Emerging drugs for the treatment of adult MOG-IgG-associated diseases

Abstract

Myelin oligodendrocyte glycoprotein (MOG), a member of the immunoglobulin (Ig) superfamily, is a myelin protein expressed at the outermost lamellae of myelin sheaths and oligodendrocytes (OGD) membranes [1,2]. Since MOG expression starts later than other myelin proteins, it is considered a marker of OGD maturation and myelin compaction. Furthermore, its location in the surface of OGD makes it extremely immunogenic and brings antibody binding susceptibility [1,2]. Although in the past anti-MOG-IgG antibodies were related to multiple sclerosis (MS) pathogenesis and proposed as a biomarker of the disease, it was not possible to reproduce this association in subsequent studies, and was considered nonspecific. So far, the presence of serum MOG-IgG can distinguish patients with MOG-associated diseases (MOGAD) from MS and aquaporin-4(AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD), evolving into a new central nervous system (CNS) inflammatory disease [1–3]. However, MOG-IgG have been found in the serum of up to 42% of AQP4-IgG-negative NMOSD patients [4]. The recent development of a reproducible cell-based assay (CBA), considered as the gold standard method for detecting MOG-IgG has improved the ability to correctly identify this entity [3]. Extensive studies in experimental autoimmune encephalomyelitis (EAE; an animal model of MS) models have shown that only antibodies that recognize folded MOG protein are pathogenic, whereas antibodies that solely bind to denatured protein or short synthetic peptides fail to induce demyelination [5]. Thus, CBA enable screening of native-folded MOG protein as an assay substrate [6]. Although titers observed varied significantly both intraand interindividual, a serum dilution > 1:160 was selected to identify people with hightiters of MOG-IgG antibodies [7]. However, the use of MOG-IgG titers for treatment planning is under debate. Using the CBA technique with cells transfected with full-length human MOG (FL-MOG), it is possible to identify positivity in a few healthy individuals and in MS patients, even at relatively high serum dilutions (up to 1: 640). Waters and collaborators have shown that the use of cells transfected with C-terminal truncation of the MOG antigen reduces assay sensitivity, and that many of the low positive antibodies found to bind to FL-MOG result from cross-reactivity of the anti-human IgG (H + L) secondary antibody with IgM [3]. Moreover, flow cytometry data demonstrated an unspecific binding to the surface of MOG transfected cells at low levels in healthy subjects and patients with different diseases, that is detected by anti-human IgG (H + L) or IgM antibodies. The specificity of the test is substantially increased when an anti-human IgG1-specific secondary antibody is used in both flow cytometry and CBA instead of antiIgG (H + L). Thus, IgG1 assay identifies not only the patients above the cutoff with the anti-IgG (H + L) secondary antibody, but also disease-relevant antibodies that fall below this cutoff [3]. Apart for the importance in the diagnosis, MOG-IgG also imply predictive capability in the course of the disease and further treatment. Prevalence and incidence of MOGAD is higher in children than in adult patients [1,2]. The clinical phenotypes can be age dependent with acute disseminated encephalomyelitis (ADEM) and ADEM-like as the predominant presentation in young children, while optic neuritis (ON) and transverse myelitis (TM) is more common in children older than 11 years old and adults [1,2,8,9]. In addition, overlap syndromes with MOGIgG and NMDAR antibodies have been described [8,9]. Classically, MOG-IgG were associated with fewer relapse rates and better functional outcomes than those with AQP4-IgGpositive NMOSD, particularly in pediatric MOGAD patients. However, longitudinal studies have reported relapses in up to 83% of adult MOGAD patients [1,2,10–12] and they present higher risk of relapse and worse functional recovery [13,14] compared to children [14]. Considering that MOGAD is an antibody-mediated inflammatory demyelinating disorder of the CNS that may have a relapsing course, neurologists should consider ongoing treatment with immunosuppressant drugs to prevent future disability. Although there are no evidence-based guidelines for MOGAD treatment, the prognosis in each particular case is uncertain and variable, depending on demographics, clinical and paraclinical factors [1,2]. In this context, recurrent course was more frequently reported in patients with higher MOGIgG titers at onset, particularly during the first months of the disease [13], as well as in patients who remain seropositive despite treatment. By contrast, transient low MOG-IgG titers or