作者: Petrushina, Irina ; Coburn, Morgan A ; Petrovsky, Nikolai ; Zagorski, Karen ; Danhash, Emma ; Hovakimyan, Armine ; Kiani Shabestari, Sepideh ; Cribbs, David H ; Davtyan, Hayk ; Ghochikyan, Anahit ; Agadjanyan, Michael G ; Svystun, Olga ; Chailyan, Gor ; Antonyan, Tatevik ; Blurton-Jones, Mathew

Abstract:

Background:

Alzheimer disease (AD) is characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline. Current therapeutic approaches have primarily aimed to reduce pathological aggregates of either Aβ or tau, yet phase 3 clinical trials of these approaches have thus far failed to delay disease progression in humans. Strong preclinical evidence indicates that these two abnormally aggregated proteins interact synergistically to drive downstream neurodegeneration. Therefore, combinatorial therapies that concurrently target both Aβ and tau might be needed for effective disease modification.

Methods:

A combinatorial vaccination approach was designed to concurrently target both Aβ and tau pathologies. Tau22/5xFAD (T5x) bigenic mice that develop both pathological Aβ and tau aggregates were injected intramuscularly with a mixture of two MultiTEP epitope vaccines: AV-1959R and AV-1980R, targeting Aβ and tau, respectively, and formulated in AdvaxCpG, a potent polysaccharide adjuvant. Antibody responses of vaccinated animals were measured by ELISA, and neuropathological changes were determined in brain homogenates of vaccinated and control mice using ELISA and Meso Scale Discovery (MSD) multiplex assays.

Results:

T5x mice immunized with a mixture of Aβ- and tau-targeting vaccines generated high Aβ- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles/neuropil threads in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aβ42, within the brains of bigenic T5x mice.

Conclusions:

AV-1959R and AV-1980R formulated with AdvaxCpG adjuvant are immunogenic and therapeutically potent vaccines that in combination can effectively reduce both of the hallmark pathologies of AD in bigenic mice. Taken together, these findings warrant further development of this vaccine technology for ultimate testing in human AD.

Scientific reports3区 · 综合性期刊

Alzheimer’s disease AdvaxCpG- adjuvanted MultiTEP-based dual and single vaccines induce high-titer antibodies against various forms of tau and Aβ pathological molecules

3区 · 综合性期刊

ArticleOA

作者: Petrushina, Irina ; Agadjanyan, Michael G ; Cribbs, David H ; Kazarian, Konstantin ; Petrovsky, Nikolai ; Rajapaksha, Harinda ; Hovakimyan, Armine ; Zagorski, Karen ; Ghochikyan, Anahit ; Davtyan, Hayk ; Davtyan, Arpine

Abstract:

Although β-amyloid (Aβ) may be the primary driver of Alzheimer’s disease (AD) pathology, accumulation of pathological tau correlates with dementia in AD patients. Thus, the prevention/inhibition of AD may require vaccine/s targeting Aβ and tau simultaneously or sequentially. Since high antibody titers are required for AD vaccine efficacy, we have decided to generate vaccines, targeting Aβ (AV-1959R), Tau (AV-1980R) or Aβ/tau (AV-1953R) B cell epitopes, based on immunogenic MultiTEP platform and evaluate the immunogenicity of these vaccines formulated with AdvaxCpG, delta inulin, Alhydrogel®, Montanide-ISA51, Montanide-ISA720, MPLA-SM pharmaceutical grade adjuvants. Formulation of AV-1959R in AdvaxCpG induced the highest cellular and humoral immune responses in mice. The dual-epitope vaccine, AV-1953R, or the combination of AV-1959R and AV-1980R vaccines formulated with AdvaxCpG induced robust antibody responses against various forms of both, Aβ and tau pathological molecules. While anti-Aβ antibody titers after AV-1953R immunization were similar to that in mice vaccinated with AV-1959R or AV-1959R/AV-1980R combination, anti-tau titers were significantly lower after AV-1953R injection when compared to the AV-1980R or AV-1959R/AV-1980R. In silico 3D-modeling provided insight into the differences in immunogenicity of these vaccine constructs. In sum, AV-1959R and AV-1980R formulated with AdvaxCpG adjuvant were identified as promising immunogenic vaccines for ongoing pre-clinical assessment and future human clinical trials.

项与 AV-1980R 相关的新闻（医药）

2022-11-04

·PRNewswire

Gates Biomanufacturing Facility Announces Manufacture of Recombinant Protein - Alzheimer's Disease Vaccine for Institute for Molecular Medicine's Clinical Trials

AURORA, Colo., Nov. 4, 2022 /PRNewswire/ -- The Gates Biomanufacturing Facility (GBF) has announced the successful completion of the full cycle manufacturing of the recombinant Bulk Drug Substance (BDS) of the anti-Tau vaccine, AV-1980R, in collaboration with the Institute for Molecular Medicine (IMM), California. Continue Reading Congresswoman Diana DeGette (D-CO) visits the Gates Biomanufacturing Facility's Protein Suite, in which GMP-grade AV-1980R was manufactured for the Institute for Molecular Medicine's phase 1 clinical trials. Vials of GMP-grade AV-1980R manufactured by the Gates Biomanufacturing Facility for Institute of Molecular Medicine's phase 1 Alzheimer's Disease Vaccine clinical trials IMM selected GBF as its exclusive cGMP-grade BDS manufacturing partner supporting clinical supply for IMM's recombinant protein vaccines, including AV-1980R. As a result of this work, AV-1980R Drug Substance can be used for phase 1 and phase 2 clinical trials in humans. This work was financed through funding provided by the U.S. National Institute on Aging (NIA). Abnormal Tau aggregation into neurofibrillary tangles is the hallmark of different tauopathies - neurodegenerative disorders that include Alzheimer's Disease (AD). Until now, AD therapeutics have mostly focused on the treatment of already diseased patients. AV-1980R vaccine targets Alzheimer's Disease (AD) and other Tau aggregation-associated neurodegenerative conditions by providing outstanding levels of antibody protection against harmful forms of Tau protein that may lead to disease. Dr. Michael Agadjanyan, Professor and Vice President of IMM commented, "But once pathology begins and neurons are damaged, it becomes impossible to stop the disease. Now, with the help of cGMP-grade AV-1980R manufactured by GBF, [IMM has] a highly immunogenic preventative vaccine that could induce significant levels of antibodies inhibiting aggregation of Tau in cognitively unimpaired people [who are] at risk of AD and halt the disease onset." Huntington Potter, PhD, Professor of Neurology, Director of Alzheimer's Disease Program at the Linda Crnic Institute for Down Syndrome, and Director of the CU Alzheimer's and Cognition Center at the University of Colorado Anschutz Medical Center maintains, "It is becoming increasingly clear that targeting Alzheimer amyloid deposits and their formation is not, alone, an effective approach to halting or reversing Alzheimer's disease. New therapeutics are needed. The development and manufacture of a Tau vaccine is one of the most promising approaches and might be used either alone or in combination with the anti-amyloid antibodies currently in clinical trials. I congratulate GBF on this important milestone." All vaccines developed by IMM are based on the proprietary MultiTEP platform technology, recently licensed to its commercial entity, Nuravax, which demonstrated therapeutic efficacy and immunogenicity in various species of transgenic animal models of AD, including non-human primates. ABOUT GBF The Charles C. Gates Center for Regenerative Medicine, in partnership with the University of Colorado School of Medicine, UCHealth University of Colorado Hospital, Children's Hospital Colorado, the Gates Frontiers Fund and the private sector have established a state-of-the-art Phase I GMP facility, which develops and manufactures investigational biologics and cell therapy products to support FDA-approved early phase clinical trials. 20,000 square feet of GMP-grade cleanrooms, laboratories, material storage are in the Fitzsimmons Innovation Zone just across the street from University of Colorado Anschutz Medical Campus research laboratories plus the adult and pediatric hospitals (). The facility currently produces therapeutic biologics; recombinant protein, nano-particle conjugate, nucleic acid-based therapeutics as well as CAR-T cells and other cell therapy products for clinical trials. The mission-based manufacturing facility serves academic researchers, clinicians, and early-stage biotechnology companies, focuses on translation of discoveries into clinical-grade products, and completes the medical ecosystem from basic research through early commercialization. ABOUT IMM The Institute for Molecular Medicine (IMM) is a non-profit organization created with the goal of understanding, preventing, and curing chronic human diseases, including neurodegenerative disorders. IMM works closely with its partner, Nuravax: a biotechnology company that licenses IMM's patented technology. Based in Orange County, California, IMM, along with Nuravax, is advancing MultiTEP: a universal vaccine platform technology that supports the development of multiple vaccine designs based on DNA, RNA, or recombinant proteins. Media Contact: Jill Cowperthwaite 303 564-8021 [email protected] SOURCE University of Colorado Anschutz Medical Campus

疫苗合作抗体细胞疗法

2021-11-22

·BioSpace

The Institute for Molecular Medicine has Received a Total $7.7M From NIH to Develop a First-of-its-Kind Vaccine Targeting Both Hallmarks of Alzheimer's Disease

HUNTINGTON BREACH, Calif., Nov. 22, 2021 /PRNewswire/ -- The Institute for Molecular Medicine (IMM), a non-profit research organization established in 1996 with the goal of understanding, preventing, and curing chronic diseases, including neurodegenerative disorders, today announced that it has been awarded an additional $3 million to the previously awarded $4.7 million grant from the National Institutes of Aging (NIA) of the NIH. The funding will support the manufacturing of a first-of-its-kind clinical cGMP grade dual vaccine, Duvax, that targets both pathological hallmarks of Alzheimer's disease (AD), amyloid beta plaques (Aβ) and neurofibrillary tangles (tau). First clinical trials of a dual vaccine for Alzheimer's disease to begin in 2023 Current clinical data on AD biomarkers found in the brain and cerebrospinal fluid demonstrate that Aβ accumulation can precede tau pathology and cognitive decline by sometimes more than a decade. The IND-enabling safety/toxicology studies with a cGMP grade recombinant protein vaccine targeting tau, AV-1980R, has been recently completed using the NIA funding and is currently on track for a Phase 1 clinical trial to evaluate its safety, tolerability, and immunogenicity. The additional funding is being used to manufacture a clinical grade recombinant protein vaccine targeting pathological Aβ, AV-1959R, and test its safety in animal models of AD. This vaccine will be tested in 2022 in a clinical setting. Importantly, the additional funding will also be used to manufacture Duvax for use in phase 1 trials that are expected to be completed in 2023. "Supported by strong pre-clinical data, we believe that Duvax will induce high titers of anti-Aβ and anti-tau antibodies that could inhibit or reduce the accumulation of both pathological molecules and halt or at least delay downstream pathological processes, such as inflammation and neurodegeneration, which would otherwise lead to an irreversible onset of AD in asymptomatic people at risk," said Vice President of IMM and Head of Immunology Michael Agadjanyan. All vaccines are based on IMM's proprietary MultiTEP platform technology, recently licensed to its commercial entity, Nuravax, that has demonstrated therapeutic efficacy and immunogenicity in special transgenic mouse models of AD, rabbits, and non-human primates with human-like immune systems. "With three INDs, two single-target vaccines and Duvax, we will be able to continue developing a pipeline that could prevent Alzheimer's disease from multiple angles," said Nuravax CEO Roman Kniazev. About MultiTEP The universal proprietary MultiTEP carrier platform is the key feature of IMM's vaccine candidates for Alzheimer's disease (AD) and Parkinson's disease (PD). Elderly immune systems are characterized by a deficiency of naïve T helper cells but fortunately, exhibit an increase of memory T helper cells. MultiTEP technology-based vaccines should overcome the shortcomings of aged immune systems by activating not only naïve but also memory T helper cells and mount a strong antibody response, especially in the elderly. About the IMM The Institute for Molecular Medicine (IMM) is a non-profit organization created with the goal of understanding, preventing, and curing chronic human diseases, including Alzheimer's disease and Parkinson's disease. IMM is advancing MuliTEP, a universal vaccine platform technology that supports the development of multiple vaccine designs based on DNA, RNA, or recombinant proteins. About Nuravax Nuravax is licensed for the patented MultiTEP platform technology for the commercialization of prophylactic vaccines against all neurodegenerative disorders. Nuravax is responsible for implementing co-development and sub-licensing agreements with larger biotech and pharmaceutical companies, and for further clinical validation of products. For more information, please visit and follow us on LinkedIn.

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100 项与 AV-1980R 相关的药物交易

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