Table 1 Mechanism of action of on-label and off-label therapies, and drugs in clinical trials used in the treatment of NMOSD

Bevacizumab [90]

intravenous infusion

10 mg/kg intravenous infusion at onset of exacerbation and, if needed, a second time during the plasma exchange phase

Bevacizumab directly binds vascular endothelial growth factor (VEGF) to inhibit angiogenesis

Ublituximab [91, 92]

Intravenous

450 mg once on day 1, plus steroids 1000 mg intravenously daily on days 1–5

Ublituximab is a monoclonal antibody that specifically binds to the trans-membrane antigen CD20. Binding induces an immune response that causes lysis of B cells.

NPB-01 (NCT01845584)

Intravenous immunoglobulin 400 mg/kg/day for five consecutive days

IgG can inactivate auto-reactive T-cells by competing for, and interrupting their interaction with, antigen presenting cells [87, 88].

HBM 9161 (NCT04227470)

injection, 340 mg or 680 mg weekly administered subcutaneously for a period of 4 weeks.

HBM9161(HL161BKN) is a human monoclonal antibody. HBM9161 targets FcRn by blocking the FcRn IgG-Fc binding site and accelerating the degradation of IgG, reducing total IgG level in blood (including pathological IgG). The serum AQP4-IgG associated with NMOSD is a pathological IgG, so the combination of standard of care which is intravenous methylprednisolone with HBM9161 is expected to rapidly reduce AQP4-IgG levels.

Azathioprine (AZA) [93,94,95,96]

Oral

Target dose: 2–3 mg/kg/daily in divided doses

Purine analog that converts to 6-mercaptopurine, its active metabolite, and thioguanine due to the action of hypoxanthine-guanine phosphoribosyl transferase and thiopurine methyltransferase enzymes. Inhibits purine synthesis resulting in the inhibition of DNA, RNA, and protein synthesis. AZA is absorbed rapidly through the GI system and does not penetrate the blood-brain barrier.

Mycofenolate mofetil (MMF) [97,98,99]

Oral

Target dose: 750–1500 mg twice a day (median dose: 1 g twice a day)

Prodrug of mycophenolic acid, an inhibitor of inosine-5'-monophosphate dehydrogenase (antimetabolite), which is the first of two enzymes involved in the conversion of inosine monophosphate (IMP) to guanosine monophosphate (GMP). It is normally converted to GDP, GTP, and dGTP. Mycophenolic acid treatment decreases guanine nucleotide pools in lymphocytes.

Rituximab (RTX) [100,101,102,103,104,105,106]

Intravenous

Induction: 1 g with re-treatment at 2 weeks or 375 mg/m² body surface area once weekly for 4 weeks.

Maintenance: 1 g with retreatment at 2 weeks every 6 mo. or one infusion of 375 mg/m² every 6 mo.

Chimeric monoclonal antibody (IgG1) against human CD20. Its binds to CD20, a protein expressed primarily on B cells (pre-B, naïve and memory B cells), reducing B cell activity (elimination of autoreactive B cell) through subsequent cytotoxic mechanisms, inducing regulatory B cells.

Tocilizumab (TCZ) [80, 107,108,109]

Intravenous

8 mg/kg every 4 weeks

Humanized monoclonal antibody (IgG1) genetically engineered from mouse antihuman anti-interleukin 6 receptor (IL-6R) antibody. It recognizes the IL-6 binding site of the human IL-6R and inhibits IL-6 signaling through competitive blockade of the IL-6 binding site (membrane-bound and soluble IL-6 receptors)

Eculizumab (ECZ) [13]

Intravenous

900 mg weekly during the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4.

Humanized monoclonal antibody (IgG2/IgG4) inhibiting terminal complement protein C5 by preventing cleavage from C5 to activated fractions C5a (pro-inflammatory peptide involved in chemotaxis, cytokine release and vasodilation) and C5b (a membrane constituent which attacks complex C5b-9).

Satralizumab [19, 20]

Subcutaneous

120 mg at weeks 0, 2, and 4 and then every 4 weeks

Humanized IL-6R monoclonal antibody type IgG2 (recycling technology). Binds to membrane IL-6R and is internalized in the endosome. It can dissociate IL-6R under acidic conditions in lysosomes and be recycled to the plasma via the neonatal Fc receptor (FcRn) instead of being degraded in lysosomes.

Inebilizumab [21]

Intravenous

300 mg in 2 doses on open-label days 1 and 15 and then 300 mg every 6 mo.

Humanized monoclonal antibody (IgG1) against CD19 (pro-B, pre-B, naïve and memory B cells), which produces rapid depletion of circulating B cells, including autoantibody-secreting plasmablasts and CD19-expressing plasma cells. CD19 is exclusively expressed on B cells.

Telitacicept

Subcutaneous

160 mg weekly

Recombinant transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI-Fc; located on CD27+ memory B cells and plasma cells) fusion antibody that works by binding to two cell-signaling molecules, B lymphocyte stimulator (BLyS), and a proliferation-inducing ligand (APRIL), both are a member of the tumor necrosis factor (TNF) family [115].

Ravulizumab

Intravenous

Infusion on day 1, followed by weight-based maintenance doses on day 15, then once every 8 weeks

Second-generation anti-C5 monoclonal antibody (binds to complement protein 5 (C5) and blocks its activation by complement pathway convertase, thus inhibiting C5 cleavage into fragments C5a and C5b, engineered from eculizumab. It is a long-lasting recycling IgG monoclonal antibody with increased affinity for FcRn and rapid endosomal dissociation of the ravulizumab-C5 complex, allowing lysosomal degradation of C5 while recycling ravulizumab to the vascular space through the FcRn [113].

Bortezomib [114]

Subcutaneous

1 mg/m² of body surface area on days 1, 4, 8, and 11 per cycle followed by a 10-day treatment-free interval.

Binds the catalytic site of the 26S proteasome with high affinity and specificity leading to elimination of both plasmablasts and plasma cells by activation of the unfolded terminal protein response. Bortezomib may protect astrocytes from NFκB-dependent inflammatory damage in early events in NMOSD pathogenesis.

Cetirizine (add-on) [115]

Oral

10 mg each day

Cetirizine (antihistaminic) could prevent damage by blocking eosinophils which have been implicated in the pathophysiology of NMOSD.

BAT4406F

Intravenous

Open-label dose escalation starting from 20 mg.

Fully humanized anti-CD20 monoclonal antibody

SHR1459

Oral

Tablets taken once daily

Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a crucial role in B cell development by transmitting intracellular signals from the pre-B cell receptor

Aquaporumab (mAb-53) (animal model) [119]

mAb-53 has not been clinically applied to patients

Aquaporumab is an engineered monoclonal antibody with high affinity for AQP4 channels that contain Fc mutations blocking cell- and complement-mediated cytotoxicity effector functions (possible mechanism of competitive inhibition as a steric inhibitor). Aquaporumab has shown beneficial effects in an NMOSD mouse model, but has not been clinically tested in NMOSD patients.