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INNOSC Theranostics and
Pharmacological Sciences Antibody therapeutics in Alzheimer’s

2. Innovative approaches and challenges accompanied by a low brain concentration (approximately
in variable heavy chain domains-based 0.6 nM) of anti-BACE1 antibodies. 15
therapeutics for CNS disorders Despite promising results in preclinical studies, the
translation of VHH-based therapies to clinical trials has
Monoclonal antibodies have emerged as an important faced challenges. The VHH-B clinical trial, terminated
field in research, offering targeted interventions against in 2021, was deemed unsafe for human subjects due to
specific molecules such as lipids and proteins. Within this unforeseen changes in cognitive function, brain volume
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realm, VHHs, known for their potential as revolutionary loss, and body weight loss. This finding highlights the
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treatments, are gaining scientific recognition. Despite imperative for further investigation and refinement of
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their versatility in addressing medical challenges, these
antibodies have seen limited application in neurological VHH-based therapeutic methods before their application
disorders due to the formidable obstacle posed by BBB. in human CNS disorders.
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In a recent study, researchers devised a gene transfer 3. Advancements and strategies in anti-tau
strategy utilizing vectors equipped with BBB-crossing therapeutics
capabilities to deliver therapeutic molecules directly
into the CNS of mammals. Specifically, the study aimed Tau, a microtubule-associated protein crucial for
to inhibit a key enzyme in the brain using a developed stabilizing axonal microtubules, becomes problematic
VHH named VHH-B9. The results indicated a high when deposited abnormally, leading to various diseases,
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selectivity of VHH-B9 for BACE1, with a single systemic including dementia. Figure 1 illustrates the pathogenesis
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dose demonstrating enduring benefits such as improved of tau, highlighting the complexities involved. Current
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cognition in mice lasting up to 12 months This innovative therapeutic approaches target intracellular and
protocol holds promise for exploring therapeutic extracellular tau to hinder pathological tau formation,
interventions in neurological disorders. accumulation, and spread. The strategies involved
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encompass protein kinase inhibition, inhibition of tau
In another investigation by Yadav et al., anti-BACE1
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antibodies were infused into primate subjects through aggregation, antisense oligonucleotides, as well as active
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intracerebroventricular administration, resulting in a and passive immunotherapies. Notably, numerous small
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substantial and sustained reduction of up to 70% in Aβ molecules directly or indirectly modify tau aggregation.
peptides within the cerebrospinal fluid (CSF). Notably, The efficiency of tau immunotherapies was initially
direct CNS injection achieved uniform antibody demonstrated in the Janus kinase- and nucleotide-binding
distribution (20 – 40 nM) in the brain parenchyma, leading oligomerization domain-like receptor protein 3 mouse
to a 50% reduction in Aβ in cortical parenchyma. However, model, also known as JNPL3 in 2007, demonstrating
intravenous administration in nonhuman primates yielded reduced tau pathology in various brain regions. At
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non-significant changes in cortical or CSF Aβ levels, present, the majority of tau-targeted therapies in preclinical

Figure 1. Proposed mechanism of pathogenesis of Tau. 20

Volume 7 Issue 3 (2024) 3 doi: 10.36922/itps.2953