The F(ab′)2 fragment of an Aβ-specific monoclonal antibody reduces Aβ deposits in the brain

Tamura, Yuma; Hamajima, Kenji; Matsui, Kengo; Yanoma, Shunsuke; Narita, Michiko; Tajima, NobuyoshiI; Xin, Ke-Qin; Klinman, Dennis M.; Okuda, Kenji

doi:10.1016/j.nbd.2005.04.007

Cited by 37 publications

(27 citation statements)

References 28 publications

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“…In addition, removal of the Fc portion from IgG4.1 will also minimize the risks associated with the inflammatory response and cerebral hemorrhaging as reported in active and some passive immunotherapy studies (26). Also, because of the larger molecular size, internalization of this probe by cells in the brain parenchyma is expected to be limited so that most of the probe should be available for imaging the amyloid plaques in the extracellular milieu.…”

Section: Discussionmentioning

confidence: 99%

Selective Contrast Enhancement of Individual Alzheimer’s Disease Amyloid Plaques Using a Polyamine and Gd-DOTA Conjugated Antibody Fragment Against Fibrillar Aβ42 for Magnetic Resonance Molecular Imaging

et al. 2008

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Purpose-The lack of an in vivo diagnostic test for AD has prompted the targeting of amyloid plaques with diagnostic imaging probes. We describe the development of a contrast agent (CA) for magnetic resonance microimaging that utilizes the F(ab′) 2 fragment of a monoclonal antibody raised against fibrillar human Aβ42Methods-This fragment is polyamine modified to enhance its BBB permeability and its ability to bind to amyloid plaques. It is also conjugated with a chelator and gadolinium for subsequent imaging of individual amyloid plaques Results-Pharmacokinetic studies demonstrated this 125 I-CA has higher BBB permeability and lower accumulation in the liver and kidney than F(ab′) 2 in WT mice. The CA retains its ability to bind Aβ40/42 monomers/fibrils and also binds to amyloid plaques in sections of AD mouse brain. Intravenous injection of 125 I-CA into the AD mouse demonstrates targeting of amyloid plaques throughout the cortex/hippocampus as detected by emulsion autoradiography. Incubation of AD mouse brain slices in vitro with this CA resulted in selective enhancement on T 1 -weighted spinecho images, which co-register with individual plaques observed on spatially matched T 2 -weighted spin-echo image Conclusions-Development of such a molecular probe is expected to open new avenues for the diagnosis of AD.

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Section: Discussionmentioning

confidence: 99%

Selective Contrast Enhancement of Individual Alzheimer’s Disease Amyloid Plaques Using a Polyamine and Gd-DOTA Conjugated Antibody Fragment Against Fibrillar Aβ42 for Magnetic Resonance Molecular Imaging

et al. 2008

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“…Studies have suggested that to reduce A␤ deposition, it is not necessary to use intact anti-A␤ antibodies (Bacskai et al, 2002;Matsuoka et al, 2003;Wilcock et al, 2003;Tamura et al, 2005). It may be possible to avoid potential side effects simply by targeting A␤ with high-affinity binding agents that lack immune effector functions.…”

Section: Introductionmentioning

confidence: 99%

Intracranial Adeno-Associated Virus-Mediated Delivery of Anti-Pan Amyloid β, Amyloid β40, and Amyloid β42 Single-Chain Variable Fragments Attenuates Plaque Pathology in Amyloid Precursor Protein Mice

et al. 2006

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Accumulation of amyloid ␤ protein (A␤) aggregates is hypothesized to trigger a pathological cascade that causes Alzheimer's disease (AD). Active or passive immunizations targeting A␤ are therefore of great interest as potential therapeutic strategies. We have evaluated the use of recombinant anti-A␤ single-chain variable fragments (scFvs) as a potentially safer form of anti-A␤ immunotherapy. We have generated and characterized three anti-A␤ scFvs that recognize A␤1-16, A␤x-40, or A␤x-42. To achieve widespread brain delivery, constructs expressing these anti-A␤ scFvs were packaged into adeno-associated virus (AAV) vectors and injected into the ventricles of postnatal day 0 (P0) amyloid precursor protein CRND8-transgenic mice. Intracranial delivery of AAV to neonatal mice resulted in widespread neuronal delivery. In situ expression of each of the anti-A␤ scFvs after intracerebroventricular AAV serotype 1 delivery to P0 pups decreased A␤ deposition by 25-50%. These data suggest that intracranial anti-A␤ scFv expression is an effective strategy to attenuate amyloid deposition. As opposed to transgenic approaches, these studies also establish a "somatic brain transgenic" paradigm to rapidly and cost-effectively evaluate potential modifiers of AD-like pathology in AD mouse models.

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“…Single chain variable fragments have been generated against A␤ that preferentially bind to the multimeric peptide, inhibit fibril formation, reduce A␤ cytotoxicity in cultured cells, and degrade brain amyloid plaques in vivo (62)(63)(64). Murine F(abЈ) 2 fragments can also clear in vivo AD plaques (65,66). Moreover, single-chain camelid antibodies, which consist of only a HC-HC dimer, that were specifically generated against A␤ inhibited A␤ fibril growth and neutralized neurotoxic A␤ assemblies in vitro (67,68).…”

Section: Discussionmentioning

confidence: 99%

Inherent Anti-amyloidogenic Activity of Human Immunoglobulin γ Heavy Chains

Adekar

Klyubin

Macy

et al. 2010

Journal of Biological Chemistry

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We have previously shown that a subpopulation of naturally occurring human IgGs were cross-reactive against conformational epitopes on pathologic aggregates of A␤, a peptide that forms amyloid fibrils in the brains of patients with Alzheimer disease, inhibited amyloid fibril growth, and dissociated amyloid in vivo. Here, we describe similar anti-amyloidogenic activity that is a general property of free human Ig ␥ heavy chains. A ␥ 1 heavy chain, F1, had nanomolar binding to an amyloid fibril-related conformational epitope on synthetic oligomers and fibrils as well as on amyloidladen tissue sections. F1 did not bind to native A␤ monomers, further indicating the conformational nature of its binding site. The inherent anti-amyloidogenic activity of Ig ␥ heavy chains was demonstrated by nanomolar amyloid fibril and oligomer binding by polyclonal and monoclonal human heavy chains that were isolated from inert or weakly reactive antibodies. Most importantly, the F1 heavy chain prevented in vitro fibril growth and reduced in vivo soluble A␤ oligomer-induced impairment of rodent hippocampal long term potentiation, a cellular mechanism of learning and memory. These findings demonstrate that free human Ig ␥ heavy chains comprise a novel class of molecules for developing potential therapeutics for Alzheimer disease and other amyloid disorders. Moreover, establishing the molecular basis for heavy chain-amyloidogenic conformer interactions should advance understanding on the types of interactions that these pathologic assemblies have with biological molecules. Alzheimer disease (AD)3 is approaching global epidemic proportions and is the most common of over 25 incurable protein misfolding diseases that are termed the amyloidoses (1, 2). A hallmark of the disease is deposition of amyloid fibril-containing neuritic plaques that are formed by abnormal processing of ␤-amyloid protein (A␤), a proteolyzed transmembrane 39 -43 fragment of amyloid precursor protein (3). Diverse experimental studies support a central pathogenic role for aggregated A␤, which in the brain initiates a cascade of events that ultimately lead to neuronal dysfunction and death (4 -6). The most neurotoxic A␤ species are low molecular weight oligomers (5), which include noncovalently linked species (7-9) and dityrosine cross-linked ␤-amyloid protein species (CAPS) (10).Active vaccination with A␤ or passive administration of anti-A␤ antibodies has shown promise in transgenic AD animal models and in some AD patients by inducing neuritic plaque clearance, neutralizing neurotoxic soluble A␤ oligomers, and/or improving cognitive functioning (6,8,(11)(12)(13). Immunotherapy has generally targeted linear sequence epitopes on A␤ (13). However, antibodies that do not distinguish between pathologic A␤ conformers and the monomeric peptide may have adverse effects because the native peptide has been implicated in normal lipid and cholesterol homeostasis (14). Of potentially greater use are antibodies that cross-react with conformational epitopes on pathogenic aggregated A...

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The F(ab′)2 fragment of an Aβ-specific monoclonal antibody reduces Aβ deposits in the brain

Cited by 37 publications

References 28 publications

Selective Contrast Enhancement of Individual Alzheimer’s Disease Amyloid Plaques Using a Polyamine and Gd-DOTA Conjugated Antibody Fragment Against Fibrillar Aβ42 for Magnetic Resonance Molecular Imaging

Selective Contrast Enhancement of Individual Alzheimer’s Disease Amyloid Plaques Using a Polyamine and Gd-DOTA Conjugated Antibody Fragment Against Fibrillar Aβ42 for Magnetic Resonance Molecular Imaging

Intracranial Adeno-Associated Virus-Mediated Delivery of Anti-Pan Amyloid β, Amyloid β40, and Amyloid β42 Single-Chain Variable Fragments Attenuates Plaque Pathology in Amyloid Precursor Protein Mice

Inherent Anti-amyloidogenic Activity of Human Immunoglobulin γ Heavy Chains

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