Michael Agadjanyan - Academia.edu (original) (raw)
Papers by Michael Agadjanyan
Journal of Biological Chemistry, 2007
Different strategies proposed as therapy for Alzheimer disease (AD) have aimed to reduce the leve... more Different strategies proposed as therapy for Alzheimer disease (AD) have aimed to reduce the level of toxic forms of A peptide in the brain. Here, we directly analyze the therapeutic utility of the polyclonal anti-A 1-11 antibody induced in 3xTg-AD mice vaccinated with the second generation prototype epitope vaccine. Substoichiometric concentrations of purified anti-A 1-11 antibody prevented aggregation of A 42 and induced disaggregation of preformed A 42 fibrils down to nonfilamentous and nontoxic species. Anti-A 1-11 antibody delayed A 42 oligomer formation but ultimately appeared to stabilize nonfibrillar conformations, including oligomer-like assemblies. The reduced oligomer-mediated cytotoxicity observed upon preincubation of A oligomers with the anti-A 1-11 antibody in the absence of oligomer disaggregation suggests a possible oligomer rearrangement in the presence of the antibody. These in vitro observations suggest that preventive vaccination may protect from AD or may delay the onset of the disease, whereas therapeutic vaccination cannot disrupt the toxic oligomers and may only minimally alleviate preexisting AD pathology. * This work was supported by National Institutes of Health R01 Grants AG20241 and NS50895 (to D. H. C. and M. G. A.) and NS3I230 (to C. G. C.) and Alzheimer's Association Grant IIRG-03-6279 (to M. G. A. and D. H. C.
Molecular Immunology, 1998
Peptides may substitute for carbohydrates in reactions with carbohydrate-specific molecules. Rece... more Peptides may substitute for carbohydrates in reactions with carbohydrate-specific molecules. Recently, we found that peptides containing aromatic residues mimic mucin and histo-blood group related carbohydrate epitopes, eliciting polyclonal responses cross-reactive with bacterial and viral antigens that express these carbohydrate forms. These results demonstrate that peptides can function in in vivo and in vitro models as carbohydrate surrogate antigens. To further
Journal of immunology (Baltimore, Md. : 1950), 2005
Immunization of amyloid precursor protein transgenic mice with fibrillar beta-amyloid (Abeta) pre... more Immunization of amyloid precursor protein transgenic mice with fibrillar beta-amyloid (Abeta) prevents Alzheimer's disease (AD)-like neuropathology. The first immunotherapy clinical trial used fibrillar Abeta, containing the B and T cell self epitopes of Abeta, as the immunogen formulated with QS21 as the adjuvant in the vaccine. Unfortunately, the clinical trial was halted during the phase II stage when 6% of the participants developed meningoencephalitis. The cause of the meningoencephalitis in the patients that received the vaccine has not been definitively determined; however, analysis of two case reports from the AN-1792 vaccine trial suggest that the meningoencephalitis may have been caused by a T cell-mediated autoimmune response, whereas production of anti-Abeta Abs may have been therapeutic to the AD patients. Therefore, to reduce the risk of an adverse T cell-mediated immune response to Abeta immunotherapy we have designed a prototype epitope vaccine that contains the ...
Vaccine design against HIV-1 is complicated both by the latent aspects of lentiviral infection an... more Vaccine design against HIV-1 is complicated both by the latent aspects of lentiviral infection and the diversity of the virus. The type of vaccine approach used is therefore likely to be critically important. In 9eneral, vaccination strategies have relied on the use of live attenuated material or inactivated/subunit preparations as specific immunogens. Each of these methodologies has advantages and disadvantages in terms of the elicitation of broad cellular and humoral immune responses. Although most success has been achieved with live attenuated vaccines, there is a conceptual safety concern associated with the use of these vaccines for the prevention of human infections. In contrast, subunit or killed vaccine preparations enjoy advantages in preparation and conceptual safety; however, their ability to elicit broad immunity is more limited. In theory, inoculation of a plasmid DNA that supports in vivo expression of proteins, and therefore presentation of the processed protein antigen to the immune system, could be used to combine the features of a subunit vaccine and a live attenuated vaccine. We have designed a strategy for intramuscular DNA inoculation to elicit humoral and cellular immune responses against expressed HIV antigens. Uptake and expression are significantly enhanced if DNA is administered in conjunction with the facilitatin9 agent bupivacaine-HCl. Usin9 this technique we have demonstrated functional cellular and humoral immune responses against the majority of HIV-1 encoded antigens in both rodents and non-human primates.
Human vaccines & immunotherapeutics, 2014
Alzheimer disease (AD) process involves the accumulation of amyloid plaques and tau tangles in th... more Alzheimer disease (AD) process involves the accumulation of amyloid plaques and tau tangles in the brain, nevertheless the attempts at targeting the main culprits, neurotoxic β-amyloid (Aβ) peptides, have thus far proven unsuccessful for improving cognitive function. Important lessons about anti-Aβ immunotherapeutic strategies were learned from the first active vaccination clinical trials. AD progression could be safely prevented or delayed if the vaccine (1) induces high titers of antibodies specific to toxic forms of Aβ; (2) does not activate the harmful autoreactive T cells that may induce inflammation; (3) is initiated before or at least at the early stages of the accumulation of toxic forms of Aβ. Data from the recent passive vaccination trials with bapineuzumab and solanezumab also indicated that anti-Aβ immunotherapy might be effective in reduction of the AD pathology and even improvement of cognitive and/or functional performance in patients when administered early in the co...
Journal of translational medicine, Jan 29, 2014
BackgroundPreviously we demonstrated that the resection of primary 4 T1 tumors only slightly prol... more BackgroundPreviously we demonstrated that the resection of primary 4 T1 tumors only slightly prolongs mouse survival, but importantly, creates a ¿window of opportunity¿ with attenuated suppressor cell and increased activated T cell populations. This suggests that additional activation of the immune system by immunostimulatory agents during this period may enhance anti-tumor immunity and potentially eradicate micro-metastatic disease in this stringent model.We hypothesized that the immunostimulator Immunomax®, which is comprised of a plant-derived polysaccharide, is non-toxic in humans and stimulates immune defense during the infectious diseases treatment, may have also anti-tumor activity and be beneficial in the adjuvant setting when endogenous anti-tumor responses are present and during the ¿window of opportunity¿ in post-resection metastatic breast cancer model. Here we provide the initial report that Immunomax® demonstrates the capacity to eliminate micro-metastatic disease in t...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 2003
There is great interest in understanding the role of costimulatory molecules in immune activation... more There is great interest in understanding the role of costimulatory molecules in immune activation. In both the influenza and HIV DNA immunization models, several groups have reported that coimmunization of mice with plasmids encoding immunogen and CD86, but not CD80, effectively boosts Ag-specific T cell activation. This difference in immune priming provided an opportunity to examine the functional importance of different regions of the B.7 molecules in immune activation. To examine this issue, we developed a series of chimeric CD80 and CD86 constructs as well as deletion mutants, and examined their immune activating potential in the DNA vaccine model. We demonstrate that the lack of an Ig constant-like region in the CD80 molecule is critically important to the enhanced immune activation observed. CD80 C-domain deletion mutants induce a highly inflammatory Ag-specific cellular response when administered as part of a plasmid vaccine. The data suggest that the constant-like domains, l...
We previously demonstrated that our second-generation DNA-based Alzheimer disease (AD) epitope va... more We previously demonstrated that our second-generation DNA-based Alzheimer disease (AD) epitope vaccine comprising three copies of a short amyloid-β (Aβ) B cell epitope, Aβ 11 fused with the foreign promiscuous Th epitope, PADRE (p3Aβ 11-PADRE) was immunogenic in mice. However, since DNA vaccines exhibit poor immunogenicity in large animals and humans, in this study, we sought to improve the immunogenicity of p3Aβ 11-PADRE by modifying this vaccine to express protein 3Aβ 11-PADRE with a free N-terminal aspartic acid fused with eight additional promiscuous Th epitopes. Generated pN-3Aβ 11-PADRE-Thep vaccine has been designated as AV-1955. We also delivered this vaccine using the TriGrid electroporation system to improve the efficiency of DNA transfection. This third-generation DNA epitope vaccine was evaluated for immunogenicity in rabbits in comparison to the parent construct p3Aβ 11-PADRE. AV-1955 vaccination induced significantly stronger humoral immune responses in rabbits compared with p3Aβ 11-PADRE vaccine. Anti-Aβ 11 antibodies recognized all forms of human β-amyloid peptide (monomers, oligomers and fibrils), bound to amyloid plaques in brain sections from an AD case and reduced oligomer- and fibril-mediated cytotoxicity ex vivo. These findings suggest that AV-1955 could represent an effective DNA epitope vaccine for AD therapy, pending safety and efficacy studies that are currently being conducted in Rhesus monkeys.
Journal of Neuroscience, 2013
Alzheimer's disease (AD) process is understood to involve the accumulation of amyloid plaques and... more Alzheimer's disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic Aβ peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-Aβ antibodies failed to slow cognitive decline in mild-moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. In an AD mouse model (Tg2576) we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. Lu AF20513 induces robust "non-self" T cell responses and production of anti-Aβ antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or CAA. Importantly, a single immunization with Lu AF20513 induces strong humoral immunity in mice with pre-existing memory Th cells. In addition, Lu AF20513 induces strong humoral responses in guinea pigs and monkeys. Collectively, these data suggest translation of Lu AF20513 to clinical setting with aims to (i) induce therapeutically potent anti-Aβ antibody responses in patients with mild AD, particularly if they have memory Th cells generated
Journal of Neuroinflammation, 2008
Background: New pre-clinical trials in AD mouse models may help to develop novel immunogenadjuvan... more Background: New pre-clinical trials in AD mouse models may help to develop novel immunogenadjuvant configurations with the potential to avoid the adverse responses that occurred during the clinical trials with AN-1792 vaccine formulation. Recently, we have pursued an alternative immunization strategy that replaces QS21 the Th1 type adjuvant used in the AN-1792 clinical trial with a molecular adjuvant, mannan that can promote a Th2-polarized immune response through interactions with mannose-binding and CD35/CD21 receptors of the innate immune system. Previously we established that immunization of wild-type mice with mannan-Aβ 28 conjugate promoted Th2-mediated humoral and cellular immune responses. In the current study, we tested the efficacy of this vaccine configuration in amyloid precursor protein (APP) transgenic mice (Tg2576).
Journal of Medical Primatology, 1996
Vaccine, 2006
We describe a study testing fibrillar β-amyloid1–42 (Aβ42) vaccination in dogs. Three young beagl... more We describe a study testing fibrillar β-amyloid1–42 (Aβ42) vaccination in dogs. Three young beagles (4.6 years) were immunized twice with Aβ42 and a Th1 adjuvant (TiterMax Gold). Animals generated primarily IgG2 and IgM antibody responses, which were specific for the Aβ11–30 region of Aβ1–42. Next, 3 aged beagles (8.9–13.8 years) were immunized 4 times with Aβ42 and a Th2 adjuvant
CNS & Neurological Disorders - Drug Targets, 2009
ABSTRACT Alzheimer's disease (AD) is the leading cause of dementia among older people. An... more ABSTRACT Alzheimer's disease (AD) is the leading cause of dementia among older people. An estimated 10% of Americans over the age of 65 and half of those over age 85 have Alzheimer's. More than four million Americans currently suffer from the disease, and the number is projected to balloon to 10-15 million over the next several decades. Alzheimer's is now the third most expensive disease to treat in the U.S., costing society close to $100 billion annually [1]. The clinical criteria for the diagnosis of AD include insidious onset and progressive impairment of memory and other cognitive functions; however a definitive diagnosis of AD can currently be made only at autopsy by examining brain tissue for amyloid plaques and neurofibrillary tangles. The extracellular amyloid plaques and intracellular neurofibrillary tangles represent examples of proteinopathies or proteopathies, which result from aberrant accumulation of misfolded or aggregated proteins that are believed to interfere with normal functions, and thereby either directly or indirectly contribute to disease pathogenesis. In addition to AD, misfolding or aberrant aggregation of proteins are central features of other neurodegenerative diseases as well, including tauopathies, Parkinson disease, amyotrophic lateral sclerosis, prion diseases, and the polyglutamine (polygln) diseases [2, 3]. Therapeutic strategies targeted at this class of diseases have focused on three areas: 1) reducing the production of the protein/peptide; 2) blocking the assembly of aberrant forms; or 3) promoting clearance [4].
Current HIV …, 2008
VGV-1, a clinical-grade formulation of bovine thymus nuclear protein (TNP) has been demonstrated ... more VGV-1, a clinical-grade formulation of bovine thymus nuclear protein (TNP) has been demonstrated to possess anti-viral activity in HIV-1 patients in five clinical trials, one of which was placebo controlled double-blinded. However, to date molecular mechanisms remain to be identified. Using surface plasmon resonance we observed TNP components bind with high affinity to HIV-1 proteins involved in viral entry, gp41 and pg120, as well as the T cell HIV-1 receptor CD4. To identify protein components of TNP, gel electrophoresis was performed followed by tandem mass spectrometry (MS/MS). Searching of bovine protein databases revealed the presence of numerous histones. Further analysis of TNP by immunoaffinity chromatography using gp120 and CD4 molecules as targets followed by gel electrophoresis and MS/MS analysis confirmed these data, demonstrating that H1.1, H2B, H4, and H2A histones are the active component of TNP that bind to HIV envelop glycoprotein and its receptor. To conclusively demonstrate binding of histones to target proteins, we repeated the surface plasmon resonance experiments using commercially available bovine histones and demonstrated high-affinity interaction of histones with gp120, and CD4. The binding of histone proteins to CD4, as well as viral molecules has profound implications for basic understanding of immune functions as well as a possible mechanism of VGV-1 activity in AIDS patients.
There are a number of rheumatologic manifestations of human retroviral infections associated with... more There are a number of rheumatologic manifestations of human retroviral infections associated with human immunode
The role of the immune response in controlling human immunodeficiency virus type 1 (HIV-1) replic... more The role of the immune response in controlling human immunodeficiency virus type 1 (HIV-1) replication is controversial. Immunotherapeutic strategies that have the ability to broaden immune responses might play a role in slowing disease progression. DNA immunization was studied as immunotherapy in infected chimpanzees. Two HIV-1 -infected chimpanzees were vaccinated with DNA plasmid vaccines, one with plasmid pCMN160, which expresses the envelope glycoprotein of HIV-1 MN and rev, and the other with a control plasmid. The chimpanzee immunized with pCMN160 demonstrated enhanced humoral responses. Virus load was monitored. Virus load in the chimpanzee receiving pCMN160 decreased at week 20 and has remained at background levels. The control chimpanzee was subsequently vaccinated with pCMN160. After immunization, the antibody responses increased and, as in the first animal, the virus load decreased. These results indicate the potential of the immune response to have a direct impact on HIV-1 replication in chimpanzees.
Alzheimer's & Dementia, 2012
Human vaccines & immunotherapeutics, 2013
We previously demonstrated that our second-generation DNA-based Alzheimer disease (AD) epitope va... more We previously demonstrated that our second-generation DNA-based Alzheimer disease (AD) epitope vaccine comprising three copies of a short amyloid-β (Aβ) B cell epitope, Aβ 11 fused with the foreign promiscuous Th epitope, PADRE (p3Aβ 11-PADRE) was immunogenic in mice. However, since DNA vaccines exhibit poor immunogenicity in large animals and humans, in this study, we sought to improve the immunogenicity of p3Aβ 11-PADRE by modifying this vaccine to express protein 3Aβ 11-PADRE with a free N-terminal aspartic acid fused with eight additional promiscuous Th epitopes. Generated pN-3Aβ 11-PADRE-Thep vaccine has been designated as AV-1955. We also delivered this vaccine using the TriGrid electroporation system to improve the efficiency of DNA transfection. This third-generation DNA epitope vaccine was evaluated for immunogenicity in rabbits in comparison to the parent construct p3Aβ 11-PADRE. AV-1955 vaccination induced significantly stronger humoral immune responses in rabbits compare...
Journal of Biological Chemistry, 2007
Different strategies proposed as therapy for Alzheimer disease (AD) have aimed to reduce the leve... more Different strategies proposed as therapy for Alzheimer disease (AD) have aimed to reduce the level of toxic forms of A peptide in the brain. Here, we directly analyze the therapeutic utility of the polyclonal anti-A 1-11 antibody induced in 3xTg-AD mice vaccinated with the second generation prototype epitope vaccine. Substoichiometric concentrations of purified anti-A 1-11 antibody prevented aggregation of A 42 and induced disaggregation of preformed A 42 fibrils down to nonfilamentous and nontoxic species. Anti-A 1-11 antibody delayed A 42 oligomer formation but ultimately appeared to stabilize nonfibrillar conformations, including oligomer-like assemblies. The reduced oligomer-mediated cytotoxicity observed upon preincubation of A oligomers with the anti-A 1-11 antibody in the absence of oligomer disaggregation suggests a possible oligomer rearrangement in the presence of the antibody. These in vitro observations suggest that preventive vaccination may protect from AD or may delay the onset of the disease, whereas therapeutic vaccination cannot disrupt the toxic oligomers and may only minimally alleviate preexisting AD pathology. * This work was supported by National Institutes of Health R01 Grants AG20241 and NS50895 (to D. H. C. and M. G. A.) and NS3I230 (to C. G. C.) and Alzheimer's Association Grant IIRG-03-6279 (to M. G. A. and D. H. C.
Molecular Immunology, 1998
Peptides may substitute for carbohydrates in reactions with carbohydrate-specific molecules. Rece... more Peptides may substitute for carbohydrates in reactions with carbohydrate-specific molecules. Recently, we found that peptides containing aromatic residues mimic mucin and histo-blood group related carbohydrate epitopes, eliciting polyclonal responses cross-reactive with bacterial and viral antigens that express these carbohydrate forms. These results demonstrate that peptides can function in in vivo and in vitro models as carbohydrate surrogate antigens. To further
Journal of immunology (Baltimore, Md. : 1950), 2005
Immunization of amyloid precursor protein transgenic mice with fibrillar beta-amyloid (Abeta) pre... more Immunization of amyloid precursor protein transgenic mice with fibrillar beta-amyloid (Abeta) prevents Alzheimer's disease (AD)-like neuropathology. The first immunotherapy clinical trial used fibrillar Abeta, containing the B and T cell self epitopes of Abeta, as the immunogen formulated with QS21 as the adjuvant in the vaccine. Unfortunately, the clinical trial was halted during the phase II stage when 6% of the participants developed meningoencephalitis. The cause of the meningoencephalitis in the patients that received the vaccine has not been definitively determined; however, analysis of two case reports from the AN-1792 vaccine trial suggest that the meningoencephalitis may have been caused by a T cell-mediated autoimmune response, whereas production of anti-Abeta Abs may have been therapeutic to the AD patients. Therefore, to reduce the risk of an adverse T cell-mediated immune response to Abeta immunotherapy we have designed a prototype epitope vaccine that contains the ...
Vaccine design against HIV-1 is complicated both by the latent aspects of lentiviral infection an... more Vaccine design against HIV-1 is complicated both by the latent aspects of lentiviral infection and the diversity of the virus. The type of vaccine approach used is therefore likely to be critically important. In 9eneral, vaccination strategies have relied on the use of live attenuated material or inactivated/subunit preparations as specific immunogens. Each of these methodologies has advantages and disadvantages in terms of the elicitation of broad cellular and humoral immune responses. Although most success has been achieved with live attenuated vaccines, there is a conceptual safety concern associated with the use of these vaccines for the prevention of human infections. In contrast, subunit or killed vaccine preparations enjoy advantages in preparation and conceptual safety; however, their ability to elicit broad immunity is more limited. In theory, inoculation of a plasmid DNA that supports in vivo expression of proteins, and therefore presentation of the processed protein antigen to the immune system, could be used to combine the features of a subunit vaccine and a live attenuated vaccine. We have designed a strategy for intramuscular DNA inoculation to elicit humoral and cellular immune responses against expressed HIV antigens. Uptake and expression are significantly enhanced if DNA is administered in conjunction with the facilitatin9 agent bupivacaine-HCl. Usin9 this technique we have demonstrated functional cellular and humoral immune responses against the majority of HIV-1 encoded antigens in both rodents and non-human primates.
Human vaccines & immunotherapeutics, 2014
Alzheimer disease (AD) process involves the accumulation of amyloid plaques and tau tangles in th... more Alzheimer disease (AD) process involves the accumulation of amyloid plaques and tau tangles in the brain, nevertheless the attempts at targeting the main culprits, neurotoxic β-amyloid (Aβ) peptides, have thus far proven unsuccessful for improving cognitive function. Important lessons about anti-Aβ immunotherapeutic strategies were learned from the first active vaccination clinical trials. AD progression could be safely prevented or delayed if the vaccine (1) induces high titers of antibodies specific to toxic forms of Aβ; (2) does not activate the harmful autoreactive T cells that may induce inflammation; (3) is initiated before or at least at the early stages of the accumulation of toxic forms of Aβ. Data from the recent passive vaccination trials with bapineuzumab and solanezumab also indicated that anti-Aβ immunotherapy might be effective in reduction of the AD pathology and even improvement of cognitive and/or functional performance in patients when administered early in the co...
Journal of translational medicine, Jan 29, 2014
BackgroundPreviously we demonstrated that the resection of primary 4 T1 tumors only slightly prol... more BackgroundPreviously we demonstrated that the resection of primary 4 T1 tumors only slightly prolongs mouse survival, but importantly, creates a ¿window of opportunity¿ with attenuated suppressor cell and increased activated T cell populations. This suggests that additional activation of the immune system by immunostimulatory agents during this period may enhance anti-tumor immunity and potentially eradicate micro-metastatic disease in this stringent model.We hypothesized that the immunostimulator Immunomax®, which is comprised of a plant-derived polysaccharide, is non-toxic in humans and stimulates immune defense during the infectious diseases treatment, may have also anti-tumor activity and be beneficial in the adjuvant setting when endogenous anti-tumor responses are present and during the ¿window of opportunity¿ in post-resection metastatic breast cancer model. Here we provide the initial report that Immunomax® demonstrates the capacity to eliminate micro-metastatic disease in t...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 2003
There is great interest in understanding the role of costimulatory molecules in immune activation... more There is great interest in understanding the role of costimulatory molecules in immune activation. In both the influenza and HIV DNA immunization models, several groups have reported that coimmunization of mice with plasmids encoding immunogen and CD86, but not CD80, effectively boosts Ag-specific T cell activation. This difference in immune priming provided an opportunity to examine the functional importance of different regions of the B.7 molecules in immune activation. To examine this issue, we developed a series of chimeric CD80 and CD86 constructs as well as deletion mutants, and examined their immune activating potential in the DNA vaccine model. We demonstrate that the lack of an Ig constant-like region in the CD80 molecule is critically important to the enhanced immune activation observed. CD80 C-domain deletion mutants induce a highly inflammatory Ag-specific cellular response when administered as part of a plasmid vaccine. The data suggest that the constant-like domains, l...
We previously demonstrated that our second-generation DNA-based Alzheimer disease (AD) epitope va... more We previously demonstrated that our second-generation DNA-based Alzheimer disease (AD) epitope vaccine comprising three copies of a short amyloid-β (Aβ) B cell epitope, Aβ 11 fused with the foreign promiscuous Th epitope, PADRE (p3Aβ 11-PADRE) was immunogenic in mice. However, since DNA vaccines exhibit poor immunogenicity in large animals and humans, in this study, we sought to improve the immunogenicity of p3Aβ 11-PADRE by modifying this vaccine to express protein 3Aβ 11-PADRE with a free N-terminal aspartic acid fused with eight additional promiscuous Th epitopes. Generated pN-3Aβ 11-PADRE-Thep vaccine has been designated as AV-1955. We also delivered this vaccine using the TriGrid electroporation system to improve the efficiency of DNA transfection. This third-generation DNA epitope vaccine was evaluated for immunogenicity in rabbits in comparison to the parent construct p3Aβ 11-PADRE. AV-1955 vaccination induced significantly stronger humoral immune responses in rabbits compared with p3Aβ 11-PADRE vaccine. Anti-Aβ 11 antibodies recognized all forms of human β-amyloid peptide (monomers, oligomers and fibrils), bound to amyloid plaques in brain sections from an AD case and reduced oligomer- and fibril-mediated cytotoxicity ex vivo. These findings suggest that AV-1955 could represent an effective DNA epitope vaccine for AD therapy, pending safety and efficacy studies that are currently being conducted in Rhesus monkeys.
Journal of Neuroscience, 2013
Alzheimer's disease (AD) process is understood to involve the accumulation of amyloid plaques and... more Alzheimer's disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic Aβ peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-Aβ antibodies failed to slow cognitive decline in mild-moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. In an AD mouse model (Tg2576) we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. Lu AF20513 induces robust "non-self" T cell responses and production of anti-Aβ antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or CAA. Importantly, a single immunization with Lu AF20513 induces strong humoral immunity in mice with pre-existing memory Th cells. In addition, Lu AF20513 induces strong humoral responses in guinea pigs and monkeys. Collectively, these data suggest translation of Lu AF20513 to clinical setting with aims to (i) induce therapeutically potent anti-Aβ antibody responses in patients with mild AD, particularly if they have memory Th cells generated
Journal of Neuroinflammation, 2008
Background: New pre-clinical trials in AD mouse models may help to develop novel immunogenadjuvan... more Background: New pre-clinical trials in AD mouse models may help to develop novel immunogenadjuvant configurations with the potential to avoid the adverse responses that occurred during the clinical trials with AN-1792 vaccine formulation. Recently, we have pursued an alternative immunization strategy that replaces QS21 the Th1 type adjuvant used in the AN-1792 clinical trial with a molecular adjuvant, mannan that can promote a Th2-polarized immune response through interactions with mannose-binding and CD35/CD21 receptors of the innate immune system. Previously we established that immunization of wild-type mice with mannan-Aβ 28 conjugate promoted Th2-mediated humoral and cellular immune responses. In the current study, we tested the efficacy of this vaccine configuration in amyloid precursor protein (APP) transgenic mice (Tg2576).
Journal of Medical Primatology, 1996
Vaccine, 2006
We describe a study testing fibrillar β-amyloid1–42 (Aβ42) vaccination in dogs. Three young beagl... more We describe a study testing fibrillar β-amyloid1–42 (Aβ42) vaccination in dogs. Three young beagles (4.6 years) were immunized twice with Aβ42 and a Th1 adjuvant (TiterMax Gold). Animals generated primarily IgG2 and IgM antibody responses, which were specific for the Aβ11–30 region of Aβ1–42. Next, 3 aged beagles (8.9–13.8 years) were immunized 4 times with Aβ42 and a Th2 adjuvant
CNS & Neurological Disorders - Drug Targets, 2009
ABSTRACT Alzheimer's disease (AD) is the leading cause of dementia among older people. An... more ABSTRACT Alzheimer's disease (AD) is the leading cause of dementia among older people. An estimated 10% of Americans over the age of 65 and half of those over age 85 have Alzheimer's. More than four million Americans currently suffer from the disease, and the number is projected to balloon to 10-15 million over the next several decades. Alzheimer's is now the third most expensive disease to treat in the U.S., costing society close to $100 billion annually [1]. The clinical criteria for the diagnosis of AD include insidious onset and progressive impairment of memory and other cognitive functions; however a definitive diagnosis of AD can currently be made only at autopsy by examining brain tissue for amyloid plaques and neurofibrillary tangles. The extracellular amyloid plaques and intracellular neurofibrillary tangles represent examples of proteinopathies or proteopathies, which result from aberrant accumulation of misfolded or aggregated proteins that are believed to interfere with normal functions, and thereby either directly or indirectly contribute to disease pathogenesis. In addition to AD, misfolding or aberrant aggregation of proteins are central features of other neurodegenerative diseases as well, including tauopathies, Parkinson disease, amyotrophic lateral sclerosis, prion diseases, and the polyglutamine (polygln) diseases [2, 3]. Therapeutic strategies targeted at this class of diseases have focused on three areas: 1) reducing the production of the protein/peptide; 2) blocking the assembly of aberrant forms; or 3) promoting clearance [4].
Current HIV …, 2008
VGV-1, a clinical-grade formulation of bovine thymus nuclear protein (TNP) has been demonstrated ... more VGV-1, a clinical-grade formulation of bovine thymus nuclear protein (TNP) has been demonstrated to possess anti-viral activity in HIV-1 patients in five clinical trials, one of which was placebo controlled double-blinded. However, to date molecular mechanisms remain to be identified. Using surface plasmon resonance we observed TNP components bind with high affinity to HIV-1 proteins involved in viral entry, gp41 and pg120, as well as the T cell HIV-1 receptor CD4. To identify protein components of TNP, gel electrophoresis was performed followed by tandem mass spectrometry (MS/MS). Searching of bovine protein databases revealed the presence of numerous histones. Further analysis of TNP by immunoaffinity chromatography using gp120 and CD4 molecules as targets followed by gel electrophoresis and MS/MS analysis confirmed these data, demonstrating that H1.1, H2B, H4, and H2A histones are the active component of TNP that bind to HIV envelop glycoprotein and its receptor. To conclusively demonstrate binding of histones to target proteins, we repeated the surface plasmon resonance experiments using commercially available bovine histones and demonstrated high-affinity interaction of histones with gp120, and CD4. The binding of histone proteins to CD4, as well as viral molecules has profound implications for basic understanding of immune functions as well as a possible mechanism of VGV-1 activity in AIDS patients.
There are a number of rheumatologic manifestations of human retroviral infections associated with... more There are a number of rheumatologic manifestations of human retroviral infections associated with human immunode
The role of the immune response in controlling human immunodeficiency virus type 1 (HIV-1) replic... more The role of the immune response in controlling human immunodeficiency virus type 1 (HIV-1) replication is controversial. Immunotherapeutic strategies that have the ability to broaden immune responses might play a role in slowing disease progression. DNA immunization was studied as immunotherapy in infected chimpanzees. Two HIV-1 -infected chimpanzees were vaccinated with DNA plasmid vaccines, one with plasmid pCMN160, which expresses the envelope glycoprotein of HIV-1 MN and rev, and the other with a control plasmid. The chimpanzee immunized with pCMN160 demonstrated enhanced humoral responses. Virus load was monitored. Virus load in the chimpanzee receiving pCMN160 decreased at week 20 and has remained at background levels. The control chimpanzee was subsequently vaccinated with pCMN160. After immunization, the antibody responses increased and, as in the first animal, the virus load decreased. These results indicate the potential of the immune response to have a direct impact on HIV-1 replication in chimpanzees.
Alzheimer's & Dementia, 2012
Human vaccines & immunotherapeutics, 2013
We previously demonstrated that our second-generation DNA-based Alzheimer disease (AD) epitope va... more We previously demonstrated that our second-generation DNA-based Alzheimer disease (AD) epitope vaccine comprising three copies of a short amyloid-β (Aβ) B cell epitope, Aβ 11 fused with the foreign promiscuous Th epitope, PADRE (p3Aβ 11-PADRE) was immunogenic in mice. However, since DNA vaccines exhibit poor immunogenicity in large animals and humans, in this study, we sought to improve the immunogenicity of p3Aβ 11-PADRE by modifying this vaccine to express protein 3Aβ 11-PADRE with a free N-terminal aspartic acid fused with eight additional promiscuous Th epitopes. Generated pN-3Aβ 11-PADRE-Thep vaccine has been designated as AV-1955. We also delivered this vaccine using the TriGrid electroporation system to improve the efficiency of DNA transfection. This third-generation DNA epitope vaccine was evaluated for immunogenicity in rabbits in comparison to the parent construct p3Aβ 11-PADRE. AV-1955 vaccination induced significantly stronger humoral immune responses in rabbits compare...