The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a medical challenge in MS to develop a treatment for progressive forms. The most common injectable disease-modifying therapies in RRMS include β-interferons 1a or 1b and glatiramer acetate. However, one of the major challenges of injectable disease-modifying therapies has been poor treatment adherence with approximately 50% of patients discontinuing the therapy within the first year. Herein, we go back to the basics to understand the immunopathophysiology of MS to gain insights in the development of new improved drug treatments. We present current disease-modifying therapies (interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, mitoxantrone), humanized monoclonal antibodies (natalizumab, ofatumumab, ocrelizumab, alemtuzumab, daclizumab) and emerging immune modulating approaches (stem cells, DNA vaccines, nanoparticles, altered peptide ligands) for the treatment of MS.

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The use of antagonist peptides derived from the myelin sheath constitutes a promising therapeutic approach for multiple sclerosis (MS). Cyclization of peptide analogues is of great interest, since the limited stability of linear peptides restricts their potential as therapeutic agents. Herein, we designed and synthesized a number of cyclic peptides by mutating TCR contact sites of the MBP 83-99 epitope. A number of cyclic analogues were tested for their ability to inhibit (antagonize) Th1 (IFN-gamma) responses, and cyclo(83-99)[A (91)]MBP 83-99 mutant peptide was found to be the most efficient inhibitor. We demonstrated that cyclo(83-99)[A (91)]MBP 83-99 peptide emulsified in CFA enhanced Th2 (IL-4) and antibody responses in vivo. Moreover, immunization of mice with antagonist cyclo(83-99)[A (91)]MBP 83-99 peptide conjugated to reduced mannan enhanced IL-4 responses compared to cyclo(83-99)MBP 83-99 peptide. Thus, cyclized peptides, which offer greater stability and enhanced responses, are novel leads for the immunotherapy of many diseases, such as MS. In particular, cyclo(83-99)[A (91)]MBP 83-99 is a promising mutant peptide analogue for the potential treatment of MS.

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Mutations of peptides to generate altered peptide ligands, capable of switching immune responses from T helper 1 (Th1) to T helper 2 (Th2), are promising candidates for the immunotherapy of autoimmune diseases such as multiple sclerosis (MS). We synthesized two mutant peptides from myelin basic protein 87-99 (MBP(87-99)), an immunodominant peptide epitope identified in MS. Mutations of residues K(91) and P(96), known to be critical T-cell receptor (TCR) contact sites, resulted in the mutant peptides [R(91), A(96)]MBP(87-99) and [A(91), A(96)]MBP(87-99). Immunization of mice with these altered peptide ligands emulsified in complete Freund's adjuvant induced both interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) responses compared with only IFN-gamma responses induced to the native MBP(87-99) peptide. It was of interest that [R(91), A(96)]MBP(87-99) conjugated to reduced mannan induced 70% less IFN-gamma compared with the native MBP(87-99) peptide. However, [A(91), A(96)]MBP(87-99) conjugated to reduced mannan did not induce IFN-gamma-secreting T cells, but elicited very high levels of interleukin-4 (IL-4). Furthermore, antibodies generated to [A(91), A(96)]MBP(87-99) peptide conjugated to reduced mannan did not cross-react with the native MBP(87-99) peptide. By molecular modelling of the mutant peptides in complex with major histocompatibility complex (MHC) class II, I-A(s), novel interactions were noted. It is clear that the double-mutant peptide analogue [A(91), A(96)]MBP(87-99) conjugated to reduced mannan is able to divert immune responses from Th1 to Th2 and is a promising mutant peptide analogue for use in studies investigating potential treatments for MS.

MUC1 is a high-molecular-weight glycoprotein that is overexpressed in adenocarcinomas and hematological cancers. Numerous preclinical studies in mice have demonstrated that MUC1 is immunogenic, and that cellular and humoral immune responses could be induced depending on the MUC1 vaccine formulation. MUC1-based vaccines have quickly entered into human clinical trials, and immune responses and some clinical responses have been reported. Here, we give an up-to-date review of some of the MUC1-based vaccines that have entered clinical trials and their results in cancer patients.

Derangement of cellular immunity is central in the pathophysiology of multiple sclerosis (MS) and is often manifested by abnormal cytokine production. We investigated cytokine secretion in peripheral blood mononuclear cells (PBMC) of 18 MS patients and 15 controls and correlated cytokine polarization with the nature of antigenic stimulus. We synthesized two novel citrullinated peptides, linear [Cit(91), Ala(96), Cit(97)]MBP(87-99) and cyclo(87-99)[Cit(91), Ala(96), Cit(97)]MBP(87-99) that resulted from citrullination of 91,97 Arg residues in antagonists, linear [Arg(91), Ala(96)]MBP(87-99) and cyclo(87-99)[Arg(91), Ala(96)]MBP(87-99) peptides. PBMC from MS patients and controls were cultured with citrullinated peptides, and both peptides caused a Th1 polarization in all MS patients studied. In contrast, culture with noncitrullinated MBP peptides resulted in heterogeneous cytokine secretion that differed between individual patients. Thus, citrullination of self-antigens may potentially trigger disease in susceptible individuals. This finding may open new avenues in drug design of new substances that inhibit citrullination and arrest epitope spreading and worsening of MS.

Until recently, in the pathogenesis of Multiple Sclerosis (MS), the contribution of B cells has been largely underestimated, and the disease was considered a T-cell-mediated disorder. However, newer evidence shows that B cells play a crucial role in the pathogenesis of MS via antigen-driven autoantibody responses and through the cross regulation of T-helper cells. As B cells express the surface molecule CD20 at all points of differentiation, it provides a specific target for monoclonal antibodies, and the development and clinical testing of anti-CD20 antibody treatments for MS have been successful. After some observations, some small clinical trials found positive effects for the first anti-CD20 therapeutic rituximab in MS; newer agents have been specifically evaluated, resulting in the development of ocrelizumab and ofatumumab. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was approved in March 2017 by the Food and Drug Administration (FDA) and is also the first proven therapy to reduce disability progression in primary progressive MS. This is particularly significant considering that disease-modifying treatment options are few for both primary and secondary progressive MS. Ofatumumab, a fully human anti-CD20 monoclonal antibody, that binds a distinct epitope, has been further investigated in phase 3 trials for relapsing forms of MS. In this review, we discuss in detail these two anti-CD20 agents and their advent for treatment of MS.