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INNOSC Theranostics and
Pharmacological Sciences Antibody therapeutics in Alzheimer’s

elderly, causing dementia characterized by abnormal failures, highlighting the need for further exploration
protein deposits leading to plaques and tangles. These and understanding of these therapies. Despite recent
manifestations result in gradual nerve cell degeneration developments in monoclonal antibody research and the
and impaired communication. Clinical studies focusing emergence of disruptive therapeutics such as variable
1
on immunotherapy targeting amyloid beta (Aβ) face heavy chain domains, which are VHHs (Table 1),
challenges due to the observed lack of correlation between their potential application in CNS disorders remains
Aβ levels and dementia severity, which raises questions underexplored due to the inherent challenge of these
about the capabilities of Aβ-focused interventions. agents crossing the blood–brain barrier (BBB). Recent
2
10
Current United States Food and Drug Administration- setbacks, such as the termination of the variable heavy
approved drugs, including acetylcholinesterase inhibitors chain domains B (VHH-B) clinical trial, underscore the
(e.g., donepezil and rivastigmine) and aducanumab, critical need for innovative systems and a comprehensive
which target Aβ plagues, offer temporary relief by understanding of the molecular mechanisms involved
delaying the progression of AD. However, they fail in targeting key proteins such as BACE1 and tau. The
11
to reverse neuronal loss, brain atrophy, or cognitive proposed gene transfer method using adeno-associated
decline. Aβ, derived from amyloid precursor protein virus (AAV)-based vectors offers a novel avenue for
3
cleavage, is a central focus of therapeutic research, with effectively delivering therapeutic antibodies into the
drugs targeting β- or γ-secretase and Aβ aggregation. CNS. Moreover, investigating the system of anti-tau
4-6
However, these approaches provide limited benefits and therapeutics, including passive immunization, active
may lead to adverse effects. Recent findings suggest that tau-targeted vaccines, and tau aggregation inhibitors,
Aβ immunotherapy not only reduces Aβ but also lowers is imperative for advancing the field and addressing the
tau levels in animal models. This discovery has prompted challenges posed by tau-related disorders. Therefore,
researchers to explore tau immunotherapy as a promising this review aims to address these gaps by elaborating
avenue, particularly in early-stage AD, given the evident on current studies exploring gene transfer methods to
interaction between Aβ and tau. The development of deliver therapeutic agents directly into the CNS, with the
7-9
single-domain antibodies (VHHs) stemmed from the goal of offering insights into therapies inhibiting BACE1
limitations of conventional antibodies, such as their and advancing our understanding of their therapeutic
larger size, limited tissue penetration, and susceptibility potential. This article holds significant implications for
to denaturation and aggregation, which hindered their both preclinical and clinical studies. For instance, it could
effectiveness in targeting specific epitopes, particularly in contribute to the broader understanding of antibody-
the central nervous system (CNS). 7 based therapies in neurodegenerative disorders, shedding
Antibody-based therapies offer a promising light on the challenges and opportunities associated with
alternative to small-molecule drugs, especially when VHHs in applications. In addition, discussions on tau-
comparing inhibitors of beta-secretase 1 (BACE1) to related therapeutics offer a comprehensive overview,
VHHs targeting BACE1. However, the development of laying a foundation for refining existing scientific models
BACE1 inhibitors has faced challenges leading to their and developing innovative methods.

Table 1. Studies and clinical trials on VHH‑based therapeutics for CNS disorders
Study/ Focus Findings Implications
Clinical trial
Singh et al. 10 Monoclonal antibody research and Underexplored potential Highlights the need for innovative approaches
VHHs in CNS disorders due to BBB challenge
Das and Yan 11 Molecular intricacies of Termination of the VHH-B trial Calls for a comprehensive approach in
targeting BACE1 and tau emphasizes the need for understanding targeting key proteins
Marino et al. 14 Gene transfer method using AAV-based Promising results in inhibiting BACE1 Offers novel avenue for effective CNS delivery
vectors to deliver VHHs into CNS
Yadav et al. 15 Infusion of anti-BACE1 antibodies via Significant reduction in Aβ peptides in Highlights potential of direct CNS injection for
i.c.v. administration in primates CSF and brain parenchyma uniform antibody distribution
Burns et al. 16 VHH-B clinical trial termination due to Emphasizes the need for further Caution in translating to human CNS disorders
safety concerns refinement of VHH-based therapeutics
Abbreviations: AAV: Adeno-associated vector; Aβ: Amyloid beta; BACE1: Beta-secretase 1; BBB: Blood–brain barrier; CNS: Central nervous system;
CSF: Cerebrospinal fluid; i.c.v.: Intracerebroventricular; VHH: Single-domain antibody.

Volume 7 Issue 3 (2024) 2 doi: 10.36922/itps.2953