NOVEL FUTURE THERAPEUTIC OPTIONS IN MYASTHENIA GRAVIS, ΜΕΡΟΣ Α’

ABSTRACT

Myasthenia gravis (MG) is an autoimmune disease caused by complement-fixing antibodies against the acetylcholine receptors (AChR). Antigen-specific CD4+ T cells, Tregs and  Th17+ are also necessary. Accordingly, antibodies, B cells, molecules associated with signalling pathways on T helper cells, cytokines and complement are targets for future treatment options in MG. Novel biological agents directed against the following targets are now in the offing: 1) T cell Intracellular Signaling Pathways associated with T cell activation, such as anti-CD52 , anti-IL2-receptor antagonist, anti-Janus tyrosine Kinases JAK1 and JAK3 inhibitors that block intracellular signaling cascade and  anti- costimulatory molecules ; 2) B cells and their trophic factors, directed against key molecules on B cells or the B-cell trophic factors BAFF and APRIL; 3) Complement, directed against C3 or C5 that intercept the formation of Membranolytic attack complex; 4) Cytokines and cytokine receptorstargetingInterleukin-6 which promotes antibody production,  Interleukin-17, the p40 subunit of IL12/1L-23, and GM-CSF; 5) T and B cell migration molecules; and 6) Tissue-specific trophic support stabilizing or enhancing re-synthesis of AChR at the end-plate.  Construction of recombinant AChR antibodies that block binding of the pathogenic antibodies, thereby eliminating complement and antibody-depended-cell-mediated cytotoxicity are new molecular tools. The therapeutic profile of these agents needs to be weighted against excessive cost and rare complications and their efficacy secured with vigorously controlled clinical trials.

1. Introduction

Myasthenia gravis (MG) is caused by target-specific pathogenic antibodies fulfilling all the criteria for a classic antibody-mediated autoimmune disease, as supported by the following:  a) the antigen, the acetylcholine receptor (AChR), is known and well-characterized; b) antibodies against the AChRs are detected and measured in 90% of the patients’ sera; c) the IgG from  MG sera binds in situ to the AChRs at the postsynaptic end-plate and by fixing complement or crosslinking causes degradation of the AChRs and simplification of the postsynaptic junctional folds;  d) the AChR  antibodies are pathogenic because they transmit the disease to experimental animals and cause destruction of the AChRs in cultured myotubes; e) immunization of healthy animals with AChRs leads to clinical signs of myasthenia which  can be subsequently passed to other animals with purified IgG; and f) removal of the pathogenic autoantibodies results in clinical improvement [1-4].  The antibody response is T cell-dependent because regulatory T cells (Tregs) and CD4+ T cells recognize AChR epitopes in the context of MHC class II molecules and exert a helper function on B cells to produce antibodies [4].

Based on the above, MG is probably the most suitable disorder to apply antigen-specific immunotherapies. As recently discussed however [1], such a therapy poses insurmountable difficulties because the autoimmune T cell and antibody responses are highly heterogeneous and, at present, it is not technically possible to specifically target only the sensitized T or B cell populations [ 5,6]. In addition, there are serious safety concerns because for the induction of tolerance and generation of regulatory T cells that recognize disease-inducing epitopes, there is a need to administer high doses of immunodominant (and potentially pathogenic) epitopes, a process that may lead to uncontrolled T cell activation [5].  For these reasons, MG is currently treated with drugs or procedures exerting a non-antigen-specific immunosuppression or immunomodulation, as used for other autoimmune diseases [7]. These therapies have been successful and led to improved survival and quality of life for the majority of MG patients. Although we have done well and we are justified not to consider anymore myasthenia as “gravis”, we need to do better because a number of patients do not respond sufficiently well to the available therapies or suffer severe side effects form the long-term use of steroids or immunosuppressants. Accordingly, there is a need for more effective therapies with long-term benefit and less severe side effects. This paper discusses the targets of future immunotherapies in MG and elaborates on the available biological agents that have the potential to offer targeted therapies, based on the experience we have gained from the application of these agents in other autoimmune diseases.

 

1.1  Immunotherapies In Myasthenia Gravis: THE PRESENT

The current therapies in MG can be subdivided into two categories [1]:

a) Conventional, non-specific therapies that consist of corticosteroids and immunosuppressants. These drugs form the cornerstone of current therapy and have been serving the patients for many years with excellent results, reducing mortality and increasing quality of life.  In spite of all the advances in immunology and immunotherapy however, high doses of corticosteroids, even up to 100 mg daily, are still needed to induce remission and low, every other day doses, are necessary to maintain a response. Immunosuppressive drugs, most often Azathioprine, Mycophenolate Mofetil, Cyclosporine and recently Methotrexate or Tacrolimus, are concurrently used in an effort to reduce, as soon as possible, the high doses of prednisone to the lowest possible every-other day dose that prevent relapses and diminish steroid side effects. The noted immunosuppressive drugs are probably effective in achieving some of these goals, but their effectiveness and tolerability are quite variable, while patient compliance is at times suboptimal. Further, the few conducted controlled trials for some of these drugs were either small or not entirely convincing.  For a chronic disease like Myasthenia Gravis, the combination of these therapies comes at a high cost, as most patients during the long-term therapy suffer several of the known side effects, especially from corticosteroids, necessitating the need for alternative and more effective therapies with less severe side effects.

b) Non-antigen specific- immunomodulating therapies  for short-term benefit, based on Intravenous Immunoglobulin (IVIg) or  plasmapheresis. These modalities are used when there is a need for immediate help, until the aforementioned agents take effect, or during an acute worsening or a crisis [1,7-9]. Although they have provided life-saving benefit to a large number of patients and probably account for the reduced mortality we have observed the last 20 years, both of these therapies are costly and  impractical for  the chronic management of the disease. Further, they exert a transient immunomodulating, but not an immunosuppressive, action that is not expected to bring finality or long-term remission to the ongoing immune process.

The need for more specific therapies with long-term action, has prompted the consideration of new biologic agents, discussed below, as future therapies.

 

1.2  Immunotherapies In Myasthenia Gravis: THE FUTURE

A number of biological agents, currently on the market or in clinical trials for a number of autoimmune disorders, offer target-specific, “missile-like” therapy relevant  to the pathogenesis of MG. They come as:  a) monoclonal antibodies (-mabs), which are chimeric when only the Fc portion of the IgG is human, or humanized when the whole IgG molecule is human except for the hypervariable region that remains from the mouse [1]; and b) therapeutic fusion proteins (-cepts), engineered when the Fc region of IgG1 is fused to the extracellular domain of  the key immune molecules directed against.  An exciting new technology aimed at re-engineering these antibodies to act as molecular decoys [10], is a promising futurist tool very appropriate in MG because the modified therapeutic antibodies can effectively block the binding of the pathogenic antibodies. Although this technique has not yet been tried in humans, it will be briefly discussed because it opens the way for new targeted therapies in antibody-mediated conditions.

To understand the rationale for using the new biological agents in MG, it is appropriate to review the main immunopathogenetic network involved in the disease and highlight the key molecules that we need to target in order to induce tolerance or restore immune balance.

Specific therapeutic targets based on the immunopathogenesis of Myasthenia Gravis

As recently discussed [1], it is unclear what triggers MG but, like all the other autoimmune disorders, the process begins when tolerance is broken probably by infections or molecular mimicry when the AChR protein shares sequence homologies with microbial antigens, resulting in cross reactivity and autoimmunity [1]. When this happens, the AChR is presented via APC’s (probably dendritic cells in the thymus or the periphery) to CD4+ T cells leading to upregulation of key cytokines, such as IL4 and IL6, that stimulate B cells to produce anti-AChR antibodies. These antibodies fix complement at the end-plate region leading to destruction of the AChR’s and simplification of the end-plate region (Figure 1). Involvement of regulatory T cells (Treg) and Th17+ cells is fundamental because they affect antibody production via a Th1/Th2 cytokine balance [11, 12]. Cytokines, such as IL-6, affect the induction of Tregs to pathogenic Th1 cells, while proinflammatory cytokines, such as IL-17A, IL-21, IL-22, which are increased in MG, enhance the immune process maintaining the immune imbalance [6,11,12]. Accordingly, as recently discussed [1] and numerically depicted in figure 1, the targets of action of specific immunotherapeutic drugs applicable for the treatment of MG are directed against the following: 1) molecules involved in T cell activation; 2) antibodies, B cells and B cell trophic factors; 3) complement; 4) FcR of the immunoglobulin molecules aimed for the targeted tissues; 5) cytokines involved in antibody production or immunoregulation; and 6) Treg and Th17+ cells that affect production of antibodies via Th1/Th2 cytokine balance. [1]. Agents against these targets, have been proposed for the treatment of other autoimmune neuromuscular disorders presumably because, at the cellular level, certain immune mechanisms are common in most of these disorders [13-18].