Monoclonal Antibodies As Neurological Therapeutics Part 3

Inebilizumab is a humanized mAb targeting CD19 which is expressed on a wider lineage of B cells, including early pro-B cells, and persisting through maturation to some short-lived plasmablasts and plasma cells spared by anti-CD20 agents [49,188,189]. 

Memory is an important factor in ensuring that our lives function properly. It helps us draw wisdom from past experiences and make correct decisions, while also protecting us from danger. However, people often feel that they cannot remember or forget important events, information, or data, which may affect their lives and work.

Targeting is a way of doing things that focuses on efficiency and elegance. It focuses energy on the most important things, thereby improving work efficiency. The essence of this method is to work with focus and not be affected by distractions so that people can concentrate more easily and complete work tasks better. If we combine targeting and memory, we can cope with various challenges in life and better achieve our goals.

There are two ways to improve memory and achieve targeting. The first way is to exercise the brain. Just as the body needs exercise, the brain also needs constant exercise and training. For example, we can improve our memory by reading, learning new skills, playing intellectual games, etc. These activities can help us improve the flexibility and reaction speed of the brain, and improve our ability to remember and understand various information.

The second way is to get rid of distractions. If we want to focus on an important thing, we should try to avoid distractions. For example, turning off mobile phones and social media, avoiding watching TV or talking to others at work, etc., can help us focus on the current work, thereby improving work efficiency and memory.

In summary, targeting and memory are related, and they can grow together. By exercising the brain and getting rid of distractions, we can improve our memory and targeting ability. This can not only help us complete work tasks better, but also improve our quality of life, make us more energetic, and full of excellent life and work performance. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammation in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

Click know supplements to boost memory

Inebilizumab is at an early stage of development for relapsing MS, but in a phase I trial it has shown a trend towards a decrease in new/newly enlarging and gadolinium-enhancing lesions on brain MRI [49]. Daclizumab, a humanized antibody directed at IL2R-α (CD25) was originally approved for the prevention of renal allograft rejection. Daclizumab blocks the high-affinity IL-2 receptors, which contain the α subunit (CD25). 

Medium-affinity receptors, on the other hand, consist of two β subunits (CD122) and are not affected by daclizumab. Its net effect is thought to be a suppression of T-cell responses and expansion of CD56bright natural killer cells [18]. 

It was tested in subcutaneous injections against placebo and interferon-β-1α and demonstrated efficacy in RRMS [19–21]. Nevertheless, the high affinity IL-2 receptor is also present on natural regulatory T cells (CD4CD25Foxp3 Tregs), which are decreased by 60% under daclizumab treatment [22]. 

This effect may explain the development of serious adverse reactions, including fulminant autoimmune hepatitis, which led to restrictions on its use only for patients who had not responded to two other disease-modifying therapies. Following reports of secondary autoimmune reactions, including cases of encephalitis it was voluntarily withdrawn from the market (EMA press release) [23]. 

Finally, opicinumab is a human monoclonal antibody that targets LINGO-1, a protein known to suppress remyelination and regrowth of transected axons. By blocking LINGO1, opicinumab has been shown to promote remyelination in vivo [133]. 

In a phase II clinical trial, in patients with optic neuritis failed to reach significance in recovery of latency in visual evoked potentials, using the contralateral eye as a baseline, compared to placebo [134]. 

A phase II RCT of ipilimumab as an add-on therapy to intramuscular IFN-β1a showed an inverted U-shaped dose-response regarding the primary endpoint (percentage of participants with confirmed improvement over 72 weeks of treatment), but the treatment effect was not statistically significant [135]. However, some subpopulations of the study seemed to benefit from the treatment. Therefore, further research is needed to better assess the potential benefits of opicinumab [135].

6.2. Migraine

Four mAbs were recently approved by the FDA as prophylactic treatments for migraine. All of them target the calcitonin gene-related peptide (CGRP), a key mediator in the pathogenesis of the disease. 

Mabs are the only disease-specific and mechanism-based prophylaxis for episodic and chronic migraine. Erenumab is the only fully human mAb and targets the CGRP receptor whilst eptinezumab, fremanezumab, and galcanezumab target the CGRP ligand [34,35,40,42–45]. 

The pooled percentage of patients that exhibited at least a 50% reduction in mean migraine days per month in a meta-analysis of phase III trials of anti-CGRP mAbs in episodic migraine was 50.8% (95% CI 44.9%–56.6%) and 41.8% (95% CI 24.6%–60.1%) in phase III trials of chronic migraine [190]. Galcanezumab was also proven to be efficacious in cluster headaches. [46]. 

Their favorable risk-benefit profile and high tolerability reflected in low drop-out rates observed in clinical trials paved the way for a new era in the preventive treatment of migraine [190,191]. 

Long-term open-label studies exceeding 1 year for fremanezumab and galcanezumab and 5 years for erenumab indicated good tolerance and demonstrated sustained improvements in many efficacy measures, suggesting that the primary disadvantage of these mAbs is their high cost [36,41,47].

6.3. Neuromyelitis Optica Spectrum Disorder (NMOSD)

Neuromyelitis optica spectrum disorder (NMOSD), or Devic disease, is a chronic autoimmune condition in which a humoral response targets astrocytes leading to inflammatory demyelinated lesions affecting primarily the optic nerves, spinal cord, and brainstem. 

In most cases, NMOSD is associated with the presence of pathogenic anti-AQP4 antibodies [192]. The most commonly used disease-modifying treatments for NMOSD are azathioprine and rituximab [193]. 

Rituximab, an anti-CD20 mAb depleting B cells has shown efficacy in preventing relapses in several case series and retrospective analyses [78–83]. Inebilizumab, a humanized mAb targeting CD19, received FDA approval for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are seropositive for immunoglobulin G autoantibodies against aquaporin-4 (AQP4-IgG) in June 2020 [50]. 

Tocilizumab is an anti-interleukin 6 receptor (IL-6R) antibody blocking IL-6R signaling [194]. Interleukin 6 (IL-6) production has been reported to increase in NMOSD and to enhance AQP4-IgG secretion. 

Studies have shown a favorable effect of tocilizumab in NMOSD patients who have failed to respond to other therapies [109,110,195]. Similar to tocilizumab, natalizumab is another humanized anti-IL-6 receptor IgG2 mAb licensed as a disease-modifying treatment for anti-AQP4 seropositive NMOSD based on two successful phase III trials [107,108]. 

Another mAb proved to be efficacious in the treatment of NMOSD is eculizumab, a humanized antibody that reduced relapse rates from 43% to 3% in the treated group in patients with AQP4-IgG-seropositive NMOSD [28]. Autoantibodies against AQP4 are known to exert their cytotoxic action via complement activation [51,52]. 

Eculizumab inhibits the activation of the terminal complement protein (C5) pathway by binding specifically and with high affinity to C5 [29]. 

Ravulizumab, a newer humanized mAb against C5 with a less frequent infusion regimen compared to eculizumab is being evaluated for efficacy and safety in a Phase 3, placebo-controlled, open-label, multicenter study in adult patients with anti-AQP-4 (+) neuromyelitis optica spectrum disorder (NMOSD) [136]. 

A recent meta-analysis of clinical trials of eculizumab, ibalizumab, rituximab, and natalizumab revealed that these mAbs significantly reduced annualized relapse rate (mean reduction −0.27, 95% CI: −0.36 to −0.18, p < 0.0001) and disability (mean Expanded disability status scale (EDSS) score reduction −0.51, 95% CI: −0.92 to −0.11, p = 0.01). 

In a subgroup analysis eculizumab was found more effective in decreasing on-trial relapse risk in anti-AQP-4+ patients [30]. 

Finally, aquaporumab is a nonpathogenic high-affinity recombinant human monoclonal antibody with slow washout competing with the pathogenic AQP4 autoantibody. 

Aquaporumab, which has not yet entered clinical trials, is a product of clonally expanded plasmablasts from the CSF of NMOSD patients with mutated Fc region to eliminate effector functions of complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity [117,118].

6.4. Idiopathic Inflammatory Myopathies (IIM)

The Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of immune-mediated myopathies comprising: dermatomyositis (DM), polymyositis (PM), inclusion body myositis, immune-mediated necrotizing myopathy, antisynthetase syndrome [196]. 

There is evidence of the efficacy of mAbs in inflammatory myopathies. Rituximab was used in an open-label study of 6 patients with dermatomyositis refractory to previous treatments and resulted in clinical improvement in muscle strength, rash, alopecia, and forced vital capacity measurements, correlating with time of B cell depletion by rituximab. [84]. Similar results have been found in small open-label clinical trials involving polymyositis [85]. 

The Rituximab in Myositis (RIM) trial was a randomized double-blind, placebo-controlled trial of refractory juvenile and adult DM and PM patients. Although it did not meet its primary or secondary endpoints of efficacy, 83% of myositis patients met the clinical studies group definition of improvement [86]. 

In addition, rituximab had a steroid-sparing effect, it reduced the incidence of skin rashes and it was more beneficial in patients with myositis autoantibodies [87,88]. The report of increased tumor necrosis factor (TNF) levels in dermatomyositis and polymyositis has led to the trial of the TNF-blocking agents etanercept and infliximab in both conditions [197]. 

A small pilot randomized, double-blind placebo-controlled trial in patients with refractory active DM and PM supported the efficacy of infliximab [198]. The results of tocilizumab, a mAb, which binds and inhibits both soluble and membrane-bound IL-6 receptors in a phase 3 trial in DM and PM are also expected shortly [111]. 

Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy affecting the elderly. Bimagrumab-a fully human monoclonal antibody blocking the activin type II receptor (ActRII-A and ActRII-B) and preventing binding to their natural ligands (myostatin, activin and growth and development factor 11), was tried in individuals with inclusion body myositis in a randomized, double-blind, placebo-controlled phase 2b trial (RESILIENT) but failed to meet its primary end-point (increased 6-min walking distance) or improve muscle strength [199]. 

Alemtuzumab has been studied as a potential therapy in the treatment of inclusion body myositis in a small open-label trial with promising results [200].

6.5. Myasthenia Gravis (MG)

Rituximab is commonly used in refractory cases of myasthenia gravis (MG) in which conventional immunomodulatory therapies have failed, even though evidence suggests that rituximab performs better in new-onset generalized MG than in cases that have become refractory to conventional immunosuppressants [89]. 

Uncontrolled studies have provided evidence of efficacy in several measures of efficacy such as clinical improvement, time to relapse, reduction in steroid use [90], decrease in antibody titers [91], and reduced in-hospital costs in a proportion of MG patients [92–97]. 

The efficacy of rituximab may be more pronounced in anti-Musk Ab MG, in which clinical improvement is associated with a significant reduction in anti-Musk Ab titers, even to levels below detection [94,95,97,98]. 

Several empirical rituximab dosing regimes have been used; fixed repeat infusions every 3 or 6 months, repeat infusions when there is clinical exacerbation and others suggest using peripheral blood CD27+ memory B cells as a biomarker of impending MG reactivation [99]. Other anti-CD20 mAbs already licensed for MS such as ocrelizumab or ofatumumab could prove even more beneficial in MG given their 100% human composition. 

However, they have not been tested for MG and they would still not overcome the limitation of all CD20 mAbs, which is that they do not target plasmablasts and plasma cells that do not express CD20. 

Survival of long-lived plasmablasts may explain why several MG patients do not respond to rituximab. Monoclonal Abs targeting CD19 (e.g., ibalizumab) or CD38 (TAK079) also expressed on some plasma cells could theoretically outperform rituximab but no data on the effects of this strategy exists yet [201]. 

On the other hand, eculizumab, which is a humanized mAb against C5 complement protein, originally used to treat paroxysmal nocturnal hemoglobinuria (PNH) is an approved treatment option for generalized AChR antibody-positive MG. Eculizumab inhibits the C5 convertase and thereby limits the formation of the terminal complement lytic complex [29,31]. It is safe and efficacious for refractory MG. 

REGAIN, a phase 3 double-blind, placebo-controlled study of eculizumab enrolled 125 treatment-refractory AChR+ patients with generalized MG of moderate to severe severity at 72 centers in Asia, Europe, Latin, and North America. 

The primary endpoint, the mean ranked difference in the change in myasthenia gravis activities of daily living (MG-ADL) score between baseline and placebo at week 26 was not met despite significant change in 18 of 21 secondary efficacy measures. 

Improvement in MG-ADL was noted from the first week after infusion, it was maximal around 12 weeks and was maintained for the duration of the 130-week observation [32]. 

Nevertheless, this is only relevant to AchR antibody + MG as in most MuSK+ cases damage is not mediated via complement pathway activation and its efficacy in double seronegative MG is unknown [91]. 

In addition, genetic variants of C5 have been shown to compromise response to eculizumab [33]. Life-threatening meningococcal infection is the most significant adverse effect of eculizumab, which necessitates vaccination against Neisseria meningitidis before treatment onset [32]. 

Ravulizumab, a newer humanized mAb against C5 is being tested in generalized MG [138], with the advantage of a less frequent infusion regimen (every 8 weeks instead of every 2 weeks in the case of eculizumab). Another promising target for MG is the CD40-CD40L interaction. Iscalimab, a fully human non-cell-depleting mAb against CD40 blocks T cell-dependent antibody responses to both neo and recall antigens [202]. 

However, a double-blind, placebo-controlled, phase II trial in generalized MG did not show a statistically significant difference in QMG scores between the iscalimab group and placebo [203]. 

Blocking the neonatal FcRn receptor is yet another novel strategy for the treatment of MG. The FcRn binds to IgGs, including anti-AchR and anti-Musk antibodies thus preventing their degradation and leading to an increase in their titers. Rozanolixizumab, nipocalimab, and batoclimab are all human mAbs that bind the FcRn, leading to a reduction in auto-antibody titers. 

In phase 2a, a randomized, double-blind, placebo-controlled trial, rozanolixizumab once-weekly SC infusions failed to demonstrate a significant change in QMG from baseline to day 29 despite a reduction in anti-AchR levels. 

Nevertheless, considering a range of pre-specified clinical efficacy measures (QMG, MG-ADL, and MGC), the data suggest rozanolixizumab has the potential to provide clinical benefit in patients with moderate-to-severe generalized MG and was well tolerated [140]. 

Nipocalimab (M281) has also completed a phase II study of generalized MG with positive results and the batoclimab (HBM9161) phase II trial is currently recruiting [119,132,204]. 

Efgartigimod is an investigational antibody fragment targeting the neonatal Fc receptor (FcRn) with positive results in completed phase II and III trials of generalized MG [125,126]. 

In the phase II trial all patients treated with efgartigimod showed a rapid decrease in anti-AChR autoantibody levels and 9 out of the 12 efgartigimod-treated patients exhibited a rapid and long-lasting improvement in all 4 measures of efficacy (Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and revised 15-item Myasthenia Gravis Quality of Life scale) [125].

For more information：1950477648nn@gmail.com