Current And Investigational Therapies Used To Alter The Course Of Disease In Multiple Sclerosis
South Med J 1997 Apr;90(4):367-375
Maimonides Medical Center, Division of Neurology, Brooklyn, NY 11219, USA
Extensive research is under way to develop PharmacoTherapeutic agents that will prevent the exacerbations and the progression of Neurologic Disability associated with Multiple Sclerosis (MS).
The most intensive research strategy has involved agents intended to limit DeMyelination by reducing Inflammation and modifying the Immune Response.
In this category are Interferon-ß-1b, the first compound approved for use outside of clinical trials; Interferon-ß-1a; and Copolymer-1.
Experimental agents include other Interferons, Methotrexate, Linomide, MonoClonal AntiBodies, T-Cell Receptor Peptides, and 2-Chlorodeoxyadenosine.
Although they have been used effectively to treat exacerbations of MS, CorticoSteroids and CorticoTropin are now under evaluation as disease-modifying agents.
A second strategy, enhancing ReMyelination by limiting DeMyelination and Oligodendrocyte injury, is represented by protein Growth Factors.
A third therapeutic approach, improving Conduction in DeMyelinated fibers, is represented by the Potassium Channel Blockers 4-AminoPyridine and 3,4-DiAminoPyridine.
Effects Of Anti-CD4+ AntiBody Treatment On Lymphocyte Subsets And Stimulated Tumor Necrosis Factor- Production: A Study Of 29 Multiple Sclerosis Patients Entered Into A Clinical Trial Of CM-T412
Llewellyn-Smith N, Lai M, Miller DH, Rudge P, Thompson AJ, Cuzner ML
Neurology 1997 Apr;48(4):810-816
National Hospital for Neurology and NeuroSurgery, Dept of Haematology, Queen Square, London, UK
T-Lymphocytes may play a central role in MS. The search for more targeted ImmunoSuppression than is currently available has led to recent clinical trials of novel therapeutics.
We studied 29 patients in a double-blind placebo-controlled trial of the chimeric MonoClonal Anti-CD4+ AntiBody, cM-T412 (Centocor, Leiden, Holland) over a period of 18 months.
Total and differential WBC counts; T, B, and Natural Killer Lymphocytes; CD4+ and CD8+ T-Cells; CD4+ and CD4- naive cells; CD4+ and CD4+- Memory Cells; InterLeukin-2 Receptor- and Major Histocompatibility Class II-positive T-Cells; Serum Tumor Necrosis Factor-alpha (TNF-); and PHA (PhytoHemAgglutinin)/LPS (LipoPolySaccharide)-stimulated whole blood TNF- production were all examined serially in peripheral blood for the duration of the trial.
In addition, for the first two treatment cycles, the above variables were tested 1 and 7 days after treatment.
The results demonstrated significant long-term reductions, lasting up to 12 months after the last treatment cycle in all CD4+ subsets studied, but with a relative preservation of CD4+ Memory Cells as opposed to CD4+ naive cells.
CD4- subsets also showed significant reductions after treatment but returned to baseline levels within 7 days. Monocyte counts were unaffected by cM-T412.
Serum TNF- and 2- and 18-hour PHA/LPS-stimulated TNF- levels were also unchanged in the long term, although significant increases were observed in the 2- and 18-hour PHA/LPS-stimulated TNF- levels the day immediately after treatment.
There was no significant correlation between any of the Immunologic markers studied and MRI measures of disease activity.
Humanization Of A Mouse AntiBody Against Human -4 Integrin: A Potential Therapeutic For The Treatment Of Multiple Sclerosis
Leger OJ, Yednock TA, Tanner L, Horner HC, Hines DK, Keen S, Saldanha J, Jones ST, Fritz LC, Bendig MM
MRC Collaborative Centre, London, UK
4 ß 1 Integrin (VLA-4) is crucial for the adhesion of Leukocytes to human Vascular Cell Adhesion Molecule-1 (VCAM-1) on inflamed Endothelium.
This cell adhesion event is the first step in Leukocyte extravasation across the Blood-Brain Barrier in Inflammatory Diseases of the Central Nervous System (CNS) such as Experimental AutoImmune EncephaloMyelitis (EAE).
Prevention of Leukocyte infiltration by AntiBodies against the 4 Integrin, which block the 4 ß 1 integrin/VCAM-1 interaction, have been shown to suppress clinical and pathological features of EAE.
In this study, two mouse MonoClonal AntiBodies (MAb) directed against human 4 Integrin were analyzed in vitro for their ability to block the interaction of Leukocytes with VCAM-1 under different assay conditions.
The best blocking MAb, AN100226m, was humanized by Complementarily-determining region grafting, associated with human C regions and expressed.
We found that modification of two structural determinants (H27 and H29) for the heavy chain CDR1 loop in one hand, and modification of framework Amino Acid H38, H40 and H44 in the other hand, had no effect on Antigen binding.
In contrast, modification of a structural determinant (H71) for the heavy chain CDR2 loop resulted in loss of binding.
The humanized AntiBody AN100226, was equivalent to the murine AntiBody. AN100226m, in binding to 4 ß 1 Integrin and in blocking cell adhesion.
More importantly, AN100226 was as effective as AN100226m in the reversal of active EAE in guinea pigs and thus may be useful in the treatment of AutoImmune Diseases such as Multiple Sclerosis.
AN100226 is currently in Phase II clinical trials in the UK for the treatment of Multiple Sclerosis exacerbations.
Current Therapy Of Multiple Sclerosis Therapy With MonoClonal AntiBodies To T-Cell Antigens
Schmidt S, Hohlfeld R
Nervenarzt 1996 Feb;67(2):170-176
Max Planck-Institut fur Psychiatrie, Abteilung NeuroImmunologie, Martinsried
This article reviews the theoretical background, the sometimes severe side effects and the possible clinical implications of treatments with MonoClonal Anti-T-Cell AntiBodies in Multiple Sclerosis (MS).
We conclude that there is no indication for treatment with MonoClonal Anti-T-Cell AntiBodies at the present time, except in controlled trials.
Multiple Sclerosis: Update On Therapies
Rinsho Shinkeigaku 1995 Dec;35(12):1505-1507
Kohnodai Hospital, Dept of Neurology
Multiple Sclerosis (MS) is a Chronic Inflammatory DeMyelinating Disease of the Central Nervous System (CNS). It is widely accepted that MS is caused by an AutoImmune response against Myelin.
The most common treatment for acute attacks or active state of exacerbation of MS is IntraVenous pulsed MethylPredonine therapy followed by ImmunoSuppressive agents, such as CorticoSteroid or Azathioprine.
Recently, recombinant Interferon-ß-1b, or natural form of Interferon ß-1a has been reported to have an effect in MS.
We reported preliminary results on a new method of Lymphocytapheresis using a Leucocyte adsorption column to treat MS patients in active state. In some MS patients, immediate improvement was observed following LymphocytaPheresis.
The more selective therapeutic trials including MonoClonal AntiBodies against chimeric CD4, anti-Antigen receptors AntiBody, Anti-Adhesion Molecules AntiBody, and the induction of tolerance to Myelin Basic Protein, or Immunity to TCR antagonist Peptides were reported in several institutes based on new strategies in ImmunoTherapy.
Current And Future Treatment
Of Multiple Sclerosis
Polman CH, Hartung HP
Curr Opin Neurol 1995 Jun;8(3):200-209
Free Univ Hospital, Dept of Neurology, Amsterdam, The Netherlands
During the past year observations have been published that might lead to further improvement in the design of future clinical trials.
At the same time, results of clinical trials have become available that suggest that a number of treatments could be of benefit in the care of patients in the various phases of Multiple Sclerosis.
Future Multiple Sclerosis clinical trials should involve a blinded investigator restricted to assessing the clinical outcome variables, and because current evidence suggests that Magnetic Resonance Imaging gives an objective and sensitive reflection of the biological evolution of the disease, such scanning should also be included.
The use of a composite outcome variable in a trial of Chronic/Progressive Multiple Sclerosis should also be considered in order to increase the percentage of patients reaching the clinical endpoint.
In 1994 recommendations were published for the selection of Relapsing/Remitting patients for treatment with Interferon-ß-1b; furthermore, large and well performed clinical trials demonstrated that Interferon ß-1a and Copolymer-1 are also partially effective, though not curative, for these patients.
Two smaller studies suggested that low-dose Methotrexate and Cladribine might have a beneficial effect on the course of the disease in patients with Secondary Chronic Progressive Multiple Sclerosis, the former drug probably being less toxic.
Unfortunately, therapeutic perspectives for patients with Primary/Progressive Multiple Sclerosis are less promising at present.
Several studies suggest that 4-AminoPyridine and Tizanidine have therapeutic potential for symptomatic treatment; the former by improving Neurological Deficits, the latter by relieving troublesome Spasticity.
Multiple Sclerosis: Immune Mechanism And Update On Current Therapies
Bansil S, Cook SD, Rohowsky-Kochan C
Ann Neurol 1995 May;37 Suppl 1:S87-S101
Univ of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103, USA
Multiple Sclerosis (MS) is a DeMyelinating Disease of the Central Nervous System (CNS) afflicting approximately 250,000 individuals in the United States.
This Inflammatory Disease has variable clinical manifestations, ranging from a Relapsing/Remitting course to a Chronic/Progressive disease.
Approximately one third of MS patients have Chronic/Progressive disease often leading to Severe Impairment of Mobility, Paralysis, poor Vision, and disturbances of Bladder and Bowel Function.
Although the Etiology and PathoGenesis remain unknown, accumulating evidence supports the hypothesis that exposure to an as yet unidentified infectious agent(s) triggers an aberrant Immune Response against self Nervous Tissue in Genetically susceptible individuals.
The tenfold higher concordance rate for MS in Monozygotic twins compared to Dizygotic twins, the increased incidence of MS in women compared to men (2:1), and
the familial and racial occurrence of MS provide strong evidence that Genetic factors influence susceptibility to MS.
The major predisposing Genes in MS are the Human Lymphocyte Antigene (HLA) Class II molecules, DR15 and DQw6, molecularly defined as HLA-DRB1, 1501-DQA1 0102-DQB1 0602.
In certain ethnic groups, MS susceptibility is more strongly associated with other DR molecules.
Environmental factors are also believed to play a role, as suggested by the unique worldwide prevalence, migration effects, and Epidemiological studies.
Increased Serum and CerebroSpinal Fluid AntiBody Titers to numerous Viruses have been reported; however, there have been no confirmed studies detecting Viral RNA or Antigen in MS Brain tissue. At the present time, no known treatment can significantly alter the progression of MS.
Based on the postulate that MS is an AutoImmune Disease associated with abnormalities in ImmunoRegulation, a number of different ImmunoSuppressive and ImmunoModulating agents have been tested as therapeutic modalities.
In this article, we review the circumstantial evidence suggesting that Immune System abnormalities are associated with the disease process, and provide an update on current therapies used in MS.