trial was
In the second study, Ludwig Kappos, M.D., of the University of Basel,
Switzerland, Lawrence Steinman, M.D., of Stanford University Medical School, and
collaborators at 14 research centers in the United States, Europe, and Canada
conducted a randomized, double-blind clinical trial designed to test the therapy
in 144 patients. The study was sponsored by Neurocrine Biosciences, Inc., and by
Novartis. After a one-month monitoring period, patients in this trial received
either a placebo or a 5-, 20-, or 50-mg dose of the therapy weekly for four
months. Patients were then offered the therapy at a dose of 5 mg weekly.
In this study, the researchers found no significant difference in the
frequency or number of relapses in patients receiving the therapy vs. the
placebo, although the volume of new inflammatory brain lesions was reduced in
some patients who received the 5-mg dose of the therapy. However, 9 percent of
the patients enrolled in the study developed systemic hypersensitivity to the
therapy. These reactions caused the trial to be stopped after only 53 patients
had completed the double-blind phase. The scientists point out that neither of
the studies tested the therapy in enough patients to show whether it can
actually relieve patientsí symptoms.
While the adverse effects in these studies were disappointing, the increase
in brain lesions in some patients proves that MPB can induce an immune response
in MS and is therefore a good target for MS immunotherapy, the researchers say.
"There is no longer any doubt in my mind that MBP is one target autoantigen
(a protein that triggers an immune response) in MS," says Dr. Martin.
These studies provide valuable information about how to design, refine, and
test targeted immunotherapies. Results from both studies suggest that lower
doses of this therapy are better than higher doses. The adverse reactions found
in these studies were not predicted by previous studies in animals or humans,
which highlights the importance of proceeding carefully with clinical research
even when an experimental therapy looks promising, says Dr. Martin. The NIH
researchers also feel their study demonstrates the importance of immunological
tests to determine how targeted immunotherapies work in patients.
While these studies provide valuable information about APL therapies,
researchers need to determine why some individuals responded differently than
others to this therapy and what dose, frequency, and mode of administration
provide the best results. More carefully controlled clinical trials of this or
similar therapies should eventually reveal the answers to these questions.
(2) Kappos L., Comi G., et al. "Induction of a non-encephalitogenic Th2 autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo controlled, randomized phase II trial. " Nature Medicine, October 2000, Vol. 6, No. 10, pp. 1176-1182.