NATURE M EDICINE • VO LUM E 6 • N UM BER 1 0 • OCTOBER 2000 1167 ARTICLES Multiple sclerosis (MS) is the most frequent demyelinating dis- ease 1 and is characterized by inflammatory demyelinating foci in the brain white matter with variable axonal damage 2–4 . Its etiology remains unknown, but the composition of plaques, immunogenetic background, response to immunomodulation and data from animal models support the idea that MS is an au- toimmune disease mediated by myelin-specific CD4 + T cells 1,5–8 , although there is considerable heterogeneity in clinical charac- teristics, magnetic resonance imaging (MRI) findings and pathological patterns 9,10 . Certain myelin epitopes that are en- cephalitogenic in experimental allergic encephalomyelitis (EAE) are also immunodominant in humans 11–15 in the context of MS-associated human leukocyte antigen (HLA) DR mole- cules 12,16,17 . The myelin basic protein (MBP) peptide of amino acids 83–99 (called MBP (83–99) here) is the best examined and is considered one candidate antigen in MS (refs. 1,18). However, the evidence described above is indirect, and the function of autoreactive T cells for disease pathogenesis has remained controversial. Specific immunotherapies of T cell-mediated autoimmune diseases have been successful in animal models with known target antigens 19–23 . Consequently, there is a strong interest in adopting such approaches for human autoimmune diseases. One strategy uses altered peptide ligand (APL) peptides with amino-acid substitutions in T-cell receptor (TCR) contact posi- tions 24–26 . APLs may block T-cell responses by acting as partial agonists, TCR antagonists or by inducing regulatory T-cell pop- ulations that mediate ‘bystander’ suppression 24,26–30 . We sought to alter disease activity in patients with active relapsing–remit- ting MS using an APL of MBP (83–99) , CGP77116. Here we report the results of our MRI-controlled, single center, baseline-to- treatment cross-over phase II clinical trial as well as comple- mentary immunological studies to elucidate the mechanism of action of APL. Safety and tolerability of APL CGP77116 We sought to assess the safety, tolerability and efficacy on MRI and immunological parameters of 50 mg CGP77116 given sub- cutaneously weekly. The study design stipulated enrollment of 24 patients with relapsing–remitting MS and six monthly clini- cal and MRI examinations as baseline, followed by 9 months of treatment. Th e adverse events encountered in patients MS501–MS507 led to a modification of the dose regimen (from 50 mg weekly to 5 mg weekly for 4 weeks and 5 mg monthly thereafter). Only patient MS601 was enrolled in this lower-dose protocol, and when he suffered an exacerbation that was con- sidered treatment-related, the trial was halted. During the base- line, treatment and post-APL phases, we monitored the course of the neurological status using the expanded disability status scale (EDSS; ref. 31) and the Scripps neurological rating scale (Scripps NRS; ref. 32), and monitored MRI findings by total gadolinium contrast-enhancing lesions and T2 bulk white mat- ter lesion load (BWMLL) (Fig. 1). Only patient MS505 com- pleted the full treatment. All other patients discontinued therapy, for a variety of reasons: exacerbations of MS (patients MS502, MS503 and MS601), systemic hypersensitivity reaction Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: Results of a phase II clinical trial with an altered peptide ligand BIBIANA BIELEKO VA 1 , BONNIE G OODWIN 1 , N ANCY RICHERT 2 , IREN E C O RTESE 1 , TAKAYUKI KONDO 1 , G H AZALEH AFSH AR 1 , BRUNO G RAN 1 , JO AN EATON 1 , JAC K ANTEL 3 , JO SEPH A. FRAN K 2 , H EN RY F. MCFARLAN D 1 & RO LAN D MARTIN 1 1 Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, 2 Laboratory of Diagnostic Radiology Research, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892-1400, USA, 3 Department of Neurology, Montreal Neurological Institute, 3801 University Avenue, Montreal, Quebec H3A 2B4, Canada Correspondence should be addressed to R.M. M yelin-specific T lymphocytes are considered essential in the pathogenesis of multiple sclerosis. The myelin basic protein peptide (a.a. 83–99) represents one candidate antigen; therefore, it was chosen to design an altered peptide ligand, CGP77116, for specific immunotherapy of mul- tiple sclerosis. A magnetic resonance imaging-controlled phase II clinical trial with this altered peptide ligand documented that it was poorly tolerated at the dose tested, and the trial had therefore to be halted. Improvement or worsening of clinical or magnetic resonance imaging pa- rameters could not be demonstrated in this small group of individuals because of the short treat- ment duration. Three patients developed exacerbations of multiple sclerosis, and in two this could be linked to altered peptide ligand treatment by immunological studies demonstrating the encephalitogenic potential of the myelin basic protein peptide (a.a. 83–99) in a subgroup of patients. These data raise important considerations for the use of specific immunotherapies in general. © 2000 Nature America Inc. • http://medicine.nature.com © 2000 Nature America Inc. • http://medicine.nature.com