Multiple Sclerosis (MS) is a chronic, typically progressive disease involving damage to the sheaths of nerve cells in the brain and spinal cord. It is the most common inflammatory, demyelinating, and neurodegenerative disorder of the central nervous system (CNS). The symptoms of this unpredictable, disabling disease in many cases, may include numbness, impairment of speech and of muscular coordination, blurred vision, and severe fatigue. This immune-mediated inflammatory disease attacks the long nerve fibers (known as axons) in the central nervous system, destroying the myelin, a kind of insulating sheath around axons, and the same axons. This may occur in variable degrees of damaging, often leading to significant physical disability within 20-25 years in more than 30% of patients. The hallmark of MS is symptomatic episodes that occur months or years apart, affecting different anatomic locations.
There have had some progress in Multiple Sclerosis vaccination. However, until now, vaccines to prevent Multiple Sclerosis may trigger or aggravate the disease, and because of the concomitant use of disease-modifying drugs, when applying the vaccine infectious complications may occur.
CD206-targeted liposomal delivery of co-encapsulated immunodominant myelin basic protein (MBP) sequences MBP46–62, MBP124–139 and MBP147–170 (Xemys) suppressed experimental autoimmune encephalomyelitis in dark Agouti rats. The objective of this study was to assess the safety of Xemys in the treatment of patients with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS, who failed to achieve a sustained response to first-line disease-modifying therapies. In this phase I, open-label, dose-escalating, proof-of-concept study, 20 patients with relapsing-remitting or secondary progressive MS received weekly subcutaneously injections with ascending doses of Xemys up to a total dose of 2.675 mg. Clinical examinations, including Expanded Disability Status Scale score, magnetic resonance imaging results, and serum cytokine concentrations, were assessed before the first injection and for up to 17 weeks after the final injection. Xemys was safe and well tolerated when administered for 6 weeks to a maximum single dose of 900 μg. Expanded Disability Status Scale scores and numbers of T2-weighted and new gadolinium-enhancing lesions on magnetic resonance imaging were statistically unchanged at study exit compared with baseline; nonetheless, the increase of number of active gadolinium-enhancing lesions on weeks 7 and 10 in comparison with baseline was statistically significant. During treatment, the serum concentrations of the cytokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and interleukin-7 decreased, whereas the level of tumor necrosis factor-α increased. These results provide evidence for the further development of Xemys as an antigen-specific, disease-modifying therapy for patients with MS.
Multiple sclerosis (MS) is a chronic neurodegenerative disease with an evident autoimmune background resulting in inflammatory demyelination and axonal and neuronal injury . MS, which was first described in 1868 , is one of the most common diseases of the nervous system. It affects people aged 20–40 years worldwide, although it has a higher occurrence in women than in men and in those residing in northern than in southern latitudes. Despite its long history and the finding that immune cells rather than exogenous pathogens are responsible for MS development , the etiology of MS remains unclear.
Several treatment strategies for MS have been found to be moderately successful . For example, the β-interferons and glatiramer acetate (GA) are disease-modifying therapies with an established history of efficacy and safety in clinical practice [5–7]. In addition, monoclonal antibodies binding to specific ligands have been found effective; these include natalizumab, which binds to α4 integrins ; daclizumab, which binds to CD25 ; and alemtuzumab, which binds to CD52 . Natalizumab and alemtuzumab have been approved by the US Food and Drug Administration for the treatment of refractory MS, while daclizumab approval is very likely in the near future. Despite their effectiveness, however, these agents have been associated with serious adverse events (SAEs), significantly restricting their further application . Novel, convenient oral therapies, including fingolimod , teriflunomide , and dimethyl fumarate , have shown efficacy and tolerability and have been approved for the treatment of patients with MS.
However, some patients remain refractory to these agents. This may be due to as yet unknown triggers of MS, together with high heterogeneity of this disease. Therefore, searching for novel, antigen-specific immunotherapeutic treatment options for MS is highly feasible . For example, myelin basic protein (MBP), the structural component of the myelin membrane, is thought to be a primary target of the immune system during MS development . Attempts have been made to induce tolerance toward MBP and its structural constituents [16–20], including MBP pulsing of dendritic cells . In our previous studies using a newly designed MBP epitope library, we determined that MBP peptides 46–62, 124–139 and 147–170, but not 83-99, were the most immunodominant in terms of autoantibody responses in patients with MS when compared with healthy individuals and patients with other neurological diseases lacking an autoimmune background [22, 23]. Nasal administration of these MBP peptides suppressed protracted relapsing experimental allergic encephalomyelitis (EAE) in dark Agouti rats . Further, selected immunodominant MBP peptides encapsulated into mannosylated liposomes were reported effective in the treatment of EAE . Mannosylation of these liposomes was found critical for their therapeutic efficiency, as animals that received nonmannosylated peptide-loaded liposomes were unable to recover from the first EAE attack. The most reasonable explanation that was confirmed experimentally suggests that mannosylation of liposomes significantly enhances their uptake by dendritic cells via the CD206 receptor , resulting in immune system tolerance towards myelin antigens. The synergistic liposome-mediated effects of coencapsulated MBP peptides reduced overall disease course, resulting in moderate severity of attacks and faster recovery from exacerbations . Preclinical studies showed that administration of the designed formulation, at doses largely exceeding those proposed for humans, did not induce significant AEs in animals. The aim of the present study was to explore the AE profile and tolerability of encapsulated MBP peptides in a cohort of patients with MS. Secondary outcomes were to evaluate the effects of these peptides on the clinical course of MS.