Novel Treatments for Antibody Mediated Aquaporin-4 (AQP4)-IgG Neuromyelitis Optica Spectrum Disorder (NMOSD): Review and Proposal

Written by: Med Dreamers Canada Research Team

Uploaded: October 25, 2024

Approximate Read Time: 10 Minutes

ABSTRACT
Neuromyelitis optica spectrum disorder (NMOSD) is a rare yet potent inflammatory and demyelinating disorder of the central nervous system. It mainly targets the spinal cord, brain stem, and optic nerve, making diagnosis and management challenging. NMOSD is strongly connected with aquaporin-4 immunoglobulin G antibodies (AQP4-IgG), requiring serologic testing to accurately evaluate its presence. This article makes use of the PubMed advanced search with the medical subject heading as neuromyelitis optica spectrum disorder and all field term as treatment. This comprehensive review aims to discuss these potential treatments in NMOSD: Inebilizumab, Monoclonal Antibody-Based Treatments, P2R Inhibitors, Rituximab, and AT2-Receptor Stimulation. In the proposal, novel combined therapies are discussed and new promising methods to treat NMOSD are introduced with evidence for further research in NMOSD treatment.

Introduction and Pathogenesis
Neuromyelitis Optica Spectrum Disorder is an atypical form of Optic Neuritis. One of the most common types of NMOSD is Antibody-mediated Aquaporin-4 (AQP4)-IgG. This means that immunoglobulin G autoantibodies against astrocyte water channel aquaporin-4 were found in the patient’s blood. Therefore, treatment options involve inactivating these antibodies with a variety of methods. The discovery of an autoantibody against aquaporin-4 (AQP4), the dominant water channel which is strongly expressed on astrocyte end-feet, distinguishes NMO from MS and helps to establish a diagnosis of NMO. At present, evidence from the laboratory and clinic suggests that AQP4–IgG is pathogenic in NMO. Thus, research on NMO treatment is mainly focused on the series of pathological inflammatory reactions caused by the binding of AQP4-IgG to AQP4. One reason for these pathogenic events is that the AQP4-IgG titer has significant clinical and immunological implications, as a higher serum titer means there is more AQP4-IgG in the CNS [28]. Therefore, studies on NMO treatment have focused on blocking the binding of AQP4–IgG to AQP4, using medications such as aquaporumab. At present, a few drugs are available for the treatment of NMO, including general immunosuppressive agents, plasma exchange, and B-cell depletion, targeting AQP4-IgG and inflammatory reactions. Therefore, improved therapies for NMO are needed to ameliorate acute attacks and prevent exacerbations.

Results
Monoclonal Antibody-Based Treatments
Current treatment options, including immunosuppressive agents, plasma exchange, and B-cell depletion, are based on small retrospective case series and open-label studies. It is noteworthy that monoclonal antibody (mAb) therapy is a better option for autoimmune diseases due to its high efficacy and tolerability. mAbs, which target B cell depletion, complement and inflammation cascade inactivation, blood-brain-barrier protection, and blockade of NMO-IgG-AQP4 binding.

The best drug regimen for monoclonal antibody-based treatments and treatment length are unknown. Some have severe long-term side effects which are better to be tested with murine and zebrafish models before human trials.

Inebilizumab
Inebilizumab is a humanized anti-CD19 monoclonal antibody. This class of drugs works by slowing or stopping the growth of cancer cells by binding to CD19, a protein found on the surface of B cells and B-cell tumors, and kills it. In the case of NMOSD, inebilizumab received global treatment to be used in the United States since 2020. It is primarily employed in adult patients who are seropositive for immunoglobulin G autoantibodies against aquaporin-4 (AQP4-IgG) (Frampton, 2020). Inebilizumab was found to be highly effective in a therapeutic trial that was randomized, double-blind, placebo-controlled, multinational, phase II/III trial. In a study of 213 participants with NMOSD that were AQP4-IgG seropositive, significantly fewer recipients of inebilizumab (n = 161) than placebo (n = 52) experienced NMOSD.

Table 1. Features and properties of inebilizumab (Frampton, 2020).

Rituximab
Rituximab is a monoclonal antibody that targets the protein CD20. It has been regarded as a highly promising method of treatment for NMOSD. For example, in a study done at Oxford Autoimmune Neurology Group, researchers hypothesized that the production of AQP4-IgG antibodies in germinal centers (GCs) in lymph nodes is central to NMOSD, and rituximab may impede this production. Thus, they conducted a study examining the deep cervical lymph node (dCLN) aspirates and blood samples from 63 NMOSD patients. They then analyzed 36 lymph node aspirates and 406 blood samples to see the effects of rituximab as well as the activity of GCs. In patients who did not receive rituximab, AQP4-IgGs were found in lymph node aspirates, and there was also specific production of AQP4-IgG within the lymph nodes, suggesting ongoing GC activity. However, in patients who received rituximab, there was a significant reduction in AQP4-IgG levels and the number of B cells in the lymph nodes (Damato et al., 2022). This study suggests that GCs are actively producing AQP4 antibodies in NMOSDs, and rituximab is highly efficient in disrupting this process.

Eculizumab
To begin, among patients with AQP4-IgG–positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. One clinical trial studied the use of eculizumab for the prevention of relapsed NMOSD. In this trial, the relapse occurred in 3 people out of the 96 patients given the medication, demonstrating statistical significance of the efficacy of the medication eculizumab. On the other note, 47 were given a placebo and 20 showed relapse and some patients even withdrew from the clinical trial. In the study there were limitations; however, in the broad perspective, eculizumab does reduce relapse rate in AQP4-IgG antibody associated NMOSD.

In NMOSD, autoantibodies against astrocytic surface antigen AQP4 cause complement-dependent death of astrocytes. However, P2R inhibitors have been proven effective when treating inflammatory diseases by preventing this AQP4 death. However, the mechanisms behind P2R inhibitors’ anti-inflammatory properties are not well-studied, nor is their impact on the central nervous system’s autoimmunity.

In Vivo Test
P2R inhibitors have been tested in a mouse model with NMOSD to monitor glial toxicity. It was found that various classes of P2R inhibitors prevented AQP4-IgG/complement-dependent astrocyte death. “In the presence of the P2R inhibitor suramin (1000 µM), all astrocytes survived (astrocyte survival after 4 h: 100.00 ± 0.00, n = 6: Fig. 1B–D). Similarly, two other widely used P2R inhibitors NF449 (500 µM) and PPADS (1000 µM) also efficiently protected astrocytes from AQP4-IgG-mediated death (astrocyte survival after 4 h, NF449: 97.93 ± 1.31, n = 5; PPADS: 100.00% ± 0.00%, n = 3: Fig. 1B and D)” (Kalluri et al., 2022).

Image 1. Taken from Kalluri, S. R. et al.’s in vivo test.

In Vitro Test
In vitro, P2R inhibitors prevented the binding of AQP4-IgG or MOG-IgG to their antigen by dose-dependent means. In the presence of various P2R inhibitors, antibodies partially unfolded. This perhaps means that there is a shared interference with IgG antibodies. Because of this, the antibodies underwent a conformational change. These roles are likely to influence the therapeutic uses in humans, and specifically in NMOSD and nervous system autoimmunity.

Methods
Search Strategy: PubMed Advanced Search: (treatment AND (fft[Filter])) AND (antibody mediated aquaporin-4 (AQP4)-IgG neuromyelitis optica spectrum disorder (NMOSD)[MeSH Major Topic] AND (fft[Filter]))
Selection Criteria: Studies and articles published in the past five years (2019-2024) that were open access, written in English, and those that provided significant documentation on treatments of Neuromyelitis Optica Spectrum Disorder.

Data Extraction

Extracted information on the characteristics of Neuromyelitis Optica Spectrum Disorder and the novel treatment options currently being studied.

Proposal of Future Work
Use of intracerebral injection of NMO-IgG and human complement (hC) in mice is sufficient to induce NMOSD-like lesions in order to do murine model tests with combined therapies to see if treatments work in the later stages of NMOSD (Gong. et al., 2020).

Most of the monoclonal antibody treatments have long-term adverse effects like HAMA reactions; therefore, combinatorial therapies with short-term monoclonal antibodies should be tested with murine and zebrafish models.

Furthermore, Tanshinone IIA and Bismuth nanoparticles can highly contribute to decreasing the neutrophilic inflammation in NMOSD as bismuth nanoparticles are a widely used medical therapeutic and have antiinflammatory action without toxicity. Bismuth nanoparticles (BiNPs) can be coated for additional efficacy. In this case, Tanshinone IIA can coat BiNPs or vice versa.

Conclusion
NMOSD has various treatment options that have proven successful. However, it is vital to experiment with other means of treatment in order to find options that have high benefits while keeping side effects minimal.

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