Monoclonal Antibodies in Neuromyelitis Optica Spectrum Disease: A Systematic Review of Pharmacotherapeutic Alternatives, Current Strategies and Prospective Biological Targets

Abstract

Background: Neuromyelitis optica spectrum disease (NMOSD) is a severe and highly disabling autoimmune astrocytopathy in which humoral immunity, mediated by the presence of autoantibodies, and cellular immunity, through Th17 cells and related cytokines, are key contributors to the pathogenesis. This neuroglial disease affects the central nervous system and is predominantly described in the young productive population. For many years, NMOSD treatment lacked disease-specific therapies and relied on conventional immunosuppressive agents. Progress in elucidating underlying mechanisms of the disease has led to the development and approval of highly specific and effective pathology-modifying drugs. Objective: The objective of this paper is to analyze current and emerging monoclonal antibody-based therapies for NMOSD. Methods: A systematic review of the literature was conducted focusing on approved and investigational monoclonal antibodies targeting major immunopathogenic pathways in NMOSD. Both long-term maintenance therapies and treatments for acute relapses were considered. Results: Targeted monoclonal antibody therapies have significantly transformed the therapeutic management of NMOSD. Drugs directed at B-cell depletion, IL-6 receptor inhibition, and complement blockade have demonstrated substantial efficacy in reducing relapse rates and improving clinical outcomes. Emerging therapies and biomolecular engineering represent promising strategies aimed at further modulating disease activity. These treatments offer improved specificity compared with traditional immunosuppressive regimens and contribute to better long-term disease control. Conclusions: The growing understanding of NMOSD immunopathogenesis has led to the development of highly specific monoclonal antibody-based therapies that have substantially redefined long-term maintenance strategies. Emerging biological targets may expand future therapeutic options. Continued research is essential to optimize individualized treatment approaches and improve outcomes for patients with NMOSD.

1. Search Strategy and Selection Criteria

A systematic review was conducted in August 2025 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Supplementary Materials), utilizing the PubMed, Ovid (including MEDLINE), SciELO, and ScienceDirect databases. Search terms for paper identification were: Neuromyelitis Optica Spectrum Disorders (NMOSD), Devic’s disease, Neuromyelitis Optica (NMO), pharmacotherapy, and monoclonal antibodies. Restriction terms included: MS, Multiple Sclerosis and Diagnosis. Additional filters applied comprised publication type (Clinical Trials, Meta-Analyses, Randomized Controlled Trials, Review Articles, Systematic Reviews, Research Articles, Conference Abstracts, Mini Reviews, and Short Communications), species (humans), timeframe (1 January 2010, to 30 November 2025), and language (English or Spanish).

After applying the search strategy and removing duplicates, 248 records were identified. Studies were excluded if they: (1) were not specific to NMOSD, (2) provided only minimal mention of NMOSD, (3) were unrelated to pharmacological treatment, (4) did not primarily focus on treatment, (5) assessed therapies not involving monoclonal antibodies or focused on treatment withdrawal regimens, (6) were not published in English or Spanish, (7) focused on specific population subgroups, (8) were case reports, case series, phase I trials, bioequivalence studies, or preclinical research, or (9) were inaccessible in full text (Figure 1 and

Table 1. Search strategy and roles chart for selection criteria based on biological targets.

Biological Targets	Specific Antibodies	Key Findings/Clinical Outcomes	Data Extraction & Review (Initials)	Search Confirmation (Initials)
B-cell–Depleting Agents	Rituximab, BAT4406F, Ofatumumab, Divozilimab, Daratumumab, MIL62, Inebilizumab, Ublituximab	Consolidated pharmacotherapeutic strategies—including approved, off-label, and investigational drugs—that reduce the risk of NMOSD attacks	A.S.-C., J.D.V.-R.	V.M.-G.
Interleukin-6 Pathway Inhibitors	Tocilizumab, Satralizumab	IL-6 pathway inhibitors typically demonstrate lower efficacy than other therapeutic categories in NMOSD but offer superior tolerability	A.S.-C., V.M.-G.	R.C.-C.
Complement Inhibitors	Eculizumab, Ravulizumab	Among the most efficacious treatments for NMOSD, frequently demonstrating superior relapse prevention and a rapid onset of action	A.S.-C., R.C.-C.	J.D.V.-R.
In Clinical Development (Maintenance, Acute Relapses)	Gefurulimab, Aquaporumab, Belimumab, Batoclimab, Rozanolixizumab, Bevacizumab	Key trends in the clinical development of monoclonal antibodies for NMOSD include the exploration of diverse biological targets and the glycoengineering of molecules to further optimize their efficacy and safety profiles	A.S.-C., J.D.V.-R., R.C.-C.	V.M.-G.

).

Following these criteria, 70 records were retained. Additional articles were included based on expert opinion, resulting in a final total of 92 publications analyzed. These documents were read in their entirety to assess the appropriateness for their inclusion in this review.

2. Neuromyelitis Optica Spectrum Disease (NMOSD)

For over a decade, neuromyelitis optica spectrum disorders have been considered a complex group of rare, heterogeneous, idiopathic, inflammatory and demyelinating syndromes of the central nervous system (CNS) that preferentially affect the optic nerve, brainstem and spinal cord [1,2]. The presence of a highly sensitive and specific antibody called anti-aquaporin 4 is present in approximately 80% of cases (between 65% and 88% of patients) [3,4]. Recently, a comprehensive review of the diagnostic criteria has highlighted the importance of these antibodies for disease confirmation, thus leading to the new nomenclature of “neuromyelitis optica spectrum disease” and distinguishing it from cases previously classified as seronegative, specifically myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and double-negative NMOSD (DN-NMOSD) [5], which may exhibit clinical overlap with NMOSD [6].

NMOSD is a highly disabling pathology that generally spares the brain and is mostly described in young adults (30–40 years), in female sex and in non-Caucasian ancestry individuals, particularly those of Asian or African descent (estimated prevalence 1–4 per 100,000). In approximately 25% of cases, it is associated with other autoimmune diseases, including systemic lupus erythematosus (SLE), Sjögren’s disease, rheumatoid arthritis (RA), and myasthenia gravis [7,8,9,10,11,12]. Disease phenotypes are influenced by race, with worse clinical outcomes reported among Asian, African, and Latin American populations [12,13].

The disease was first described in 1894 [14] and as in most other autoimmune disorders, the trigger of the pathophysiological cascade is represented by an unknown mechanism of loss of self-tolerance. It is generally characterized by severe, recurrent episodes of optic neuritis, longitudinally extensive transverse myelitis, and the possible presence of area postrema syndrome—manifested by intractable hiccups, nausea, and vomiting [15]. Symptoms such as pain, bladder dysfunction, pruritus, excessive yawning, fatigue, depression, and sleep disturbances are also common in these patients [16,17,18,19,20].

In the absence of treatment, the disease is associated with progressive accumulation of permanent and non-reversible disability (largely due to the frequently incomplete recovery from relapses [7,21]) over a relatively short period of time. It is estimated that among untreated patients, within five years of the first attack, 50% will develop paraplegia and blindness, and approximately one third will die [22,23,24]. Fortunately, therapy has shown beneficial effects on prognosis and mortality rates; therefore, to prevent the accumulation of disability, treatment should be initiated as soon as the diagnosis is confirmed [25,26].

As complete recovery following relapses is less common and acute attacks are frequently associated with persistent deficits resulting from axonal damage, disability in this pathology is often more severe than that observed in multiple sclerosis (MS) [27]. NMOSD was previously conceptualized as a variant of MS; however, distinct clinical, laboratory, immunological (B-cell mediated humoral response in the case of NMOSD) [28,29] and pathological features clearly differentiate the two conditions [30].

Aquaporin-4 (AQP4) is an integral membrane protein for which five isoforms have been described, with M1-AQP4 and M23-AQP4 being the two isoforms more relevant in humans [31]. This protein is highly expressed in the CNS, particularly in the brainstem, hypothalamus, diencephalon, spinal cord, and optic nerves. AQP4 has also been identified in skeletal muscle, lungs, kidneys, stomach, and exocrine glands. Within the CNS, AQP4 is predominantly expressed in the podocytes of astrocytes (adjacent to the blood–brain barrier (BBB)), where it assembles into tetramers that promote the formation of channels regulating the selective passage of water molecules. Specifically, it forms a bidirectional, osmotically driven channel that is impermeable to anions and glycerol [32,33]. Fluid exchange through these channels is critically important for the formation and maintenance of the BBB, as it preserves energy balance and buffers the metabolic load within the CNS [24,34]. Moreover, this exchange has been implicated in the regulation of extracellular glutamate homeostasis [35].

The presence of autoantibodies against aquaporin-4 (AQP4-AB) that belong to the IgG1 subclass and selectively bind to an extracellular loop of AQP4, is an essential feature in the disease pathogenesis [36]. Both in vivo and in vitro administration of these autoantibodies reproduce key aspects of NMOSD, thereby demonstrating their pathogenicity. Accordingly, they are considered intrinsically harmful, as they trigger the classical complement cascade, leading to cytotoxicity (resulting in damage to astrocytes and surrounding cells), focal lesions, disruption of the BBB, and necrosis [1,3,37]. Although it was previously thought that serum levels of these antibodies correlated with clinical disease activity [38], more recent studies have reported a lack of correlation between antibody titers and relapse rates [39,40,41,42].

Although AQP4-AB may be produced within the CNS, their primary source is the circulating compartment, from which they cross the BBB [43,44,45]. This occurs either via endothelial transcytosis, through areas of increased BBB permeability or through regions lacking a BBB [46,47].

AQP4-AB presence also promotes the activation of effector cells, such as natural killer (NK) cells, which induce antibody-dependent cellular cytotoxicity, thereby triggering astroglial damage [48]. Autoantibody binding to aquaporin facilitates complement activation, cytokines derived from astrocytes (particularly interleukin-6 (IL-6)), and attracts inflammatory cells such as eosinophils, neutrophils, and macrophages [49,50]. This process leads to a characteristic perivascular deposition of AQP4-AB and activated complement components, which results in further disruption of the BBB and facilitates additional entry of AQP4-AB into the CNS [51,52,53,54,55]. Eosinophils in turn secrete IL-4, which promotes a T helper 2 (Th2) immune response, thus promoting the synthesis of more autoantibodies [26].

Degranulation of inflammatory cells and astrocytic damage induce secondary injury to oligodendrocytes [56], resulting in accelerated loss of the myelin sheath, deprivation of trophic support, axonal injury (neuronal involvement) and neurological deficits [27,57,58,59].

Moreover, AQP4-AB induces internalization of the water channel [26,60] and loss of glial fibrillary acidic protein (GFAP) in astrocytes. GFAP is a classical biomarker of astrogliosis, and in some lesions, it remains detectable in the absence of AQP4, indicating that AQP4 disappearance precedes astrocyte loss [52,61]. An association between NMOSD disease activity and serum GFAP concentrations has also been reported [62].

Despite the expression of AQP4 in certain tissues and organs outside the CNS, the relative lack of inflammatory signals in these areas in the context of NMOSD has been attributed to higher peripheral co-expression of complement regulatory proteins, such as the complement inhibitor CD59 [63]. In particular, this co-expression is especially diminished in astrocytic podocytes [57,64].

B lymphocyte stimulator (BLyS/BAFF) is a key mediator in the pathogenesis of multiple autoimmune diseases. In NMOSD, it is overexpressed, and this contributes to disease progression by promoting the survival and activity of B cells that produce pathogenic autoantibodies [65,66,67]. Multiple studies have demonstrated elevated levels of BLyS in the serum and cerebrospinal fluid (CSF) of NMOSD patients, as well as a correlation with disability, which has led to the investigation of therapeutic strategies aimed at reducing BLyS levels [68,69]. However, in MS, BAFF inhibition causes alteration of B cell subsets (attenuation of regulatory B cells and increased memory B cells) that enhances inflammatory responses [70].

Although historically considered as an adult disease, pediatric-onset NMOSD has revealed important differences in disease expression, treatment response, and long-term outcomes between children and adults. The pediatric form, defined by onset before 18 years of age, exhibits a lower female-to-male ratio (3:1) and accounts for approximately 3% to 5% of all cases. Pediatric patients frequently present with more severe and widespread relapses, often involving bilateral optic neuritis or extensive spinal cord lesions. Despite this, children tend to demonstrate a more favorable recovery following acute attacks compared to adults, likely reflecting greater neuroplasticity and regenerative capacity, and consequently exhibit a slower rate of disability. Therapeutic use of mAbs in pediatric NMOSD patients is largely extrapolated from adult data. The scarcity of large-scale pediatric trials represents a critical gap, limiting the ability to establish age-specific treatment algorithms [71].

3. Therapeutic Approach to NMOSD

Before disease-modifying therapies (DMTs) received regulatory approval for NMOSD, pharmacological management of the disease was largely based on clinical experience and the use of conventional immunosuppressants. However, the limited effectiveness of azathioprine, mycophenolate mofetil [15], and other less commonly used agents such as cyclosporine A and tacrolimus caused relapses in nearly 50% of patients. Moreover, prolonged or extensive immunosuppression is often associated with serious adverse effects [72,73,74].

The emergence and use of monoclonal antibodies (mAbs) targeting CD20 or IL-6 for indications other than NMOSD, and in the absence of controlled studies supporting their efficacy in NMOSD, facilitated the consolidation of these therapies in “off-label” settings. Under these circumstances, corticosteroids, azathioprine, mycophenolate mofetil, and rituximab became established as first-line treatment options, demonstrating acceptable therapeutic effectiveness in most cases [26,75,76].

NMOSD pharmacological management can be divided into two phases: treatment of the acute attack and maintenance therapy. During the acute phase, management closely resembles that used for relapses in MS and aims to rapidly reverse the attack, primarily through the administration of high-dose corticosteroids or plasmapheresis to maximize reversibility [15,61,76,77]. Maintenance therapy is generally initiated after the first relapse and is intended to prevent future attacks and thereby reduce cumulative disability [74,78]. Consequently, achieving a substantial reduction in the annualized relapse rate (ARR) is a key therapeutic objective [22,79].

In general, DMTs with proven clinical efficacy in MS such as interferons, glatiramer acetate, fingolimod, natalizumab, dimethyl fumarate, and alemtuzumab, are ineffective in NMOSD and may even be harmful [15,71,80,81,82].

Until recently, there were no therapies specifically approved for NMOSD, and most evidence regarding clinical efficacy was derived from manuscripts with low-level evidence, like case reports, observational studies, and expert opinion. However, advances in the understanding of NMOSD pathogenesis, like the discovery of anti-aquaporin-4 antibodies and their role in disease pathophysiology have driven the development and approval of highly specific and effective DMTs for the management of patients with NMOSD [24,83,84,85].

As in other areas of medicine, the management of NMOSD has been strongly influenced by monoclonal antibodies. These agents have demonstrated a broad range of benefits due to their high specificity, translating into greater efficacy and fewer adverse effects compared with conventional treatments [73,86,87,88]. The expanding understanding of NMOSD has enabled the identification of multiple therapeutic targets suitable for monoclonal antibody-based interventions, including B-cell depletion, interleukin-6 (IL-6) receptor blockade, and complement inhibition. The most common adverse effects associated with monoclonal antibodies include upper respiratory and urinary tract infections, headache, and infusion-related reactions. Other less frequent but more serious adverse events may involve meningococcal infection, progressive multifocal leukoencephalopathy (PML), and reduced immunoglobulin levels [89].

4. Maintenance Therapies

4.1. B-Cell-Depleting Agents

Although the primary immunizing event in NMOSD remains unknown [90,91], converging evidence from clinical and laboratory studies indicates that B cells play a central role in the immunopathogenesis of the disease [65,92]. In particular, this occurs via autoantibody production, increased activity of pro-inflammatory B cells and plasmablasts, as well as other mechanisms such as checkpoint dysregulation, impaired regulatory function, and loss of B-cell anergy [65,93]. Even though modulation of B-cell responses influences disease activity, B-cell depletion alone is insufficient to induce complete remission in NMOSD patients [94]. This suggests that humoral immunity mediated by short-lived plasmablasts may not be the sole factor involved in disease pathogenesis [95]. Similarly, a proportion of patients treated with B-cell-depleting therapies experience new relapses, a phenomenon that may be related to the persistence of long-lived antibody-secreting cells that do not express CD20 or CD19 [96,97]. Although CD19 cells play an important role during neuromyelitis optica attacks, increased peripheral B-cell concentrations have not been observed during these episodes [98].

The main adverse effects of B-cell depletion are secondary immunodeficiencies, such as hypogammaglobulinemia with reduced serum levels of immunoglobulin M (IgM) and immunoglobulin G (IgG) [99]. These reductions are associated with an increased risk of common and severe infections, as well as the potential development of malignancies [100].

4.1.1. Anti-CD20 Monoclonal Antibodies

CD20 is a surface glycoprotein with four transmembrane domains that is highly specific in B-cell lineage [101], although it may also be expressed on some T cells [55]. This protein is involved in B-cell activation, differentiation, and calcium transport. Anti-CD20 monoclonal antibodies can be classified into two types, based on whether antigen binding induces reorganization of CD20 molecules into lipid rafts (dynamic microdomains of the cell membrane enriched in cholesterol and sphingolipids). Type I mAbs (rituximab, ocrelizumab, ofatumumab, and ublituximab) promote reorganization of these microdomains and activate the complement pathway, resulting in high complement-dependent cytotoxicity (CDC). In contrast, type II mAbs (obinutuzumab) do not induce CD20 reorganization and show limited CDC induction, but can promote direct cell death upon antigen binding. These differences between type I and type II anti-CD20 mAbs do not translate into differences in their ability to induce antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) [102].

Rituximab

Rituximab (RTX) was the first chimeric (murine/human) IgG1 monoclonal antibody directed against CD20 (Figure 2). CD20 is expressed on pre-B cells, mature B lymphocytes, and memory B cells, but not on plasma cells (Figure 3). Accordingly, RTX primarily acts by depleting plasma cell precursors, as CD20 expression is restricted to the late pre-B-cell stage and is maintained until B lymphocytes differentiate into antibody-producing plasma cells, at which point CD20 expression is typically downregulated. To date, no endogenous ligands for CD20 or its precise physiological function have been identified, and the mechanisms regulating CD20 expression therefore remain incompletely understood [103].

B-cell depletion following RTX treatment may persist for up to 12 months (before regeneration), and serum AQP4-AB levels are reduced or remain low after therapy [104]. It is generally understood that RTX does not alter the proportion of autoreactive and polyreactive B cells and therefore does not restore defective early B-cell tolerance checkpoints [105]. However, recent reports indicate that treatment with this mAb for 6 months to one year may induce beneficial changes in B-cell populations [106].

Three potential, not necessarily exclusive, mechanisms of action have been proposed for RTX-mediated B-cell depletion, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and activation of the intrinsic apoptotic pathway (Figure 4) [107,108]. In addition, it has been suggested that in certain conditions RTX may exert immunomodulatory effects similar to nonspecific intravenous immunoglobulin (IVIg), as in vitro studies using conventional doses demonstrated inhibition of C3a and C5a calcium-induced responses, as well as blockade of cell migration and circulatory effects mediated by C5a in vivo [109,110,111].

Indicated for the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, RA in adult patients, and autoantibody-associated vasculitis [112], RTX has been widely used off-label for the treatment of NMOSD. Even though more than 50 retrospective and prospective studies have provided compelling evidence that it reduces relapse rates and expert groups have recommended RTX use, it still does not have regulatory approval for NMOSD in many latitudes. Recently, following the development and implementation of an academic, randomized, double-blind, placebo-controlled clinical trial demonstrating a 50–90% reduction in ARR, it received approval in Japan for NMOSD treatment [113,114,115]. Subsequent meta-analyses have confirmed a significant reduction in ARR, a greater effect compared to azathioprine, and improvements in disability as measured by the Expanded Disability Status Scale (EDSS) [116,117,118]. Notably, reductions in ARR do not correlate with age at disease onset, disease duration, infusion dose, length of follow-up, or AQP4-AB serostatus [22,98,119,120].

RTX is most frequently administered at a dose of 1 g intravenously every six months following an induction period of two infusions of 1 g on days 1 and 15. However, dosage regimens of RTX in NMOSD are highly heterogeneous. Some authors administer it at fixed intervals [120], whereas others tailor reinfusions based on peripheral CD19 B-cell monitoring [121] or CD27 B-cell levels [122], or use mixed protocols [123,124]; therapeutic failure in some cases may be corrected by adjusting dosing regimen. There is broad consensus that therapy is more effective when initiated before disease symptoms become severe.

The most common adverse reactions to RTX in NMOSD treatment are mild infusion-related reactions (including flu-like syndrome, urticaria, hypotension, angioedema, and bronchospasm), which can be mitigated by premedication and slow infusion rates. Respiratory or urogenital infections, particularly in patients with reduced mobility [125] are also frequently described. RTX usage has been associated with hypogammaglobulinemia, neutropenia, and increased levels of B-cell activating factor (BAFF) [126]. In general, the frequency of adverse events increases with longer treatments. Initiation of rituximab therapy immediately after an acute relapse is not recommended, as disease exacerbations have been reported in such cases, particularly in the period immediately following infusion. Events presumably related to a sudden increase in pro-inflammatory cytokines are likely triggered by RTX [127,128,129].

RTX treatment may lead to reactivation of opportunistic infections, such as herpetic rash and tuberculosis [130]. Although reports in the context of NMOSD treatment are limited, RTX (similar to other immunosuppressive biological agents) is considered a potential risk for the development of PML, a rare and often fatal demyelinating disease of the CNS caused by the John Cunningham virus [131]. Cases of hepatitis B virus reactivation have also been described [132]; therefore, screening for hepatitis B and C is advisable prior treatment initiation. An overall mortality rate of approximately 1.5% has been reported among patients receiving RTX; however, underlying causes have not been clearly identified [61].

Approximately one quarter of NMOSD patients are refractory to RTX treatment, and the persistence of long-lived antibody-secreting cells that do not express CD20 or CD19, resulting in sustained humoral autoimmunity [133,134,135,136], is a possible explanation. The efficacy of the drug is also strongly influenced by its interaction with the FcγR3A receptor (also known as CD16) expressed on natural killer (NK) cells, which serve as effector cells. This interaction triggers antibody-dependent cellular cytotoxicity (ADCC), a process whereby NK cells, activated upon engagement with rituximab-coated target cells, mediate the elimination of these cells (in this context, CD20 B-cells). The presence of the single-nucleotide polymorphism rs396991, that results in a valine-to-phenylalanine substitution at position 158 (FCGR3A-V158F) reduces the affinity between NK cells and the mAb, leading to diminished NK-cell cytotoxicity and consequently, a reduced therapeutic response [15,124,137,138,139].

The therapeutic effectiveness of RTX may be further compromised by the generation of anti-rituximab antibodies (ARA) due to the immunogenic nature of its murine component, together with its restricted capacity to cross the CNS [15,140,141,142,143]. However, clinical efficacy does not appear to be significantly influenced by factors such as sex, age at symptom onset, baseline disability, time to treatment initiation, number and nature of previous therapies, or pre-treatment ARR [123,144,145]. Similarly, treatment response does not seem to be determined by seropositivity [121]. However, an insufficient response to rituximab has been observed in some MOGAD patients [104]. No standardized criteria exist to identify patients who are most likely to respond favorably to RTX, nor are there universally accepted guidelines to determine the optimal dosing and treatment frequency.

Given the elevated risk of relapses observed in NMOSD patients during the postpartum period [146], together with the expression of AQP4 in placental tissue and the potential for pathogenic autoantibodies to induce placentitis and increase the risk of spontaneous abortion [147,148], the use of RTX in this setting has been explored. Although some authors consider it to be relatively safe [149,150], partly because mAbs are not actively transported to the fetus until the second trimester [151], its use remains highly controversial [152,153] and should be critically assessed [154]. This caution is warranted because, despite the absence of adverse effects on embryonic development in preclinical studies, human data are still limited. B-cell-depleting mAbs such as rituximab and inebilizumab can cross the placental barrier, and transient hematological abnormalities have been reported in exposed infants [150,155,156]. Even though the strength of evidence varies among individual mAbs, no therapies currently used for NMOSD are considered completely safe or have been proven harmless to the fetus [157]. Therefore, women with childbearing potential should be advised to use an effective contraception method during treatment. Although rituximab concentrations in breast milk are low and gastrointestinal absorption in the infant is unlikely [158,159], all mAbs can be excreted by milk in varying degrees, and their effects on breastfed infants remain incompletely understood. RTX has also been used off-label in pediatric NMOSD, demonstrating a reduction in the ARR, and in some cases, almost a complete suppression of relapses [160,161].

NMOSD treatment with RTX is considerably less expensive than treatment with indication-approved mAbs such as eculizumab, satralizumab, ravulizumab and inebilizumab and is currently the most prescribed drug for this condition [90,162].

Other Anti-CD20 Antibodies Under Investigation

Targeting the same therapeutic pathway, several additional anti-CD20 mAbs show potential utility in NMOSD management. These agents are either under development or have previously demonstrated efficacy or effectiveness in other indications, potentially expanding future treatment options for NMOSD. Among the most notable are BAT4406F, ofatumumab, and ocrelizumab.

• BAT4406F

BAT4406F is a fully human monoclonal IgG1-type antibody that has undergone modifications in its immunoglobulin glycosylation pattern, an aspect that enhances ADCC. Both in vitro studies and animal models have demonstrated sustained dose-dependent B-cell depletion and significantly superior activity when compared with ofatumumab, ocrelizumab, and rituximab [163]. Clinical studies in humans have shown a favorable safety and tolerability profile, relatively low immunogenicity, and a significant effect on B-cell depletion [164]. After receiving a positive recommendation from an independent data monitoring committee, patient enrollment for the pivotal phase 2/3 trial [165] was completed and regulatory approval is expected in the near future.

• Ofatumumab

Ofatumumab is a recombinant, fully human IgG1 kappa monoclonal antibody directed against the CD20 antigen expressed on human B lymphocytes. It is currently indicated for the treatment of refractory chronic lymphocytic leukemia, relapsing–remitting multiple sclerosis, and clinically isolated syndrome. The main adverse effects reported with ofatumumab are those typically associated with B-cell depletion [166]. Owing to its potential utility, ofatumumab has recently been investigated in NMOSD treatment and has shown promising efficacy, with a significant reduction in relapse rates reported in emerging studies [167,168,169].

• Divozilimab

Divozilimab is a humanized IgG1 kappa monoclonal antibody targeting the CD20 antigen on B lymphocytes. Results from a recently published open-label phase III clinical trial (AQUARELLE) [170] evaluated the efficacy and safety of divozilimab compared with placebo in NMOSD patients. The study demonstrated a reduction in the ARR along with an acceptable tolerability profile [171]. However, certain methodological aspects of the trial warrant cautious interpretation of the findings and suggest the need for additional confirmatory evidence.

• MIL62

MIL62 is a type II anti-CD20 monoclonal antibody. It has been structurally engineered to remove nearly all fucose residues from the N-glycans in its Fc region, thereby increasing its affinity for the FcγR3A receptor. In vitro studies have demonstrated enhanced ADCC when compared with RTX and obinutuzumab, while in vivo experiments have shown significant inhibition of CD20-positive B-cell growth. A phase I study further demonstrated that MIL62 presents a manageable safety profile [172,173]. More recently, in a double-blind, placebo-controlled phase III trial [174], MIL62 significantly reduced the risk of relapse (by 93.1%) and slowed disability progression in NMOSD patients. The most frequently reported adverse events included infusion-related reactions, elevated liver enzymes and decreased lymphocyte counts.

• Ocrelizumab

Ocrelizumab is a humanized, type I IgG1 monoclonal antibody designed for B-cell depletion via CD20 targeting. While officially indicated for relapsing–remitting and primary progressive multiple sclerosis, its mechanism of action also supports off-label use in NMOSD. However, clinical evidence for its efficacy in NMOSD remains limited compared to other established anti-CD20 agents like rituximab. Safety considerations include increased susceptibility to infections, potential malignancies, and the rare risk of PML [175].

4.1.2. Anti-CD19 Monoclonal Antibodies

Inebilizumab

Inebilizumab (MEDI-551) is a humanized IgG1 kappa monoclonal antibody directed against the CD19 surface antigen (Figure 2), specifically targeting the extracellular loop of the protein, which is expressed on B lymphocytes. In June 2020, it was approved by the U.S. Food and Drug Administration (FDA) for the treatment NMOSD, following the early termination of its pivotal trial due to clear evidence of clinical efficacy [176,177] (Table 2). Although the precise mechanism underlying B-cell depletion remains incompletely understood, its activity appears to be mediated primarily through ADCC. In contrast to the anti-CD20 monoclonal antibody RTX, inebilizumab does not induce complement-dependent cytotoxicity [178].

Inebilizumab selectively targets B cells without significantly affecting other immune cell lineages [179,180]. Unlike the transmembrane protein CD20, CD19 is more broadly expressed across nearly all stages of B-cell maturation, including pro-B cells, plasmablasts, and terminally differentiated antibody-producing plasma cells (Figure 3) [119,180]. This broader cell target cell may represent an advantage over anti-CD20 mAbs, as it could enable more comprehensive depletion of pathogenic antibody-producing cells [55,181].

Because CD20 and CD19 expression overlaps across various stages of B-cell development, treatment with MEDI-551 also results in a reduction of CD20 B cells, leading to an extended B-cell depletion. Furthermore, CD19 protein is selectively expressed on B cells, whereas CD20 can also be expressed on T-cell populations [182,183].

In addition, inebilizumab was designed to exhibit a substantially higher affinity (10-fold) for the FcγR3A receptor of NK cells (effector cells). This enhanced affinity is achieved through reduction or elimination of fucose residues in the Fc region [184]. Consequently, in vitro studies have shown that lower concentrations were required to achieve primary depletion of human B cells when compared with RTX [178,180].

Before initiating inebilizumab treatment, active hepatitis B infection and latent or active tuberculosis must be excluded, as MEDI-551 is contraindicated in these settings. It is also important to screen for other active infections due to the risk of reactivation [46]. As with other B-cell-depleting therapies, monitoring serum immunoglobulin levels during treatment is advisable, given the risk of opportunistic or recurrent infections associated with hypogammaglobulinemia [185]. It remains uncertain whether this extended B-cell depletion confers a higher risk of hypogammaglobulinemia compared with CD20 depleting therapies [55].

While CD19-directed B-cell depletion eliminates a major source of pathogenic autoantibodies, pre-existing humoral immunity against pathogens such as influenza, tetanus, measles, mumps, rubella, and poliovirus remains intact, as it is maintained by CD19-negative cells [55]. However, live attenuated virus vaccines should not be administered in the 4 weeks prior to the introduction of inebilizumab.

MEDI-551 is degraded by proteolytic enzymes and is not metabolized by cytochrome P450 enzymes; therefore, the risk of drug–drug interactions is low [186]. It has an elimination half-life of approximately 18 days [46,187] and is administered intravenously at a dose of 300 mg. Treatment is initiated with a first infusion followed by a second dose two weeks later, with subsequent administrations given every six months [185].

Compared with placebo, studies of inebilizumab have demonstrated a significant reduction in the risk of attacks. Notably, efficacy was assessed as the risk of experiencing an attack in patients with active disease (defined as at least one attack requiring treatment in the year prior to enrollment or two attacks within two years) rather than as the ARR [188]. This protective effect appears to increase after the first year of treatment, similar to observations with other B-cell-depleting therapies [127,189], and is independent of race or ethnicity, body mass index, or baseline disability.

In comparison to other NMOSD therapies, inebilizumab has demonstrated a statistically significant reduction in disability worsening, measured by the EDSS (despite scale limitations as an outcome measure in NMOSD trials) [15,176,177,190]. Relative to placebo, inebilizumab use has also been associated with fewer new lesions and reduced hospitalization rates [119,185,191]. More recently, case reports have suggested that combination therapy with intravenous corticosteroids during the acute phase may significantly enhance visual recovery [192].

Overall, inebilizumab is generally well tolerated, and most adverse events are mild to moderate in severity. The most frequently reported side effects include infusion-related reactions, urinary tract infections, arthralgia, ocular pain, nasopharyngitis, headache, mild neutropenia, and back pain [177,185]. Immunoglobulin levels should be monitored before and during treatment due to the potential development of hypogammaglobulinemia and the associated increased risk of bacterial infections [193,194]. The risk of hypogammaglobulinemia may be higher with anti-CD19 therapies compared with anti-CD20 treatments, given that CD19 is expressed across a broader spectrum of B-cell populations.

Although no confirmed cases of malignancy or PML have been reported during inebilizumab therapy, these conditions remain as potential risks, given they have been described in patients receiving other B-cell-depleting antibodies [195]. During clinical trials, two deaths were reported in association with newly identified brain lesions; however, it remains unclear whether these were attributable to acute disseminated encephalomyelitis, an atypical NMOSD relapse, or PML [177]. More recently, a case of marked creatine kinase elevation accompanied by generalized myalgia was described [196]. Similar to other therapeutic monoclonal antibodies, recent case reports have described its use in pediatric NMOSD as both safe and useful in the prevention of further relapses.

4.1.3. Anti-CD38 Monoclonal Antibodies

Daratumumab

Daratumumab is a fully human IgG1 kappa monoclonal antibody directed against the transmembrane glycoprotein CD38 (Figure 2), which is predominantly expressed on antibody-secreting cells. CD38 is involved in receptor-mediated adhesion, cellular signaling, and modulation of cyclase and hydrolase activity [197,198]. Daratumumab reduces circulating plasmablasts and plasma cells through CDC and ADCC [199], making it the first clinically relevant anti-CD38 monoclonal antibody, widely used in the treatment of multiple myeloma. More recently, several case reports and small series have described the efficacy of daratumumab in the management of autoimmune disorders refractory to conventional therapies [200]. Overall, daratumumab is generally well tolerated; however, infusion-related reactions are common and often require prolonged infusion times. Other reported adverse events include hypogammaglobulinemia and increased infection [163]. Notably, the recent transition from intravenous to subcutaneous formulations has been associated with a lower incidence of infusion-related reactions [201]. Its potential role as a maintenance therapy in NMOSD is currently under investigation [202].

4.2. Interleukin-6 Pathway Inhibitors

Cytokines produced by Th17 helper cells, including interleukin-6 (IL-6) and interleukin-17 (IL-17), as well as cytokines produced by Th2 helper cells, such as IL-5 and IL-13, are elevated in the serum and CSF of patients with NMOSD [203,204,205]. Human IL-6 is a soluble cytokine composed of 212 amino acids, encoded by a gene located on chromosome 7p21; while its unglycosylated core protein has a molecular weight of approximately 20 kDa, the native forms range from 21 to 26 kDa as a result of glycosylation [206]. IL-6 can be produced by a wide range of cells, including immune cells such as monocytes, macrophages, T cells, and B cells, as well as non-immune cells such as fibroblasts, vascular endothelial cells, epithelial cells, adipocytes, neurons, and astrocytes. IL-6 participates in the mediation of inflammatory and immune responses across multiple systems and pathways, predominantly activating the intracellular Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling pathway [207].

IL-6 generally exerts a pro-inflammatory effect, particularly in the context of chronic inflammatory conditions, an aspect that has also been implicated in the development of pain and fatigue characteristic of certain diseases [208,209]. This cytokine is also involved in complement regulation, especially C3 levels, primarily by enhancing its production and functioning as a link between innate and adaptive immune responses, a feature that may contribute to specific pathological processes [210,211].

Multiple lines of evidence implicate IL-6 in the pathophysiology of NMOSD, where it is released primarily by CD4 T cells and astrocytes [207,212]. IL-6 crosses the BBB and within the CNS, increased levels exacerbate demyelination and neurological deficits [213,214]. This cytokine is also elevated during NMOSD relapses [215], and in animal models like experimental autoimmune encephalomyelitis (EAE), a widely used animal model of autoimmune inflammatory disease [216], although increased levels of this molecule are uncommon in MS and other neurological disorders [217,218]. In NMOSD, IL-6 levels correlate with autoantibody titers, BBB dysfunction, disease severity and progression [50,213,219,220,221]; consequently, it is considered a marker of disease activity.

IL-6 also promotes the mobilization of inflammatory cells, stimulates the differentiation pathway of Th17 helper cells—which, as previously mentioned, are characterized by the production of IL-17 and other cytokines such as IL-21, IL-22, and IL-23 that contribute to inflammation and immune cell recruitment—and inhibits the activation of regulatory T cells [188,222]. In addition, this cytokine promotes the survival of plasmablasts, a B-cell subpopulation capable of producing and secreting autoantibodies, including AQP4-AB [29,54,223]. IL-6 also induces the production of vascular endothelial growth factor (VEGF), thereby enhancing angiogenesis and increasing vascular permeability [224]. Consequently, blockade of the IL-6 receptor leads to reductions in AQP4-AB levels, complement proteins, C-reactive protein, and fibrinogen, and is associated with clinical improvement [211].

There are two IL-6 signaling pathways: classical and trans-signaling (Figure 5). Classical signaling is considered an anti-inflammatory pathway in which the cytokine binds to a membrane-bound receptor on specific cells and subsequently forms a complex with gp130, promoting regenerative functions such as the acute-phase response. In contrast, trans-signaling is a predominantly pro-inflammatory pathway that is initiated when IL-6 binds to a soluble receptor, forming a complex capable of activating any cell that expresses the signaling receptor gp130, even in the absence of a membrane-bound IL-6 receptor. This mechanism favors inflammatory processes such as those observed in RA and COVID-19 [225].

Both pathways activate the downstream JAK/STAT3 signaling cascade [226]; however, trans-signaling is particularly relevant because of its broader reach, as it involves a much wider range of cell types, including endothelial cells and fibroblasts. For this reason, it is often referred to as the “amplifier” arm of the IL-6 signaling pathway [227] (Figure 5).

Certain tumor cells and tumor-associated fibroblasts are major sources of IL-6 production and secretion within the tumor microenvironment, thereby promoting overexpression of this cytokine in this setting. This increased IL-6 availability has been associated with immunopathogenic effects linked to tumor growth, metastasis, and therapeutic resistance [228].

IL-6 pathway inhibition can be achieved through several strategies, including the use of direct IL-6 inhibitors, IL-6 receptor blockers, direct gp130 inhibitors, JAK inhibitors, and STAT3 phosphorylation blockers [229]. Designer proteins (monoclonal antibodies/fusion proteins), such olamkicept (sgp130Fc), with selective effects on the IL-6 trans-signaling pathway, are in development. This approach may reduce adverse effects associated with global IL-6 blockade [230,231].

The inhibition of the IL-6 pathway may increase the activity of several cytochrome P450 (CYP450) enzyme isoforms—specifically CYP1A2, CYP2C9, CYP2C19, and CYP3A4—which can lead to reduced plasma levels of certain medications, including omeprazole, warfarin, statins, cyclosporine, and oral contraceptives [157]. Consequently, caution is warranted when co-administering drugs, particularly prodrugs with narrow therapeutic range that are substrates of these isoforms [205].

In the management of NMOSD, IL-6 pathway inhibitors do not demonstrate the highest efficacy compared with other therapeutic categories but are generally associated with better tolerability profiles [90].

4.2.1. Satralizumab

Satralizumab (SA237) is a humanized IgG2 kappa monoclonal antibody produced in Chinese hamster ovary cells using recombinant technology. Specifically developed for NMOSD, it is a modified version of tocilizumab (TCZ) and similarly targets the interleukin-6 receptor (IL-6R) (Figure 5). Through amino acid sequence alterations in the complementarity-determining regions (CDRs) and in the variable and constant domains, its affinity for IL-6R has been optimized [191].

Satralizumab inhibits IL-6 signaling pathways by binding to both soluble and membrane-bound IL-6 receptors with high affinity at physiological pH, thereby reducing inflammation and subsequent autoimmune activation (including BBB dysfunction). This mechanism appears to underlie its therapeutic effects in NMOSD [232].

Unlike conventional antibodies that bind to their antigen once, satralizumab can repeatedly bind to IL-6R, prolonging its circulation time in the organism [61,233]. This process occurs after the internalization of the antibody–antigen complex via vesicle formation and subsequent endosome generation. In the late stage, the organelle exhibits an acidic environment (pH 5.5–6.0), which promotes dissociation of satralizumab from IL-6R and its transport back to the plasma membrane, where it is released into the circulation and can bind again to another IL-6 receptor at physiological pH (mechanism known as recycling technology) [191,234,235].

This recycling technology allows for an extended dosing interval, enabling once-monthly administration, in contrast to TCZ, which is dosed every one to two weeks. Satralizumab exhibits approximately fourfold higher affinity for the IL-6 receptor compared with TCZ [214] and it is the only NMOSD-approved mAb administered via the subcutaneous route.

Clinical studies have demonstrated that satralizumab significantly reduces the risk of relapse (defined as time to first relapse) compared with placebo in seropositive, but not in MOGAD or double-negative patients. Its use is associated with a reduction in disability [204]; however, it has not been correlated with improvements in pain or fatigue [234,236], despite well-established evidence implicating IL-6 in neuropathic and inflammatory pain pathways [237]. Satralizumab has also been reported to have a relatively slower onset of action compared to eculizumab [238].

Adverse events associated with the use of satralizumab generally occur within 24 h after its administration and include injection-site reactions, reductions in neutrophil and platelet counts, arthralgia, elevations in liver enzymes, and increased cholesterol levels [205,220]. In most cases, these changes are transient and resolve without the need for dose interruption [234,239], although continuous monitoring is recommended. Cases of respiratory and urinary tract infections have also been reported [236,239]. Although satralizumab therapy does not appear to result in a significant loss of immune surveillance [57], its use is contraindicated in patients with hepatitis B and active or untreated latent tuberculosis.

Some case reports suggest that satralizumab use may be safe during pregnancy and breastfeeding, showing minimal or no transfer to the fetus or infant [240]. Satralizumab was first approved in 2020 in Canada as monotherapy or combination therapy for adults and children aged 12 years or older, making it the only NMOSD treatment approved (with an adequate efficacy and safety profile) for use in adolescents [69] (Table 2). It is currently under investigation for the treatment of thyroid eye disease [241].

4.2.2. Tocilizumab

Tocilizumab (TCZ) is a humanized IgG1 kappa-type monoclonal antibody directed against the α subunit of the IL-6 receptor (IL-6R) (Figure 2), targeting both membrane-bound and soluble forms. By preventing the binding of the endogenous ligand to the IL-6R α subunit, TCZ inhibits both classical and trans IL-6 signaling pathways. Through this mechanism of action, it blocks inflammatory signal transduction and is approved for the treatment of moderate to severe RA, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, juvenile idiopathic arthritis, and cytokine release syndrome [242].

Reports indicate that binding of TCZ to the IL-6 receptor may paradoxically lead to increased circulating IL-6 levels [243,244], a phenomenon attributed to receptor occupancy by the drug and the pharmacokinetics of complexes formed with soluble IL-6R. Nevertheless, it is well established that as long as free TCZ remains present in the circulation, IL-6 signaling is effectively inhibited [245]. Similarly, in some patients, autoantibody titters may remain persistently elevated during TCZ treatment [246,247]. This lack of correlation between autoantibody levels and relapse activity—previously described in other cohorts [39,40]—may indicate the involvement of additional pathogenic mechanisms influencing disease activity.

Despite being used off-label in NMOSD, TCZ is considered an escalation or rescue therapy for highly active disease [45,194] (Table 2). It is typically administered intravenously at doses of 6–8 mg/kg every 4–6 weeks or subcutaneously at a dose of 162 mg every 1–2 weeks [248] and has demonstrated a consistent reduction in relapse rates [73,249], including in patients who have not responded to RTX [250,251,252]. However, its effects on reducing disability, fatigue, or pain are inconsistent [71,220,236,248,253]. The effectiveness of the subcutaneous route in NMOSD appears to be comparable to that reported for intravenous formulations [254].

A study that analyzed the rates of spontaneous abortion, congenital anomalies, and other pregnancy outcomes in RA patients treated with TCZ found no differences when compared with the general population [255]. Accordingly, the use of TCZ during pregnancy in patients with severe disease, as well as its use during breastfeeding under close monitoring, has been recommended by an expert consensus [256]. Data on the use of TCZ in pediatric NMOSD is limited and relies on scarce case reports, in which the therapy has been associated with clinical stabilization, without an increased frequency of infections or the adverse events typically observed in adults.

Respiratory and urinary tract infections, leukopenia, lymphopenia, neutropenia, anemia, hypercholesterolemia, and coagulation abnormalities are the most frequently reported adverse events associated with TCZ in NMOSD patients [157,236]. However, serious infections such as pneumonia, cellulitis, and diverticulitis, as well as intestinal perforation, have been reported with the use of this medication in RA. The latter has been attributed to the role of IL-6 in preventing intestinal epithelial apoptosis and supporting tissue regeneration [257,258]. Prescribing information also includes warnings regarding the risk of tuberculosis, invasive fungal infections, and opportunistic diseases.

The mechanisms of action proposed for IL-6 pathway inhibitors are similar to those of agents used in other diseases, suggesting potential applicability to NMOSD; however, these therapies have not yet been formally evaluated for this indication. Siltuximab is a chimeric human–murine monoclonal antibody that forms stable, high-affinity complexes with soluble human IL-6, thereby preventing cytokine binding to soluble and membrane-bound receptors and ultimately blocking signal transduction [259]. It is currently indicated for the treatment of Multicentric Castleman Disease.

Sarilumab, a fully human IgG1 monoclonal antibody, is used in conditions such as RA, polymyalgia rheumatica, and polyarticular juvenile idiopathic arthritis. It selectively binds both soluble and membrane-bound IL-6 receptors with an affinity 15–22 times greater than TCZ, effectively blocking IL-6-mediated signaling [260]. Elsilimomab (B-E8), a murine anti-IL-6 monoclonal antibody, has been employed in the treatment of multiple myeloma, and served as the basis for the development of a fully humanized derivative, mAb 1339 (OP-R003) [261]. Additional monoclonal antibodies targeting the IL-6 pathway include sirukumab, clazakizumab, olokizumab, and vobarilizumab [262].

4.3. Complement Inhibitors

The binding of autoantibodies to aquaporin-4 activates the classical complement pathway through the crystallizable (Fc) region of the IgG1 fragment, specifically leading to the proteolytic cleavage of C5 into C5a and C5b. The larger fragment, C5b, is a terminal product of the common complement pathway and orchestrates the inflammatory process, the formation of membrane attack complexes that increase membrane permeability, and subsequent astrocytic injury. C5a, in contrast, is a pro-inflammatory anaphylatoxin that further increases BBB permeability, recruits granulocytes and monocytes expressing the C5a receptor, and amplifies complement activation [263,264,265,266]. Granulocytes and monocytes cause less specific damage to the CNS and promote demyelination. The loss of astrocytes and oligodendrocytes deprives axons and dendrites of nutritional support. As a result, tissue recovery is impaired in NMOSD.

Selective inhibition of the early stages of the complement pathway has the advantage of preserving lectin-mediated activation involved in bacterial killing [44]. In addition, C1 inhibition prevents the generation of C3a and C3b, which participate in CDC. However, unlike strategies targeting later stages of the pathway, the adverse effects of therapies directed at these early steps are less predictable; consequently, this biological target has not been extensively developed [61,267].

4.3.1. Eculizumab

Eculizumab is a hybrid humanized IgG2/4 kappa monoclonal antibody that blocks the terminal steps of the complement system. It binds to the MG7 domain of the common mediator C5 and prevents the association of convertases (serine proteases) with C5, thereby inhibiting its cleavage into C5a and C5b [268,269,270] and reducing AQP4-AB-induced deposition of the C5b–C9 membrane attack complex (Figure 2). This, in turn, attenuates neuronal damage.

In this context, eculizumab has demonstrated high efficacy in relapse prevention—greater than that reported for RTX, satralizumab, and inebilizumab [162,204,271]—and consequently a significant reduction in the annualized rate of NMOSD attack-related hospitalizations [3,272] (Table 2), even in refractory disease patients. It was the first drug formally approved in 2019 for the treatment of NMOSD, given that AQP4-AB are responsible for complement fixation.

Although eculizumab is not currently approved for pediatric NMOSD and clinical trial results in this population are still pending [273], several reports have reported that its use was both effective and well-tolerated in pediatric patients [274,275]. Moreover, it is approved for the treatment of juvenile myasthenia gravis [276].

Because eculizumab acts rapidly—within one hour of the first dose—and because it has a short elimination half-life (requiring biweekly administration during maintenance therapy, with omission of a single dose potentially allowing recovery of C5 complement activity) [90,162], it is occasionally used as rescue therapy in the management of severe attacks that are refractory to standard treatments [277].

The high cost of eculizumab limits its use and availability [278]; in response a reference product biosimilar has been developed and is authorized for marketing in Russia and Turkey [279].

Although eculizumab does not impair adaptive immunity and therefore does not compromise acquired immunosurveillance, inhibition of complement—an essential component of antibacterial defense—has been associated with an increased risk of infections. Its use has been linked to a markedly higher risk (approximately 1000–2000-fold) of meningococcal disease compared with the general population [238,280]. Consequently, patients must be vaccinated against meningococcal serogroups ACW135Y and B prior to treatment initiation, and booster doses are recommended while therapy is ongoing [69]. Transient increases in relapse risk have been reported in association with meningococcal vaccination and prior to the initiation of eculizumab [280]. Importantly, cumulative exposure to eculizumab or ravulizumab has not been associated with an increased long-term incidence of meningococcal infections or related mortality [281]. There is also an increased risk of infection by encapsulated organisms; therefore, vaccination against Haemophilus influenzae and pneumococcal infections is commonly recommended. Likewise, antibiotic prophylaxis is advised in certain circumstances, such as when eculizumab infusion is initiated within 14 days after vaccination [3].

Other adverse events reported with the use of this complement inhibitor include infusion-related reactions, headache, arthralgia, nausea, diarrhea, and nasopharyngitis [157,268]. Because eculizumab has more than a decade of post-marketing experience in other indications—paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and generalized myasthenia gravis—it is generally considered to have a well-characterized safety profile [272]. In the context of NMOSD, a recent retrospective European cohort with nearly eight years of follow-up reported five deaths among patients treated with eculizumab; most of these individuals were 50 years or older and shared substantial degrees of disability prior to treatment initiation [280]. As with TCZ, the use of eculizumab during pregnancy in patients with very severe disease may be considered under close clinical monitoring [88,282,283].

A polymorphism in C5, R885C/H (C5 Arg885His), specifically located in the MG7 domain, has been reported to render patients unresponsive to eculizumab [15,284]. For other indications, in cases of suboptimal response to anti-C5 MG7 therapy, the development of alternative therapeutic strategies is being explored, including anti-C5 MG4/MG5 therapies and peptide inhibitors that bind to C3 and block its activation by convertases [285,286].

4.3.2. Ravulizumab

Ravulizumab is a humanized monoclonal antibody of the IgG2/4 kappa subtype that is structurally and functionally related to eculizumab; therefore, it is expected to bind to the same C5 epitope, within the macroglobulin MG7 domain [287,288]. Substitution of four amino acids in the immunoglobulin heavy chain produces an enhanced endosomal dissociation from C5 and, consequently, a recycling process [289] similar to satralizumab. These modifications increase the elimination half-life of ravulizumab, thereby prolonging the duration of C5 inhibition and allowing for an extended dosing interval (intravenous administration every 8 weeks versus every 2 weeks) [290,291,292]. Consistent with the reduction in relapse rates observed in the pivotal studies [288,293], the final results of the phase III CHAMPION-NMOSD extension trial showed zero relapses in patients treated with ravulizumab. A safety profile similar to eculizumab has been described [294] (Table 2). Ravulizumab is currently approved for the treatment of NMOSD, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome and myasthenia gravis with positive antibodies against the acetylcholine receptor [295,296,297].

Table 2. Common monoclonal antibodies used or in clinical development for NMOSD maintenance and acute relapse management.

Therapy Type	Regulatory Status NMOSD	mAb	Mechanism of Action	Clinical Trial Strategy/Evidence Status
Maintenance	Approved	Inebilizumab	Humanized anti-CD19 mAb; depletes a broader spectrum of B cells (including plasmablasts/plasma cells) via ADCC.	In the pivotal phase 2/3 N-MOmentum trial time to the onset of an adjudicated NMOSD attack was considered the primary endpoint and a randomization ratio 3:1 was used. Inebilizumab reduced the risk of NMOSD attacks compared with placebo and significantly reduced the risk of disability score worsening. Primarily enrolled AQP4-IgG seropositive patients, with a small percentage of seronegative patients [176,177].
Maintenance	Approved	Satralizumab	Humanized anti-IL-6 receptor (IL-6R) mAb; inhibits IL-6 signaling pathways. Reduces inflammation and BBB dysfunction.	Specifically developed for NMOSD; utilizes “recycling antibody” technology for prolonged circulation and repeated binding. Pivotal, randomized, placebo-controlled phase 3 trials SAkuraStar (2:1) and SAkuraSky (1:1) included both seropositive and seronegative patients. Primary endpoint was time to the first protocol-defined relapse [234].
Maintenance	Approved	Eculizumab	Humanized anti-C5 complement protein mAb; blocks C5 cleavage preventing terminal complement activation.	The primary end point was the first adjudicated relapse; clinical trials established efficacy in reducing relapse rates. Trials focused heavily on AQP4-IgG seropositive patients (around 90% of the cohort) and used a randomization ratio 2:1 [272].
Maintenance	Approved	Ravulizumab	Humanized anti-C5 mAb; structurally related to eculizumab with a longer half-life due to recycling modifications.	Phase III CHAMPION-NMOSD trial (open label) considered time to first adjudicated on-trial relapse as primary endpoint. Showed zero relapses in treated patients; primary treatment period extends from 26 weeks to 2.5 years. Exclusively tested in AQP4-IgG seropositive patients [288,293,294]
Maintenance	Not approved used in most countries	Rituximab	Chimeric anti-CD20 mAb; depletes B cells via complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and apoptosis.	Widely used “off-label”; approved in Japan after academic randomized, double-blind, placebo-controlled trial. Primary outcome was defined as time to first relapse within 72 weeks and participants were randomly allocated (1:1). Trial included seropositive for aquaporin 4 (AQP4) antibody patients and showed 50–90% reduction in ARR [113,114].
Maintenance	Not approved Use	Tocilizumab	Anti-IL-6R mAb; inhibits IL-6 signaling and prevents autoimmune activation.	Used off-label as escalation or rescue therapy; demonstrated reduction in relapse rates, including in RTX-refractory patients [73,249].
Maintenance	In clinical development	Belimumab	Anti-BLyS (B lymphocyte stimulator) mAb; inhibits B-cell survival and maturation into plasma cells.	Clinical development as NMOSD maintenance therapy is currently in early stages. Drug approved for the treatment of high activity autoantibody-positive SLE and lupic nephritis.
Maintenance	In clinical development	Aquaporumab	Nonpathogenic humanized anti-AQP4 mAb; competitively inhibits binding of pathogenic AQP4-IgG without triggering complement activation.	No current known clinical development program despite high specificity and low toxicity in animal models.
Acute Relapse	In clinical development	Ublituximab	Type I chimeric anti-CD20 mAb with enhanced affinity for FcγR3A (CD16) aspect that increases ADCC potency.	Investigated for use during acute relapses; glycoengineered for higher potency compared to RTX. Early studies have shown that used in combination with corticosteroids may be potentially effective.
Acute Relapse	In clinical development	Bevacizumab	Humanized mAb against VEGF reduces BBB disruption	Stabilization of the BBB and reduction of AQP4-IgG and inflammatory cells entry to the CNS. Limited reports available

Table 2. Common monoclonal antibodies used or in clinical development for NMOSD maintenance and acute relapse management.

Therapy Type	Regulatory Status NMOSD	mAb	Mechanism of Action	Clinical Trial Strategy/Evidence Status
Maintenance	Approved	Inebilizumab	Humanized anti-CD19 mAb; depletes a broader spectrum of B cells (including plasmablasts/plasma cells) via ADCC.	In the pivotal phase 2/3 N-MOmentum trial time to the onset of an adjudicated NMOSD attack was considered the primary endpoint and a randomization ratio 3:1 was used. Inebilizumab reduced the risk of NMOSD attacks compared with placebo and significantly reduced the risk of disability score worsening. Primarily enrolled AQP4-IgG seropositive patients, with a small percentage of seronegative patients [176,177].
Maintenance	Approved	Satralizumab	Humanized anti-IL-6 receptor (IL-6R) mAb; inhibits IL-6 signaling pathways. Reduces inflammation and BBB dysfunction.	Specifically developed for NMOSD; utilizes “recycling antibody” technology for prolonged circulation and repeated binding. Pivotal, randomized, placebo-controlled phase 3 trials SAkuraStar (2:1) and SAkuraSky (1:1) included both seropositive and seronegative patients. Primary endpoint was time to the first protocol-defined relapse [234].
Maintenance	Approved	Eculizumab	Humanized anti-C5 complement protein mAb; blocks C5 cleavage preventing terminal complement activation.	The primary end point was the first adjudicated relapse; clinical trials established efficacy in reducing relapse rates. Trials focused heavily on AQP4-IgG seropositive patients (around 90% of the cohort) and used a randomization ratio 2:1 [272].
Maintenance	Approved	Ravulizumab	Humanized anti-C5 mAb; structurally related to eculizumab with a longer half-life due to recycling modifications.	Phase III CHAMPION-NMOSD trial (open label) considered time to first adjudicated on-trial relapse as primary endpoint. Showed zero relapses in treated patients; primary treatment period extends from 26 weeks to 2.5 years. Exclusively tested in AQP4-IgG seropositive patients [288,293,294]
Maintenance	Not approved used in most countries	Rituximab	Chimeric anti-CD20 mAb; depletes B cells via complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and apoptosis.	Widely used “off-label”; approved in Japan after academic randomized, double-blind, placebo-controlled trial. Primary outcome was defined as time to first relapse within 72 weeks and participants were randomly allocated (1:1). Trial included seropositive for aquaporin 4 (AQP4) antibody patients and showed 50–90% reduction in ARR [113,114].
Maintenance	Not approved Use	Tocilizumab	Anti-IL-6R mAb; inhibits IL-6 signaling and prevents autoimmune activation.	Used off-label as escalation or rescue therapy; demonstrated reduction in relapse rates, including in RTX-refractory patients [73,249].
Maintenance	In clinical development	Belimumab	Anti-BLyS (B lymphocyte stimulator) mAb; inhibits B-cell survival and maturation into plasma cells.	Clinical development as NMOSD maintenance therapy is currently in early stages. Drug approved for the treatment of high activity autoantibody-positive SLE and lupic nephritis.
Maintenance	In clinical development	Aquaporumab	Nonpathogenic humanized anti-AQP4 mAb; competitively inhibits binding of pathogenic AQP4-IgG without triggering complement activation.	No current known clinical development program despite high specificity and low toxicity in animal models.
Acute Relapse	In clinical development	Ublituximab	Type I chimeric anti-CD20 mAb with enhanced affinity for FcγR3A (CD16) aspect that increases ADCC potency.	Investigated for use during acute relapses; glycoengineered for higher potency compared to RTX. Early studies have shown that used in combination with corticosteroids may be potentially effective.
Acute Relapse	In clinical development	Bevacizumab	Humanized mAb against VEGF reduces BBB disruption	Stabilization of the BBB and reduction of AQP4-IgG and inflammatory cells entry to the CNS. Limited reports available

4.3.3. Gefurulimab (ALXN1720)

Gefurulimab is a humanized, bispecific single-domain antibody (nanobody, VHH antibody) directed against terminal complement protein C5 and albumin that is administered subcutaneously. It acts similarly to eculizumab and ravulizumab, exerting anti-inflammatory and immunomodulatory effects [298]; however, gefurulimab binds to the MG4/MG5 region of C5, which is involved in the interaction of C5 with the C5 convertase, and unlike eculizumab and ravulizumab, it is administered via the subcutaneous route. It is currently under clinical development for myasthenia gravis but is considered a potential future therapeutic alternative for NMOSD [299] (has not been assessed in NMOSD). Because VHH antibodies exhibit rapid renal clearance and consequently a short elimination half-life [300], gefurulimab is engineered to also bind albumin, enabling association with serum albumin, which has a prolonged circulating half-life due to FcRn-mediated recycling [301].

4.4. Direct AQP4 Inhibitors

Aquaporumab

Because the binding of autoantibodies to AQP4 is considered the primary and triggering event in the pathogenesis of NMOSD, blocking this interaction represents an attractive therapeutic strategy [61]. However, the first molecules identified with therapeutic potential showed low affinity and were unable to penetrate the CNS [302].

Aquaporumab is a nonpathogenic humanized monoclonal antibody of the IgG1 subtype directed against aquaporin-4. It was initially isolated from plasma cells obtained from the CSF of patients with NMOSD and through the introduction of modifications in the Fc region, the binding to AQP4 via the Fab fragment does not trigger complement activation (Figure 2). This neutralizes the effector functions of antibody-mediated CDC and ADCC [303,304]. Aquaporumab not only exhibits high affinity for the extracellular domain of AQP4—thereby competitively inhibiting the binding site of pathogenic autoantibodies—but also demonstrates adequate penetration into the CNS and very slow dissociation kinetics, features that are essential for its biological activity. In animal models, this molecule has been shown to prevent the development of disease [189,305]. Furthermore, affinity-maturation approaches have been implemented to further optimize its binding characteristics [163,303]. Despite its high specificity, lack of immunosuppressive effects (thereby not increasing the risk of infections or malignancy), potential use in both acute attacks and maintenance therapy, and its apparently low toxicity and immunogenicity in preliminary studies [27,306], there is currently no known clinical development program for this molecule.

Using a therapeutic strategy similar to that of aquaporumab, the development of agents that specifically bind to AQP4-AB is also being explored [307].

4.5. BLyS Inhibitors

Belimumab

Belimumab is a monoclonal antibody of the IgG1 lambda subtype directed against BLyS, which selectively binds with high affinity to this B-cell survival factor (Figure 2). The interaction neutralizes BLyS and blocks its effects on the three distinct receptors expressed on B cells [66]. Consequently, belimumab inhibits B-cell survival, promotes apoptosis, and reduces the differentiation and maturation of B cells into immunoglobulin-producing plasma cells [308,309,310].

Actually, this drug is indicated for the treatment of high activity autoantibody-positive SLE and active lupus nephritis [162]. Although its mechanism of action could be useful in the management of NMOSD, its clinical development as a maintenance therapy remains in early stages [311].

4.6. Non-Depleting B-Cell Modulators

Obexelimab

Obexelimab is an investigational, bifunctional, noncytolytic, humanized monoclonal antibody subtype (IgG1) directed against the B-cell-specific cell surface antigens. It simultaneously targets CD19 and FcγR2b (CD32B), which play important roles in B-cell receptor signaling, cell activity and survival. Thereby this mAb inhibits B cells, plasmablasts, and CD19-positive plasma cells. In clinical studies, intravenous administration of obexelimab has been well tolerated and has shown clinical activity in patients with rheumatoid arthritis, systemic lupus erythematosus, and IgG4-related disease [312]. Based on its mechanism of action, it represents a promising therapeutic candidate for neuromyelitis optica spectrum disorder (NMOSD).

5. Acute Relapse Treatment

5.1. Ublituximab

Ublituximab (LFB-R603) is a type I chimeric monoclonal antibody directed against the transmembrane protein CD20 (Figure 2). The antibody was developed with reduced Fc-region fucosylation. As in other cases, this monosaccharide reduction enhances affinity for the FcγR3A receptor (CD16—a transmembrane protein that functions as a low-affinity IgG receptor and mediates ADCC) which is primarily expressed on the surface of NK cells, monocytes, and macrophages [313,314,315]. Reduction of steric hindrance through sugar depletion favors binding of the Fc region of the anti-CD20 antibody to the FcγR3A receptor (which is not a target of RTX), resulting in markedly increased potency—approximately 100-fold greater than RTX—and an enhanced capacity to induce B-cell destruction by immune effector cells while preserving CDC. These properties have been associated with greater therapeutic efficacy [313,316], although they must be carefully considered, as a more potent and sustained B-cell depletion may also be associated with a higher incidence of adverse events [317]. Additionally, ublituximab is characterized by a short infusion time of 1–2 h, which may be considered a clinical advantage [318,319].

Although ublituximab is currently approved only for the treatment of relapsing forms of MS—largely because its clinical development has primarily focused on autoimmune disorders—its potential application in oncology cannot be ruled out, based on evidence from early phase studies and by analogy with other anti-CD20 agents (RTX and obinutuzumab) used in the treatment of B-cell malignancies, such as non-Hodgkin lymphoma and chronic lymphocytic leukemia [320,321]. Specifically, in NMOSD, given its potential to modulate immune responses, early studies have shown that ublituximab used in combination with corticosteroids is safe and well tolerated during relapses and potentially effective. Moreover, B-cell depletion has been associated with improved disability scores in some patients [61,322,323].

5.2. Neonatal Fc Receptor (FcRn) Inhibitors

Autoantibodies (IgG) play a crucial role in the pathogenesis of autoimmune diseases; therefore, their removal has long represented a relevant therapeutic strategy, particularly in the management of acute disease exacerbations [324,325]. Immunoglobulins may have an elimination half-life of up to 21 days, a process in which the neonatal Fc receptor (FcRn) is involved. FcRn interacts with immunoglobulins and protects them from lysosomal degradation; therefore, FcRn inhibitors accelerate the catabolism of IgG antibodies, including pathogenic IgG autoantibodies, by targeting and blocking the interaction between FcRn and IgG [167].

The effects of FcRn inhibition do not alter serum concentrations of IgA, IgE, IgM, or IgD; consequently, this therapeutic approach is considered analogous to plasmapheresis but with fewer adverse effects and a more selective and accessible profile [326]. In addition, FcRn plays an important role in albumin recycling and recirculation, as well as in antigen presentation [206,327].

In the management of NMOSD, FcRn inhibitors demonstrate an onset of action comparable to that of eculizumab, and faster than that observed with inebilizumab and satralizumab; as a result, they are being considered for acute relapse treatment [328]. Although clinically significant decreases in albumin levels have not been reported in clinical trials with efgartigimod, rozanolixizumab and SYNT001, relevant reductions on batoclimab and nipocalimab treatment have been observed. In NMOSD, a phase 1b study of batoclimab documented treatment discontinuation in one participant as a result of hypoalbuminemia [329].

5.2.1. Batoclimab

Batoclimab (IMVT-1401, RVT-1401, and HBM9161 (HL161BKN)) is a fully humanized monoclonal antibody of the IgG1 lambda2 isotype directed against FcRn, which has demonstrated high affinity for the IgG binding site [330]. It competitively binds to this site and blocks FcRn-mediated IgG recycling, resulting in increased IgG degradation and a subsequent reduction in autoantibody levels against aquaporin-4 [326,331]. This mechanism produces an AQP4-AB clearance effect comparable to that achieved with plasmapheresis and immunoadsorption, suggesting its potential utility as an alternative approach for the management of exacerbations.

Batoclimab is currently under clinical development as a low-volume subcutaneous injection for the treatment of several IgG-mediated autoimmune diseases, including induction and maintenance therapy for patients with myasthenia gravis, thyroid eye disease, and chronic inflammatory demyelinating polyneuropathy [332,333,334,335]. Specifically in acute relapses of NMOSD, it has been preliminarily investigated as an adjunctive therapy to intravenous methylprednisolone pulses [329,336,337]. These studies report acceptable tolerability, with the main adverse events including transient hypoalbuminemia, hypercholesterolemia (secondary to hypoalbuminemia), urinary tract infections, hypernatremia, and peripheral edema [329,338,339].

5.2.2. Rozanolixizumab

Rozanolixizumab is a humanized monoclonal antibody of the IgG4P subtype directed against FcRn. Blockade of FcRn promotes the degradation of pathogenic IgG autoantibodies, including those associated with myasthenia gravis, Guillain–Barré syndrome and MOGAD. It is currently approved for the treatment of generalized myasthenia gravis in adult patients who are positive for anti-acetylcholine receptor or anti-muscle-specific tyrosine kinase antibodies, and it is under investigation for MOGAD. Although its utility in NMOSD has not yet been established (have not been assessed in NMOSD), its mechanism of action makes it an attractive therapeutic candidate in conditions in which pathogenic IgG autoantibodies play a central role and in diseases where plasma exchange has demonstrated clinical benefit [336,340].

5.3. Vascular Endothelial Growth Factor Blockade

In NMOSD, vascular endothelial growth factor (VEGF) contributes to disruption of the BBB, by increasing its permeability through weakening of tight junctions, in part by reducing the expression of proteins such as claudin-5. This process allows proinflammatory immune cells and autoantibodies, including anti-aquaporin-4 antibodies to penetrate the CNS [341]. Additionally, it has been described that in NMOSD, circulating antibodies may directly target endothelial cells, leading to endothelial activation and enhanced VEGF secretion, thereby further amplifying BBB dysfunction [342,343].

Bevacizumab

Bevacizumab is a humanized mAb of the IgG1 kappa isotype directed against VEGF approved for the treatment of several types of cancer [344]. Because VEGF induces disruption of the BBB through mechanisms that are not fully understood [345,346], and because the dysfunction of this barrier appears to be a fundamental component in the etiopathogenesis of NMOSD [189], VEGF blockage is considered an attractive therapeutic strategy (Figure 2). Bevacizumab binds to overexpressed circulating VEGF-A and prevents its interaction with endothelial cell surface receptors, primarily VEGFR-1 and VEGFR-2 [25,44,343]. This contributes to stabilization of the BBB and reduces the entry of AQP4-AB and inflammatory cells into the CNS. In the limited reports available, bevacizumab has been shown to be well tolerated as an adjunctive therapy to intravenous corticosteroids during NMOSD relapses [347].

6. Conclusions

Pharmacological management of neuromyelitis optica spectrum disease (NMOSD) has undergone a substantial transformation, switching from employing broadly acting immunosuppressive therapies (predominantly in an “off-label” context) to a more targeted strategy with regulatory approved drugs. A paradigm shift in this evolution was the introduction of immunotherapy, particularly monoclonal antibodies which are now employed both for acute relapse management and long-term maintenance treatment. As illustrated, a broad range of biological targets has been explored; therapies have been approved and refined to improve both efficacy and safety; and deeper knowledge of disease pathophysiology has catalyzed the emergence of new therapeutic approaches.

Despite these advances, significant limitations persist, like the absence of head-to-head studies, insufficient real-world data and substantial differences in trial designs (endpoint definition, additional immunotherapies permitted, inclusion of MOGADs and double-negative patients). These aspects limit drug comparison and selection for first-line treatment or suboptimal response. Therefore, a group of experts recommends: (1) that approved treatments may be used as first-line for newly diagnosed patients or proposed after relapses due to the failure of existing treatments, (2) monotherapy is preferred in order to reduce possible side effects, (3) patients free of disease activity and using “off-label” treatments should not be switched. Other factors that influence treatment decisions include previous experience with therapy, tolerability, accessibility, cost and convenience.

Recent analyses comparing efficacy and safety aspects between approved monoclonal antibodies and those used off-label have found that both are significantly superior to traditional treatments; however, the difference between seems not to be substantial [348]. This has led to the suggestion that, when considering economic factors, off-label monoclonal antibodies could be used as first-line therapy in the management of NMOSD, particularly in low- and middle-income countries.

To further advance NMOSD management, future strategies must prioritize the standardization of clinical trial endpoints, the harmonization of participant selection criteria, and a strong focus on patients’ functional recovery. Meaningful progress will require a multi-faceted approach, including active government involvement to ensure affordability and access, strengthened academic collaborations to support the advancement of promising drug candidates, enhancement of academic clinical trials by non-commercial entities and partnerships with patient advocacy groups to drive the repurposing of existing therapeutics for NMOSD.