Monoclonal Antibodies As Neurological Therapeutics Part 4

6.6. Immune-Mediated Peripheral Neuropathies

Rituximab has been tried in several peripheral neuropathies, which are thought to be antibody-mediated and do not respond to the administration of intravenous immunoglobulins or require very frequent infusions. 

Rituximab is a monoclonal antibody drug that can treat a variety of cancers. With the continuous development of medical technology in recent years, rituximab has been widely used in clinical practice and has become one of the conventional drugs for treating a variety of cancers.

The main function of rituximab is to inhibit the growth and spread of tumors by blocking a growth factor in the human body. Similarly, rituximab can also help patients enhance their immunity and improve their body's resistance, to better resist the invasion and spread of cancer.

In addition to its therapeutic effect on cancer, rituximab has also been found to help protect and improve the human body's intelligence and memory. Studies have found that rituximab can promote the growth and regeneration of brain cells, thereby improving the human body's memory and intelligence to a certain extent.

Furthermore, rituximab can also reduce the inflammatory response of the brain and nervous system, and relieve the pressure and load of the nervous system to a certain extent, thereby protecting and improving the human body's intelligence and memory.

In daily life, we should maintain good eating habits and a healthy lifestyle. At the same time, we can also consider some auxiliary treatment methods, such as the use of drugs such as rituximab, to better protect and improve our memory and intelligence levels, making our lives better and more positive. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche can also improve blood flow and promote oxygen delivery, which can ensure that the brain obtains sufficient nutrition and energy, thereby improving brain vitality and endurance.

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In multifocal motor neuropathy (MMN), a rare, symmetric, demyelinating, purely motor neuropathy, rituximab has had conflicting results: one case report showed yearly rituximab infusions resulting in reduction of IVIG dosage from every seven days to every 12 days over five years, [100] but another showed that in two patients with MMN, one had a decrease in total IVIG dosage while the other required an increase, whilst there was no significant clinical improvement, or change in Rankin disability scores [101]. 

In addition, anti-myelin-associated glycoprotein (anti-MAG) neuropathy, a chronic sensorimotor demyelinating polyneuropathy is another entity in which rituximab has been tested. 

Open-label studies indicate that 30–50% of patients respond to rituximab [205] and two double-blind placebo-controlled trials confirmed these findings [102,103]. 

In a double-blind, placebo-controlled RCT of rituximab in anti-MAG neuropathy, four of 13 patients treated with rituximab showed improvement in leg disability scores whereas none of 13 placebo patients showed improvement. Also, there was a significant reduction in time to ten-meter walk in the rituximab group [102]. 

Gazzola et al. retrospectively also found that rituximab was effective in 10/33 patients and that the beneficial response lasted 42 ± 23 months after an average 5-year follow-up [104]. 

With all available treatments for chronic inflammatory demyelinating polyneuropathy (CIDP), one in three cases remains refractory, indicating that there is a need for efficacious alternatives [206]. 

Rituximab has been tried in CIDP with some case reports suggesting a favorable response [85,101]. Muley et al. A small retrospective study of 11 patients with refractory CIDP described a rapid and in many cases impressive response, indicating that rituximab may be a useful alternative to established treatments [105]. 

A subcutaneous efgartigimod phase II study in adults with CIDP (ADHERE trial) has recently commenced recruiting [127]. 

Interestingly, eculizumab was examined in phase II, a randomized, placebo-controlled, masked trial in 34 subjects with Guillain–Barré syndrome, which indicated that eculizumab was safe but it did not achieve a clinical measure of efficacy [207]. 

6.7. Neurooncology

Advances in our understanding of the genetic and cellular changes that drive carcinogenesis in the brain have been translated into new treatment targets. Targeting cell signaling pathways with mAbs is a promising strategy in oncology. 

However, in the case of brain tumors, the BBB is a special concern as it may prevent therapeutic antibody entry to the parenchyma [208]. 

Bevacizumab, a humanized recombinant monoclonal antibody that targets vascular endothelial growth factor (VEGF), is well tolerated and efficacious in delaying tumor progression in the treatment of recurrent malignant glioma and is FDA-approved for recurrent glioblastoma [14–16,209]. 

Rilotumumab, a fully human IgG2 anti-hepatocyte growth factor (HGF) mAb, preventing activation of the c-Met receptor and tumor cell growth was not associated with significant antitumor activity in patients with recurrent glioblastoma in a phase II study [138]. 

A more recent phase II trial of rilotumumab combined with bevacizumab failed to significantly improve objective response compared with bevacizumab alone [17]. 

Preclinical safety data of a fully human, CD3-binding bispecific antibody (hEGFRvIIICD3-bi-scFv) for immunotherapy of malignant glioma have been reported [210]. 

The hEGFRvIII: CD3 bi-scFv mAb comprises two single-chain antibody fragments (bi-scFvs) that bind mutant epidermal growth factor receptor variant III (EGFRvIII), a mutation frequently seen in malignant glioma, and human CD3ε on T cells and aims to promote T cell-mediated destruction of glioma cells [211].

6.8. Alzheimer's Disease (AD)

Over the past three decades, our efforts to discover neuroprotective disease-modifying treatments for Alzheimer's disease (AD) have been dominated by the amyloid hypothesis [212]. 

Among other treatments aiming to reduce the load of Aβ in the brain parenchyma mAbs have been employed to target and promote Aβ clearance. Ponezumab, a humanized mAb against Aβ failed to show clinical benefits in a phase II trial and its development was discontinued [213]. 

Three anti-Aβ mAbs failed to show benefit in phase III trials and were terminated early; bapineuzumab and solanezumab in mild to moderate AD [214,215] and crenezumab in prodromal and mild AD [216]. 

Interestingly, in bapineuzumab trials, a spectrum of imaging alterations were observed on MRI, termed: amyloid-related imaging abnormalities (ARIA). These include FLAIR signal abnormalities thought to represent parenchymal vasogenic edema and sulcal effusions (ARIA-E), and signal changes on GRE/T2* sequences thought to represent microhemorrhages and hemosiderosis (ARIA-H). 

ARIAs are commonly asymptomatic and evidence suggests that they are associated with transient increases in vascular permeability and amyloid clearance. The greater incidence of ARIAs with bapineuzumab, compared to solanezumab or crenezumab is probably because it binds to both soluble and insoluble forms of Aβ [217]. 

Gantenerumab is currently being tested in two phase III trials of prodromal and mild AD at doses higher than those used in a previous phase III trial which was terminated early for futility [128,129]. 

Aducanumab, a human mAb targeting aggregated forms of Aβ had some initial promising results showing a significant decrease of Aβ and potential slowing of cognitive decline in phase I trials [112], but two phase III trials in prodromal to mild AD discontinued early for futility in March 2019 [113]. 

However, subgroup analysis of data from patients treated with high dose aducanumab in one of the two phase III trials (EMERGE trial) showed a 23% reduction in cognitive decline on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) score, along with a 27% reduction on the AD Assessment Scale–Cognitive Subscale 13 Items (ADAS-Cog-13) and a 40% reduction on the AD Cooperative Study–Activities of Daily Living Inventory for Mild Cognitive Impairment (ADCS-ADL-MCI) [114,115], keeping aducanumab, which is under consideration for FDA approval on track [116]. 

Donanemab (LY3002813), a humanized anti-Aβ is currently in a phase 2 clinical trial to evaluate the safety, tolerability, and efficacy of donanemab in mild AD. Although at its original design, this trial included an arm treated with donanemab in combination with a BACE 1 inhibitor (LY3202626), to inhibit the production of beta-amyloid, this treatment arm was dropped due to poor results of the BACE inhibitor in other trials. Completion of this study is expected in November of 2021. 

BAN2401 was shown to be safe and probably efficacious in Aβ load and slowing cognitive deterioration in a phase I and II trial [122,123]. Since March 2019, BAN2401 has been in the recruitment of a phase III trial enrolling prodromal to mild AD patients [124]. 

The lack of clear proof of the efficacy of Aβ targeting therapies so far has raised skepticism regarding the validity of the amyloid hypothesis, driving researchers to explore tau pathology as a plausible therapeutic target, particularly as cognitive decline in AD exhibits a better correlation with tau accumulation than with Aβ deposition [218–221]. 

Monoclonal antibodies targeting abnormal forms of tau protein and particularly soluble oligomers which appear to be the most neurotoxic form of p-tau [222] are being explored for efficacy in AD. 

To date, gosuranemab, zagotenemab, tilavonemab, and semorinemab are in Phase II trials of prodromal to mild AD [130]. RG7345, UCB0107, JNJ-63733657, and BIIB076 are other anti-tau mAbs at phase I clinical trials with RG7345 having already been discontinued [223]. 

Gosuranemab has also been tested in a phase II trial in progressive supranuclear palsy (PSP), another tauopathy manifesting with vertical gaze palsy, gait instability, other extrapyramidal signs, and dementia, but failed to meet its primary efficacy end-point, leading to its discontinuation (PASSPORT trial) [131].

6.9. Parkinson's Disease (PD)

There are no approved therapies that can modify the progressive course of Parkinson's disease (PD). α-Synuclein is a core component of Lewy bodies and neurites, a sine qua nonpathological feature of PD. a-Synuclein mutations are causative for some cases of familial PD and other lines of evidence support a key role of α-synuclein in PD pathogenesis [224]. 

Accumulation and aggregation of α-synuclein protein is observed throughout the nervous system in PD. Recent experimental data suggest that PD progression may arise due to the spreading of pathological forms of extracellular α-synuclein throughout the brain via a cellular release, uptake, and seeding mechanism. 

Cinpanemab, a recombinant humanized anti-α synuclein IgG1 mAb targeting aggregated α-synuclein is currently in Phase 2 trial (BIIB054) [120], which followed a single ascending dose phase 1 study [121]. 

Another high affinity α-synuclein mAb, (MEDI1341), which binds both monomeric and aggregated forms has been shown to sequester extracellular α-synuclein and attenuate its spreading in vivo. 

After intravenous injection into rats and cynomolgus monkeys, MEDI1341 rapidly enters the central nervous system and lowers free extracellular αsynuclein levels in the interstitial fluid (ISF) and CSF compartments. 

In a lentiviral-based in vivo mouse model of α-synuclein spreading in the brain, treatment with MEDI1341 significantly reduced α-synuclein accumulation [225]. 

MEDI1341 is now in Phase 1 clinical trial to develop it as progression progression-modifying treatment for PD and probably also other synucleopathies.

6.10. Duchene's Muscular Dystrophy (DMD)

Monoclonal antibody-mediated blockade of myostatin, a member of the transforming growth factor-β (TGF-β) family of ligands, has been shown to increase muscle mass and volume in wild-type mice and non-human primates and to increase muscle mass and improve function in murine models of DMD [226]. However, a phase 2 randomized placebo-controlled trial of domagrozumab, a humanized anti-myostatin mAb in 6 to 16-year-old children with DMD did not exhibit a significant treatment effect in its primary efficacy measure (time to 4 stair-climb) [227].

7. Safety Considerations of mAbs

Although mAbs have changed the treatment landscape in many neurological diseases, their ever-increasing use has been associated with several immune-mediated and other adverse reactions [228]. 

The development of fully human mAbs has significantly reduced their immunogenic potential and it has improved their tolerability, compared to earlier chimeric or humanized mAbs [229]. 

Nevertheless, even human mAbs maintain the potential for adverse reactions, such as anaphylactic reactions and infusion-related reactions (IRRs) [230]. Given the considerable overlap in manifestations of immunologically mediated reactions, it is frequently difficult to distinguish them on clinical grounds [231]. 

7.1. Infusion-Related Reactions (IRRs)

Infusion reactions are among the most common adverse events of mAb administration. IRRs are defined as "any signs or symptoms experienced by patients during the infusion of pharmacologic or biologic agents or any event occurring on the first day of drug administration [231]. 

Manifestations are typically related in time to drug administration and may range from pyrexia, pruritus, and rash, to dyspnea, generalized edema, and cardiac arrest [230]. 

Mild IRRs are considered common and most infusion protocols include strategies to prevent or minimize the severity of IRRs by prophylactic administration of antipyretics, antihistaminics, and corticosteroids. 

IRRs manifest within 24 h, but they occur most frequently from 10 min to 4 h from the onset of administration [229]. When these reactions appear and depending on their intensity and severity, infusion may have to be slowed down or stopped and the manifestations may have to be specifically managed.

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