Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials

The DNA vaccine, AV-1959D, targeting N-terminal epitope of Aβ peptide, has been proven immunogenic in mice, rabbits, and non-human primates, while its therapeutic efficacy has been shown in mouse models of Alzheimer's disease (AD). Here we report for the first time on IND-enabling biodistributi...

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Main Authors:	Irina Petrushina, Armine Hovakimyan, Indira S. Harahap-Carrillo, Hayk Davtyan, Tatevik Antonyan, Gor Chailyan, Konstantin Kazarian, Maxim Antonenko, Amandine Jullienne, Mary M. Hamer, Andre Obenaus, Olga King, Karen Zagorski, Mathew Blurton-Jones, David H. Cribbs, Harry Lander, Anahit Ghochikyan, Michael G. Agadjanyan
Format:	Article
Language:	English
Published:	Elsevier 2020-06-01
Series:	Neurobiology of Disease
Subjects:	Alzheimer's disease (AD) DNA Aβ-vaccine Biodistribution Safety toxicology Magnetic resonance imaging (MRI) Immunohistochemistry (IHC)
Online Access:	http://www.sciencedirect.com/science/article/pii/S096999612030098X

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language	English
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author	Irina Petrushina Armine Hovakimyan Indira S. Harahap-Carrillo Hayk Davtyan Tatevik Antonyan Gor Chailyan Konstantin Kazarian Maxim Antonenko Amandine Jullienne Mary M. Hamer Andre Obenaus Olga King Karen Zagorski Mathew Blurton-Jones David H. Cribbs Harry Lander Anahit Ghochikyan Michael G. Agadjanyan
spellingShingle	Irina Petrushina Armine Hovakimyan Indira S. Harahap-Carrillo Hayk Davtyan Tatevik Antonyan Gor Chailyan Konstantin Kazarian Maxim Antonenko Amandine Jullienne Mary M. Hamer Andre Obenaus Olga King Karen Zagorski Mathew Blurton-Jones David H. Cribbs Harry Lander Anahit Ghochikyan Michael G. Agadjanyan Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials Neurobiology of Disease Alzheimer's disease (AD) DNA Aβ-vaccine Biodistribution Safety toxicology Magnetic resonance imaging (MRI) Immunohistochemistry (IHC)
author_facet	Irina Petrushina Armine Hovakimyan Indira S. Harahap-Carrillo Hayk Davtyan Tatevik Antonyan Gor Chailyan Konstantin Kazarian Maxim Antonenko Amandine Jullienne Mary M. Hamer Andre Obenaus Olga King Karen Zagorski Mathew Blurton-Jones David H. Cribbs Harry Lander Anahit Ghochikyan Michael G. Agadjanyan
author_sort	Irina Petrushina
title	Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials
title_short	Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials
title_full	Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials
title_fullStr	Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials
title_full_unstemmed	Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials
title_sort	characterization and preclinical evaluation of the cgmp grade dna based vaccine, av-1959d to enter the first-in-human clinical trials
publisher	Elsevier
series	Neurobiology of Disease
issn	1095-953X
publishDate	2020-06-01
description	The DNA vaccine, AV-1959D, targeting N-terminal epitope of Aβ peptide, has been proven immunogenic in mice, rabbits, and non-human primates, while its therapeutic efficacy has been shown in mouse models of Alzheimer's disease (AD). Here we report for the first time on IND-enabling biodistribution and safety/toxicology studies of cGMP-grade AV-1959D vaccine in the Tg2576 mouse model of AD. We also tested acute neuropathology safety profiles of AV-1959D in another AD disease model, Tg-SwDI mice with established vascular and parenchymal Aβ pathology in a pre-clinical translational study. Biodistribution studies two days after the injection demonstrated high copy numbers of AV-1959D plasmid after single immunization of Tg2576 mice at the injection sites but not in the tissues of distant organs. Plasmids persisted at the injection sites of some mice 60 days after vaccination. In Tg2576 mice with established amyloid pathology, we did not observe short- or long-term toxicities after multiple immunizations with three doses of AV-1959D. Assessment of the repeated dose acute safety of AV-1959D in cerebral amyloid angiopathy (CAA) prone Tg-SwDI mice did not reveal any immunotherapy-induced vasogenic edema detected by magnetic resonance imaging (MRI) or increased microhemorrhages. Multiple immunizations of Tg-SwDI mice with AV-1959D did not induce T and B cell infiltration, glial activation, vascular deposition of Aβ, or neuronal degeneration (necrosis and apoptosis) greater than that in the control group determined by immunohistochemistry of brain tissues. Taken together, the safety data from two different mouse models of AD substantiate a favorable safety profile of the cGMP grade AV-1959D vaccine supporting its progression to first-in-human clinical trials.
topic	Alzheimer's disease (AD) DNA Aβ-vaccine Biodistribution Safety toxicology Magnetic resonance imaging (MRI) Immunohistochemistry (IHC)
url	http://www.sciencedirect.com/science/article/pii/S096999612030098X
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spelling	doaj-89f760f61a67409099ed9195e4e4ddd02021-03-22T08:41:43ZengElsevierNeurobiology of Disease1095-953X2020-06-01139104823Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trialsIrina Petrushina0Armine Hovakimyan1Indira S. Harahap-Carrillo2Hayk Davtyan3Tatevik Antonyan4Gor Chailyan5Konstantin Kazarian6Maxim Antonenko7Amandine Jullienne8Mary M. Hamer9Andre Obenaus10Olga King11Karen Zagorski12Mathew Blurton-Jones13David H. Cribbs14Harry Lander15Anahit Ghochikyan16Michael G. Agadjanyan17Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USADepartment of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USADepartment of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USAInstitute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA; Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA, USADepartment of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USADepartment of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USADepartment of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USADepartment of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USAInstitute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USADepartment of Pediatrics, University of California, Irvine, CA, USADepartment of Pediatrics, University of California, Irvine, CA, USA; Preclinical and Translational Imaging Center, University of California, Irvine, CA, USADepartment of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USADepartment of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USAInstitute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA, USA; Department of Neurobiology and Behavior, University of California, Irvine, CA, USAInstitute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USADepartment of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USADepartment of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USA; Corresponding authors at: The Institute for Molecular Medicine, 16371 Gothard Str., H, Huntington Beach, CA 92647, USA.Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA, USA; Corresponding authors at: The Institute for Molecular Medicine, 16371 Gothard Str., H, Huntington Beach, CA 92647, USA.The DNA vaccine, AV-1959D, targeting N-terminal epitope of Aβ peptide, has been proven immunogenic in mice, rabbits, and non-human primates, while its therapeutic efficacy has been shown in mouse models of Alzheimer's disease (AD). Here we report for the first time on IND-enabling biodistribution and safety/toxicology studies of cGMP-grade AV-1959D vaccine in the Tg2576 mouse model of AD. We also tested acute neuropathology safety profiles of AV-1959D in another AD disease model, Tg-SwDI mice with established vascular and parenchymal Aβ pathology in a pre-clinical translational study. Biodistribution studies two days after the injection demonstrated high copy numbers of AV-1959D plasmid after single immunization of Tg2576 mice at the injection sites but not in the tissues of distant organs. Plasmids persisted at the injection sites of some mice 60 days after vaccination. In Tg2576 mice with established amyloid pathology, we did not observe short- or long-term toxicities after multiple immunizations with three doses of AV-1959D. Assessment of the repeated dose acute safety of AV-1959D in cerebral amyloid angiopathy (CAA) prone Tg-SwDI mice did not reveal any immunotherapy-induced vasogenic edema detected by magnetic resonance imaging (MRI) or increased microhemorrhages. Multiple immunizations of Tg-SwDI mice with AV-1959D did not induce T and B cell infiltration, glial activation, vascular deposition of Aβ, or neuronal degeneration (necrosis and apoptosis) greater than that in the control group determined by immunohistochemistry of brain tissues. Taken together, the safety data from two different mouse models of AD substantiate a favorable safety profile of the cGMP grade AV-1959D vaccine supporting its progression to first-in-human clinical trials.http://www.sciencedirect.com/science/article/pii/S096999612030098XAlzheimer's disease (AD)DNA Aβ-vaccineBiodistributionSafety toxicologyMagnetic resonance imaging (MRI)Immunohistochemistry (IHC)

Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials

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