Emerging Therapies in Neuroimmunology

The treatment landscape for neuroimmunologic conditions is evolving rapidly, driven by advances in understanding disease-specific pathogenic mechanisms. Whereas earlier therapeutic strategies relied on broad immunosuppression, current and pipeline agents increasingly target discrete pathways—complement activation, IgG recycling, B-cell subsets, and T-cell costimulation—with the goal of greater efficacy and fewer off-target effects. This topic reviews emerging therapies that are reshaping treatment paradigms across NMOSD, MOGAD, autoimmune encephalitis, multiple sclerosis, and other neuroimmunologic conditions.

FcRn Inhibitors

The neonatal Fc receptor (FcRn) plays a critical role in IgG homeostasis by recycling internalized IgG antibodies back to the cell surface, thereby maintaining high serum IgG concentrations and prolonging antibody half-life. Therapeutic FcRn inhibitors block this recycling pathway, accelerating IgG catabolism and reducing pathogenic antibody levels. This mechanism is particularly attractive for antibody-mediated neurologic conditions in which the pathogenic role of specific IgG antibodies is well established.

Rozanolixizumab

Rozanolixizumab is an anti-FcRn humanized monoclonal antibody that received FDA approval for generalized myasthenia gravis (MG) in 2023. It is currently under investigation for MOGAD in a Phase 3 clinical trial. By blocking FcRn, rozanolixizumab accelerates IgG catabolism and reduces pathogenic antibody levels by approximately 50–70%. The drug is administered via subcutaneous infusion.

The rationale for its use in MOGAD is compelling: MOG-IgG is directly pathogenic, and rapid reduction of circulating pathogenic IgG may translate to clinical benefit. Adverse effects include headache, diarrhea, nausea, infections, and hypersensitivity reactions.

Efgartigimod

Efgartigimod is an FcRn antagonist consisting of an engineered Fc fragment. It was the first FcRn inhibitor approved by the FDA, receiving approval for generalized MG in 2021. It is being explored for other antibody-mediated neurologic conditions, including autoimmune encephalitis. Both intravenous and subcutaneous formulations are available.

Efgartigimod reduces total IgG by approximately 70% while selectively sparing IgA, IgM, IgD, and IgE—an important distinction from plasmapheresis, which removes all immunoglobulin classes nonselectively.

Nipocalimab

Nipocalimab is an anti-FcRn monoclonal antibody currently under study for generalized MG and NMOSD. A Phase 3 trial in AQP4-IgG-positive NMOSD is ongoing. If successful, nipocalimab would represent another mechanistically distinct option for NMOSD prevention.

Complement Pathway Inhibitors (Beyond Eculizumab)

Eculizumab, a monoclonal antibody targeting terminal complement component C5, was the first biologic approved for AQP4-IgG-positive NMOSD. Its success validated complement-mediated injury as a therapeutic target. Newer complement inhibitors address limitations of eculizumab, including its biweekly infusion schedule, intravenous-only administration, and incomplete C5 blockade in some patients.

Ravulizumab

Ravulizumab is a long-acting anti-C5 complement inhibitor engineered from eculizumab with an extended half-life. It is FDA approved for paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and generalized MG, and is under investigation for NMOSD.

The key advantage of ravulizumab over eculizumab is its dosing interval: every 8 weeks compared with every 2 weeks for eculizumab. This represents a significant convenience improvement for patients requiring long-term treatment. The meningococcal infection risk remains the same as eculizumab, and vaccination with meningococcal vaccine is required prior to initiation.

Zilucoplan

Zilucoplan is a small peptide C5 inhibitor that received FDA approval for generalized MG in 2023. It is administered subcutaneously as a self-injectable formulation, offering a meaningful practical advantage over intravenous complement inhibitors. Potential applications include AQP4-IgG-positive NMOSD and other complement-mediated neurologic conditions.

Iptacopan

Iptacopan is a Factor B inhibitor that targets the alternative complement pathway upstream of C5. It is under investigation for various complement-mediated conditions. The potential advantage of targeting the alternative pathway at an earlier step is more selective complement inhibition, potentially preserving some protective complement functions while blocking the pathogenic cascade.

Aquaporumab

Aquaporumab represents a conceptually innovative approach: a non-pathogenic AQP4 antibody engineered to competitively block pathogenic AQP4-IgG binding to its target on astrocytic endfeet. Proof of concept has been demonstrated in preclinical models. If translated to clinical use, aquaporumab would provide a truly disease-specific treatment for AQP4-IgG-positive NMOSD by preventing the antibody–target interaction that initiates the pathogenic cascade. This agent remains in early development and has not yet entered clinical trials.

Next-Generation B-Cell Therapies

Anti-CD20 monoclonal antibodies have become foundational treatments across multiple neuroimmunologic conditions. Newer anti-CD20 agents offer improvements in administration, infusion time, and immunogenicity. Additionally, agents targeting CD19 rather than CD20 can deplete plasmablasts and some plasma cells—populations that are CD20-negative but actively produce pathogenic antibodies.

Obinutuzumab

Obinutuzumab is a type II anti-CD20 monoclonal antibody that has been glycoengineered to enhance antibody-dependent cellular cytotoxicity. Compared with rituximab, it induces enhanced direct cell death of target B cells. It is under investigation in multiple sclerosis and could have applications in other B-cell-mediated neuroimmunologic conditions.

Ofatumumab

Ofatumumab is a fully human anti-CD20 monoclonal antibody approved by the FDA for relapsing forms of MS (2020). It is administered as a monthly subcutaneous self-injection following initial loading doses. As a fully human antibody, it has a lower risk of infusion reactions and anti-drug antibody formation compared with chimeric agents such as rituximab. Its subcutaneous administration model could potentially be applied to other neuroimmunologic conditions.

Ublituximab

Ublituximab is a glycoengineered anti-CD20 monoclonal antibody approved by the FDA for relapsing forms of MS (2022). Its distinguishing feature is a 1-hour infusion time, significantly faster than other intravenous anti-CD20 antibodies. Enhanced glycoengineering improves antibody-dependent cellular cytotoxicity.

Anti-CD19 Agents Beyond Inebilizumab

CD19 targeting is mechanistically important because it captures plasmablasts and some plasma cells in addition to mature B cells. These antibody-secreting cells have typically lost CD20 expression and therefore escape anti-CD20 therapy. In conditions where pathogenic antibodies are produced by CD20-negative cells, CD19-directed therapies may achieve more complete depletion of the relevant effector population. Inebilizumab (FDA approved for NMOSD) is the prototype, but additional CD19-targeting agents are in development.

Targeted T-Cell Therapies

While B-cell-directed therapies dominate the emerging pipeline for most antibody-mediated neurologic conditions, T-cell-targeted agents remain relevant for diseases in which cellular immunity plays a primary or contributory role.

Alemtuzumab (Anti-CD52)

Alemtuzumab depletes both B and T cells through targeting CD52. It is FDA approved for relapsing MS but its use is restricted to patients who have had inadequate responses to two or more other disease-modifying therapies, owing to serious autoimmune adverse effects including thyroid disease, immune thrombocytopenia, and anti-glomerular basement membrane disease. It is not commonly used outside of MS.

Abatacept

Abatacept is a CTLA-4 immunoglobulin fusion protein that blocks T-cell costimulation by preventing CD80/CD86 interaction with CD28. It is FDA approved for rheumatoid arthritis and is under investigation for immune-mediated neurologic conditions in which T-cell activation plays a pathogenic role.

Vidofludimus Calcium (IMU-838)

Vidofludimus calcium is a dihydroorotate dehydrogenase (DHODH) inhibitor that targets activated T and B cells by inhibiting de novo pyrimidine synthesis, which is required for lymphocyte proliferation. It is currently in Phase 3 trials for relapsing MS and represents a potential oral alternative to injectable therapies.

CAR-T Cell Therapy and Cellular Therapies

Chimeric antigen receptor (CAR) T-cell therapy represents a paradigm shift from conventional pharmacologic immunosuppression to cellular immunotherapy. Originally developed for hematologic malignancies, CAR-T cell therapy is now being explored for refractory autoimmune diseases with remarkable early results.

CD19 CAR-T Cells

CD19 CAR-T cells are autologous T cells engineered to express a chimeric antigen receptor targeting CD19-positive B cells. Upon infusion, these engineered T cells seek out and eliminate CD19-expressing B cells, achieving deep and potentially durable B-cell depletion that may exceed what is achievable with antibody-based therapies.

The key advantage over rituximab and other anti-CD20 antibodies is that CAR-T cells may access tissue-resident B cells in lymphoid organs and other compartments not effectively penetrated by monoclonal antibodies. Preliminary results in refractory systemic lupus erythematosus (SLE) have been dramatic, with multiple case series demonstrating sustained remissions following a single infusion of CD19 CAR-T cells.

Ongoing investigations include applications in refractory NMOSD, refractory MG, and anti-NMDA receptor encephalitis. However, significant risks must be considered:

• Cytokine release syndrome (CRS): systemic inflammatory response from massive T-cell activation; ranges from mild fever to life-threatening multiorgan failure
• Immune effector cell-associated neurotoxicity syndrome (ICANS): encephalopathy, seizures, cerebral edema; particularly concerning in patients with pre-existing neurologic disease
• Prolonged immunosuppression: deep B-cell depletion and hypogammaglobulinemia may persist for months to years
• Infections: increased susceptibility during B-cell aplasia
• Uncertain long-term safety: long-term consequences in autoimmune populations remain unknown

CAR-T cell therapy for autoimmune neurologic conditions is currently investigational and not yet standard of care.

BCMA-Targeted CAR-T Cells

B-cell maturation antigen (BCMA) is expressed on plasma cells, including long-lived plasma cells that reside in bone marrow niches and continuously produce antibodies. BCMA-targeted CAR-T cells could eliminate these long-lived plasma cells that are resistant to both anti-CD20 and anti-CD19 therapies. This approach is under early investigation for antibody-mediated autoimmune diseases and may be particularly relevant for conditions in which pathogenic antibodies are produced by long-lived plasma cells.

Regulatory T-Cell (Treg) Therapy

Adoptive transfer of expanded regulatory T cells aims to restore immune tolerance rather than simply depleting pathogenic immune cells. This approach is under investigation for MS, type 1 diabetes, and other autoimmune conditions. Its potential application in autoimmune neurologic conditions is conceptually appealing but remains in very early stages of development.

Precision Medicine Approaches

The growing understanding of pathogenic mechanisms in neuroimmunologic conditions is enabling a shift from empiric immunosuppression toward rationally targeted therapy. Two key principles drive this evolution: biomarker-guided treatment decisions and antibody subclass-directed therapy selection.

Biomarker-Guided Therapy

Serum neurofilament light chain (NfL) is emerging as a biomarker of neuroaxonal injury across multiple neurologic conditions. In neuroimmunology, NfL levels can help guide treatment decisions by providing an objective measure of ongoing neural damage and can be used to monitor treatment response over time.

Glial fibrillary acidic protein (GFAP) is a marker of astrocytic injury that is characteristically elevated in NMOSD and GFAP astrocytopathy. Serum GFAP levels may complement NfL in distinguishing conditions with primary astrocytic injury from those with primarily neuronal or axonal damage.

MOG-IgG titers have prognostic implications in MOGAD: seroconversion to negative is associated with a lower relapse risk and may guide decisions about maintenance treatment duration and cessation.

B-cell monitoring is critical for timing rituximab re-dosing in NMOSD, as relapses have been observed coinciding with B-cell repopulation, particularly the CD27+ memory B-cell subset.

Antibody Subclass-Directed Therapy

The IgG subclass of pathogenic antibodies has direct implications for mechanism of injury and rational therapeutic selection:

Understanding the specific pathogenic mechanism—whether complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, direct receptor blockade, or receptor internalization—enables rational therapy selection and avoids exposing patients to therapies unlikely to address their disease mechanism.

Key Ongoing Clinical Trials

Challenges and Future Directions

References

1. McKeon A, Pittock SJ. Overview and diagnostic approach in autoimmune neurology. Continuum (Minneap Minn). 2024;30(4):960-994.
2. Sechi E, Flanagan EP. NMOSD and MOGAD. Continuum (Minneap Minn). 2024;30(4):1052-1090.
3. Muller F, Boeltz S, Knitza J, et al. CD19-targeted CAR T cells in refractory antisynthetase syndrome. N Engl J Med. 2023;388(25):2344-2348.
4. Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N Engl J Med. 2019;381(7):614-625.