Active and Passive Immunotherapy for Neurodegenerative Disorders

Brody, David L.; Holtzman, David M.

doi:10.1146/annurev.neuro.31.060407.125529

Cited by 230 publications

(211 citation statements)

References 88 publications

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“…2 On the other hand, several candidate anti-beta-amyloid vaccines described in the literature do not elicit anti-beta-amyloid antibodies in all vaccinated subjects, require several injections to trigger a measurable anti-beta-amyloid titer, and only display therapeutic efficacy when administered monthly or, in some instances, weekly. In contrast, vaccine E2(1-11), described in this paper, is highly immunogenic and triggers anti-beta-amyloid antibodies in all vaccinated mice after a single injection.…”

Section: Discussionmentioning

confidence: 99%

“…A single injection also induces immunological memory that can be rapidly mobilized by a single booster injection, leading to very high serum concentration of anti-beta-amyloid antibodies. Two injections of Alternative beta-amyloid immunogens F Mantile et al E2 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) are sufficient to obtain a persistent, high titer anti-betaamyloid response, which is dominated by the presence of the IgG1 isotype relative to the IgG2a isotype, implying that a Th2-type response has been induced. Cells from mice immunized with (1-11)E2 produce IL-4 in response to (1-11)E2 and E2 particles, but not in response to the synthetic peptide 1-11, indicating that the Th2-like response to the (1-11)E2 vaccine is directed to a T-cell epitope internal to E2.…”

Section: Discussionmentioning

confidence: 99%

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A multimeric immunogen for the induction of immune memory to beta‐amyloid

et al. 2010

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The development of active immunotherapy for Alzheimer's disease (AD) requires the identification of immunogens that can ensure a high titer antibody response toward beta-amyloid, whereas minimizing the risks of a cell-mediated adverse reaction. We describe here two novel anti-beta-amyloid vaccines that consist of 'virus like particles' formed by a domain of the bacterial protein E2 that is able to self-assemble into a 60-mer peptide. Peptides 1-11 and 2-6 of beta-amyloid were displayed as N terminal fusions on the surface of the E2 particles. E2-based vaccines induced a fast-rising, robust and persistent antibody response to beta-amyloid in all vaccinated mice. The immune memory induced by a single administration of vaccine (1-11) E2 can be rapidly mobilized by a single booster injection, leading to a very high serum concentration of anti-beta-amyloid antibodies (above 1 mg ml À1 ). E2 vaccination polarizes the immune response toward the production of the anti-inflammatory cytokine interleukin-4 and does not induce a T cell response to beta-amyloid. Thus, E2-based vaccines are promising candidates for the development of immunotherapy protocols for AD. Alzheimer's disease (AD) is characterized by deposition of insoluble protein aggregates in the brain, known as amyloid plaques, which are mainly composed of beta-amyloid peptide. Active and passive immunization studies performed in transgenic mouse models of beta-amyloid deposition have demonstrated that antibodies against beta-amyloid are able to reduce plaques and improve cognition (reviewed in 1-3 ). In mouse models of AD, induction of a high titer of anti-beta-amyloid antibodies correlated with the therapeutic efficacy of vaccination [4][5][6] A clinical trial of immunization of AD patients with whole preaggregated beta-amyloid peptide has shown that immunization has the potential to reduce amyloid plaques in the brains of AD patients and delay disease progression. 7,8 However, the trial was interrupted when 6% of patients developed an adverse inflammatory reaction involving infiltration of T cells into the brain; moreover, only 59 of 300 individuals who received the vaccine mounted a humoral anti-beta-amyloid response with a titer higher than 1:2200. 9 Individuals with the highest titers of anti-beta-amyloid antibodies demonstrated the most pronounced depletion of plaques. 10 The development of a Th1-type response was found to correlate with an adverse inflammatory reaction. 11 The development of an effective and safe immunotherapy protocol faces two challenges, namely, overcoming the low immunogenicity of the beta-amyloid peptide and avoiding detrimental inflammatory reactions in the brain.The N-terminus of beta-amyloid is considered the most promising antibody target for inclusion in recombinant vaccines. 1 We have previously observed reduced deposition of beta-amyloid plaques in mice that received monthly injections of phage-based vaccine fdAD (2-6), a bacteriophage that displays the epitope AEFRH of betaamyloid as an N terminal fusion to the major capsid p...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A multimeric immunogen for the induction of immune memory to beta‐amyloid

et al. 2010

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“…Removing Amyloid Via Anti-Aβ Treatment Numerous reviews have addressed the immunotherapeutic approaches to target Aβ [4,34,[55][56][57]; thus, we will focus on the debate around the mechanism(s) of anti-Aβ action ( Fig. 2b) and the most recent clinical advances.…”

Section: Using Anti-bace1 To Reduce Aβ Productionmentioning

confidence: 99%

“…However, target specificity, reduced off-target side effects, and better pharmacokinetics make antibody and protein therapeutics an attractive and promising approach for targeting CNS diseases [2,3]. Furthermore, progress in the field of Alzheimer's passive immunotherapy-particularly results showing that peripherally administered beta amyloid (Aβ) antibodies can cross the BBB and reduce amyloid plaque-have spurred efforts to raise antibodies to other CNS targets [4]. We review the recent advances in antibody drug development for neurodegenerative disease, focusing almost exclusively on passive antibody therapy with only a brief comment on active immunization approaches that provided initial proof-of-concept for immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Developing Therapeutic Antibodies for Neurodegenerative Disease

Yu¹,

Watts²

2013

Neurotherapeutics

180

171

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The central nervous system has been considered off-limits to antibody therapeutics. However, recent advances in preclinical and clinical drug development suggest that antibodies can cross the blood-brain barrier in limited quantities and act centrally to mediate their effects. In particular, immunotherapy for Alzheimer's disease has shown that targeting beta amyloid with antibodies can reduce pathology in both mouse models and the human brain, with strong evidence supporting a central mechanism of action. These findings have fueled substantial efforts to raise antibodies against other central nervous system targets, particularly neurodegenerative targets, such as tau, beta-secretase, and alpha-synuclein. Nevertheless, it is also apparent that antibody penetration across the blood-brain barrier is limited, with an estimated 0.1-0.2 % of circulating antibodies found in brain at steady-state concentrations. Thus, technologies designed to improve antibody uptake in brain are receiving increased attention and are likely going to represent the future of antibody therapy for neurologic diseases, if proven safe and effective. Herein we review briefly the progress and limitations of traditional antibody drug development for neurodegenerative diseases, with a focus on passive immunotherapy. We also take a more in-depth look at new technologies for improved delivery of antibodies to the brain.

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“…Accordingly, immunization against A␤ has offered a promising approach toward the therapeutic management of AD (4)(5)(6). In animal models of AD, both active and passive anti-A␤ immunotherapies improve cognitive function and clear the parenchymal accumulation of amyloid (plaques) in the brain (7)(8)(9)(10)(11)(12)(13).…”

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confidence: 99%

Intracerebroventricular amyloid-β antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice

Thakker

Weatherspoon

Harrison

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

121

112

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Although immunization against amyloid-␤ (A␤) holds promise as a disease-modifying therapy for Alzheimer disease (AD), it is associated with an undesirable accumulation of amyloid in the cerebrovasculature [i.e., cerebral amyloid angiopathy (CAA)] and a heightened risk of micro-hemorrhages. The central and peripheral mechanisms postulated to modulate amyloid with anti-A␤ immunotherapy remain largely elusive. Here, we compared the effects of prolonged intracerebroventricular (icv) versus systemic delivery of anti-A␤ antibodies on the behavioral and pathological changes in an aged Tg2576 mouse model of AD. Prolonged icv infusions of anti-A␤ antibodies dose-dependently reduced the parenchymal plaque burden, astrogliosis, and dystrophic neurites at doses 10-to 50-fold lower than used with systemic delivery of the same antibody. Both icv and systemic anti-A␤ antibodies reversed the behavioral impairment in contextual fear conditioning. More importantly, unlike systemically delivered anti-A␤ antibodies that aggravated vascular pathology, icv-infused antibodies globally reduced CAA and associated micro-hemorrhages. We present data suggesting that the divergent effects of icv-delivered anti-A␤ antibodies result from gradually engaging the local (i.e., central) mechanisms for amyloid clearance, distinct from the mechanisms engaged by high doses of anti-A␤ antibodies that circulate in the vasculature following systemic delivery. With robust efficacy in reversing AD-related pathology and an unexpected benefit in reducing CAA and associated micro-hemorrhages, icv-targeted passive immunotherapy offers a promising therapeutic approach for the long-term management of AD.Alzheimer disease ͉ passive immunotherapy ͉ vascular amyloid ͉ microglia ͉ peripheral sink

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Active and Passive Immunotherapy for Neurodegenerative Disorders

Cited by 230 publications

References 88 publications

A multimeric immunogen for the induction of immune memory to beta‐amyloid

A multimeric immunogen for the induction of immune memory to beta‐amyloid

Developing Therapeutic Antibodies for Neurodegenerative Disease

Intracerebroventricular amyloid-β antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice

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