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INNOSC Theranostics and
Pharmacological Sciences Antibody therapeutics in Alzheimer’s

investigations revolve around immunotherapies. altered form of tau pathology. This first-generation
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In addition, passive immunization, which involves active immunotherapy targets 12 amino acid sequences
administering monoclonal immune-proteins, has marked in the microtubule-binding region of the tau protein.
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a significant growth. The development of passive Axon neuroscience initiated a phase 1 trial in May 2013
immunization techniques such as the JNJ-63733657 and with 30 patients with mild-to-moderate AD. The results
UCB0107 marks a significant improvement in the quest from the trial indicate high immunogenicity, with IgG
for effective anti-tau treatment, offering hope in the fight antibodies against tau peptides induced in 29 out of
against tau-related neurodegenerative diseases. 30 patients. Overall, AADvac-1 demonstrated encouraging
safety and tolerability profiles. The subsequent phase 2 trial
JNJ-63733657 is a humanized IgG1 monoclonal
antibody that targets the temperate region of tau and involved 196 patients with mild-to-moderate AD, meeting
the major objectives and secondary objectives, including
exhibits potential to prevent tau’s cell-to-cell propagation the evaluation of immunogenicity and treatment efficacy.
and aggregation. Janssen Research and Development
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conducted two phase 1 clinical trials, demonstrating 3.2. Tau aggregation inhibitor
safety and tolerability, pharmacokinetics, and The primary direct tau binder is methylene blue, also
pharmacodynamics of a drug candidate in a small group known as methylthionine chloride. Variants of methylene
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of healthy volunteers or patients. In a 2019 phase 1 trial,
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dose-dependent increases in exposures were reported, blue have demonstrated particular promise in blocking
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with CSF concentrations of approximately 0.2% of serum tau clumping. TRx0237 (LMTM), a second-generation
tau aggregation inhibitor for AD and frontotemporal
levels, and dose-dependent reductions in p217+ tau in dementia, is the purified form of methylene blue. Wilcock
CSF were observed. A phase 2 study commenced in and colleagues explored the effectiveness of LMTM as
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January 2021, involving 420 patients with the early AD monotherapy in a non-randomized cohort during an
symptoms and a positive tau PET scan, set to conclude in 18-month phase 3 trial in mild AD. The results supported
2025. Similarly, UCB0107 is a humanized monoclonal the hypothesis that it could be effective as monotherapy,
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IgG4 antibody that exhibits an affinity for binding to particularly when administered at a dose of 4 mg twice a
paired helical filaments of tau, recognizing amino acids day. Although the phase 3 trial did not slow cognitive or
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235–250 near tau’s microtubule-binding domain. Union functional decline in mild-to-moderate AD, re-investigation
Chimique Belge (UCB) completed a phase 1 trial in March of the data revealed a significantly lower brain atrophy
2019, assessing adverse events and pharmacokinetics in 24 rate in patients receiving monotherapy compared to those
healthy Japanese men who received a single, unspecified receiving placebo. A phase 3 trial with a lower dose has
UCB0107 dosage or placebo. The ongoing phase 2 trial been conducted and concluded in December 2022. 25
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aims to randomize 450 individuals with mild cognitive
impairment or mild AD dementia to different doses or a 4. Implications of findings
placebo for 80 weeks, concluding in 2025. 25
The ever-evolving nature of research addressing
3.1. Active tau-targeted vaccines neurological conditions presents promising avenues and
challenges for future exploration. The change from a singular
At present, ACI 35 and AADvac-1 are two active anti-
tau vaccines undergoing clinical research. ACI 35, a focus on Aβ in AD to an exploration of alternative targets
such as tau highlights the need for novel advancements
liposome-based vaccine, consists of 16 copies of synthetic in therapeutic methodologies. Innovations in VHH-based
tau fragments phosphorylated at S396 and S404. These therapies, such as the gene transfer method using AAV-
fragments are anchored into a lipid bilayer to stimulate the based vectors, offer the potential to overcome challenges
immune system and generate antibody proteins. In July associated with BBB penetration. However, setbacks in
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2019, AC Immune and Janssen initiated a small phase 1b/2a clinical studies, such as the termination of the VHH-B
trial to assess the safety and immunogenicity of ACI-35 in trial, indicate the imperative for rigorous preclinical
individuals with early AD. By July 2020, the lowest-dose investigation and improvement of methodology. In
cohort had completed the trial, revealing favorable safety, addition, utilizing VHH-based therapy is accompanied by
tolerability, and immunogenicity data. limitations, including potential immunogenicity, limited
In February 2022, interim data from the trial confirmed epitope diversity, and challenges in large-scale production
the consistent safety and potent immunogenicity of and formulation for therapeutic use. In addition, their
the p-Tau Alzheimer’s vaccine in a high-dose cohort in small size may lead to rapid renal clearance, necessitating
early AD. AADvac-1, an active vaccine, is designed to modifications to improve their pharmacokinetic
provoke an immune response against a pathologically properties. Therefore, this comprehensive review of anti-

Volume 7 Issue 3 (2024) 4 doi: 10.36922/itps.2953