Immunogenicity of MultiTEP platform technology-based Tau vaccine in non-human primates

Hovakimyan, Armine; Zagorski, Karen; Chailyan, Gor; Antonyan, Tatevik; Melikyan, Levon; Petrushina, Irina; Batt, Dash G.; King, Olga; Ghazaryan, Manush; Donthi, Aashrit; Foose, Caitlynn; Petrovsky, Nikolai; Cribbs, David H.; Agadjanyan, Michael G.; Ghochikyan, Anahit

doi:10.1038/s41541-022-00544-3

Cited by 8 publications

(7 citation statements)

References 87 publications

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“…To achieve robust and reliable immunogenicity, we applied our well-characterized universal vaccine platform MultiTEP, which is currently being evaluated in multiple preclinical IND enabling studies [ 42 , 43 , 44 , 46 , 68 ] and is in a first-in-human DNA vaccine Phase I clinical trial (NCT05642429). This vaccine platform is designed to induce strong immune responses in genetically diverse populations and potentially in immunosenescence individuals by activating pre-existing memory T helper cells with select universal foreign T helper (Th) epitopes.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, using short, well-characterized universal epitopes allows for the minimalistic design of the MultiTEP platform, reducing potential safety concerns. Finally, the MultiTEP protein spontaneously assembles into oligomeric nanoparticles, thus protecting the target epitopes from rapid degradation, efficiently delivering them to antigen-presenting cells, and providing additional stimulation to the B cells due to the simultaneous presentation of multiple copies of the antigen [ 44 ]. Thus, our preclinical data demonstrated exceptionally potent and robust immune responses towards various neurodegeneration-associated target molecules [ 42 , 43 , 46 ], and, in this work, we presented the first MultiTEP-based conjugate vaccine for a post-translationally modified target—specifically, pE 3 Aβ.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, taking advantage of the immunogenic and universal MultiTEP platform technology, we have developed and tested a vaccine candidate against pE 3 Aβ in a stringent 5XFAD mouse model of AD [ 41 , 42 , 43 , 44 , 45 , 46 ].…”

Section: Introductionmentioning

confidence: 99%

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Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer’s Disease

Zagorski

King

Hovakimyan

et al. 2023

IJMS

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Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 (pE3Aβ) is a highly pathogenic molecule with increased neurotoxicity and propensity for aggregation. In the brains of Alzheimer’s Disease (AD) cases, pE3Aβ represents a major constituent of the amyloid plaque. The data show that pE3Aβ formation is increased at early pre-symptomatic disease stages, while tau phosphorylation and aggregation mostly occur at later stages of the disease. This suggests that pE3Aβ accumulation may be an early event in the disease pathogenesis and can be prophylactically targeted to prevent the onset of AD. The vaccine (AV-1986R/A) was generated by chemically conjugating the pE3Aβ3-11 fragment to our universal immunogenic vaccine platform MultiTEP, then formulated in AdvaxCpG adjuvant. AV-1986R/A showed high immunogenicity and selectivity, with endpoint titers in the range of 105–106 against pE3Aβ and 103–104 against the full-sized peptide in the 5XFAD AD mouse model. The vaccination showed efficient clearance of the pathology, including non-pyroglutamate-modified plaques, from the mice brains. AV-1986R/A is a novel promising candidate for the immunoprevention of AD. It is the first late preclinical candidate which selectively targets a pathology-specific form of amyloid with minimal immunoreactivity against the full-size peptide. Successful translation into clinic may offer a new avenue for the prevention of AD via vaccination of cognitively unimpaired individuals at risk of disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer’s Disease

Zagorski

King

Hovakimyan

et al. 2023

IJMS

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“…The greater number of studies involve MABs, and the TANGO trial with the humanized MAB, gosuranemab, which like other anti-tau MABs (semorinemab and tilavonemab) directed at the N-terminal region of tau, showed no significant benefits (see Table 2 ; Monteiro, et al, 2023 ). AV-1980R/A, which targets the N-terminus of tau, has also shown promise in cynomolgus Monkeys ( Macaca fascicularis ) with a robust anti-tau antibody response, which, in theory, should reduce tau tangles ( Hovakimyan et al, 2022 ). Subject to positive data from trials in humans this MAB could be used in patients at risk of AD.…”

Section: Hypotheses and Drug Targetsmentioning

confidence: 99%

Alzheimer’s disease and its treatment–yesterday, today, and tomorrow

Kim,

Al Jerdi,

MacDonald

et al. 2024

Front. Pharmacol.

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Alois Alzheimer described the first patient with Alzheimer’s disease (AD) in 1907 and today AD is the most frequently diagnosed of dementias. AD is a multi-factorial neurodegenerative disorder with familial, life style and comorbidity influences impacting a global population of more than 47 million with a projected escalation by 2050 to exceed 130 million. In the USA the AD demographic encompasses approximately six million individuals, expected to increase to surpass 13 million by 2050, and the antecedent phase of AD, recognized as mild cognitive impairment (MCI), involves nearly 12 million individuals. The economic outlay for the management of AD and AD-related cognitive decline is estimated at approximately 355 billion USD. In addition, the intensifying prevalence of AD cases in countries with modest to intermediate income countries further enhances the urgency for more therapeutically and cost-effective treatments and for improving the quality of life for patients and their families. This narrative review evaluates the pathophysiological basis of AD with an initial focus on the therapeutic efficacy and limitations of the existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, and the N-methyl-D-aspartate receptor (NMDA) receptor allosteric modulator, memantine. The hypothesis that amyloid-β (Aβ) and tau are appropriate targets for drugs and have the potential to halt the progress of AD is critically analyzed with a particular focus on clinical trial data with anti-Aβ monoclonal antibodies (MABs), namely, aducanumab, lecanemab and donanemab. This review challenges the dogma that targeting Aβ will benefit the majority of subjects with AD that the anti-Aβ MABs are unlikely to be the “magic bullet”. A comparison of the benefits and disadvantages of the different classes of drugs forms the basis for determining new directions for research and alternative drug targets that are undergoing pre-clinical and clinical assessments. In addition, we discuss and stress the importance of the treatment of the co-morbidities, including hypertension, diabetes, obesity and depression that are known to increase the risk of developing AD.

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“…Conversely, over 17 years ago, we decided to develop an immunogenic and safe vaccine for the prophylactic treatment of cognitively unimpaired individuals over 50 years old at risk of AD. To generate therapeutically potent antibodies in asymptomatic, vaccinated people, we developed a novel vaccine platform, MultiTEP [ 6 , 7 , 8 , 9 , 10 , 11 ]. This innovative vaccine platform consists of a string of promiscuous foreign T helper (Th) cell epitopes derived from pathogens and a synthetic Th epitope called PADRE [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

mRNA Vaccine for Alzheimer’s Disease: Pilot Study

Hovakimyan,

Chilingaryan,

King

et al. 2024

Vaccines

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The escalating global healthcare challenge posed by Alzheimer’s Disease (AD) and compounded by the lack of effective treatments emphasizes the urgent need for innovative approaches to combat this devastating disease. Currently, passive and active immunotherapies remain the most promising strategy for AD. FDA-approved lecanemab significantly reduces Aβ aggregates from the brains of early AD patients administered biweekly with this humanized monoclonal antibody. Although the clinical benefits noted in these trials have been modest, researchers have emphasized the importance of preventive immunotherapy. Importantly, data from immunotherapy studies have shown that antibody concentrations in the periphery of vaccinated people should be sufficient for targeting Aβ in the CNS. To generate relatively high concentrations of antibodies in vaccinated people at risk of AD, we generated a universal vaccine platform, MultiTEP, and, based on it, developed a DNA vaccine, AV-1959D, targeting pathological Aβ, completed IND enabling studies, and initiated a Phase I clinical trial with early AD volunteers. Our current pilot study combined our advanced MultiTEP technology with a novel mRNA approach to develop an mRNA vaccine encapsulated in lipid-based nanoparticles (LNPs), AV-1959LR. Here, we report our initial findings on the immunogenicity of 1959LR in mice and non-human primates, comparing it with the immunogenicity of its DNA counterpart, AV-1959D.

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Immunogenicity of MultiTEP platform technology-based Tau vaccine in non-human primates

Cited by 8 publications

References 87 publications

Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer’s Disease

Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer’s Disease

Alzheimer’s disease and its treatment–yesterday, today, and tomorrow

mRNA Vaccine for Alzheimer’s Disease: Pilot Study

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