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Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies

Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies
Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies
Immunotherapy is a promising strategy for the treatment of Alzheimer’s disease (AD). Antibodies directed against Amyloid Beta (A?) are able to successfully clear plaques and reverse cognitive deficits in mouse models. Excitement towards this approach has been tempered by high profile failures in the clinic, one key issue has been the development of inflammatory side effects in the brain (ARIAs). New antibodies are entering the clinic for Alzheimer’s disease; therefore, it is important to learn all we can from the current generation. In this study, we directly compared 3 clinical candidates in the same pre-clinical model, with the same effector function, for their ability to clear plaques and induce inflammation in the brain. We produced murine versions of the antibodies: Bapineuzumab (3D6), Crenezumab (mC2) and Gantenerumab (chGantenerumab) with an IgG2a constant region. 18-month transgenic APP mice (Tg2576) were injected bilaterally into the hippocampus with 2 µg of each antibody or control. After 7 days, the mice tissue was analysed for clearance of plaques and neuroinflammation by histology and biochemical analysis. 3D6 was the best binder to plaques and in vitro, whilst mC2 bound the least strongly. This translated into 3D6 effectively clearing plaques and reducing the levels of insoluble A?, whilst chGantenerumab and mC2 did not. 3D6 caused a significant increase in the levels of pro-inflammatory cytokines IL-1? and TNF?, and an associated increase in microglial expression of CD11B and CD68. chGantenerumab increased pro-inflammatory cytokines and microglial activation, but minimal changes in CD68, as an indicator of phagocytosis. Injection of mC2 did not cause any significant inflammatory changes. Our results demonstrate that the ability of an antibody to clear plaques and induce inflammation is dependent on the epitope and affinity of the antibody.
0001-6322
699-711
Fuller, J.P.
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Stavenhagen, J.
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Christensen, S.
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Kartberg, Fredrik
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Glennie, M.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Teeling, J.
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Fuller, J.P.
1cc7f516-492a-4cd4-ad6b-854045ad81fe
Stavenhagen, J.
49bb18cd-b00c-4eb9-a2cf-618ba5405622
Christensen, S.
d1bd0c6c-0f1e-4458-a9d2-2619c5330322
Kartberg, Fredrik
44a68f0e-4dea-42d7-87bb-b59ca2f0fdd3
Glennie, M.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Teeling, J.
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a

Fuller, J.P., Stavenhagen, J., Christensen, S., Kartberg, Fredrik, Glennie, M. and Teeling, J. (2015) Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies. Acta Neuropathologica, 130 (5), 699-711. (doi:10.1007/s00401-015-1484-2). (PMID:26433971)

Record type: Article

Abstract

Immunotherapy is a promising strategy for the treatment of Alzheimer’s disease (AD). Antibodies directed against Amyloid Beta (A?) are able to successfully clear plaques and reverse cognitive deficits in mouse models. Excitement towards this approach has been tempered by high profile failures in the clinic, one key issue has been the development of inflammatory side effects in the brain (ARIAs). New antibodies are entering the clinic for Alzheimer’s disease; therefore, it is important to learn all we can from the current generation. In this study, we directly compared 3 clinical candidates in the same pre-clinical model, with the same effector function, for their ability to clear plaques and induce inflammation in the brain. We produced murine versions of the antibodies: Bapineuzumab (3D6), Crenezumab (mC2) and Gantenerumab (chGantenerumab) with an IgG2a constant region. 18-month transgenic APP mice (Tg2576) were injected bilaterally into the hippocampus with 2 µg of each antibody or control. After 7 days, the mice tissue was analysed for clearance of plaques and neuroinflammation by histology and biochemical analysis. 3D6 was the best binder to plaques and in vitro, whilst mC2 bound the least strongly. This translated into 3D6 effectively clearing plaques and reducing the levels of insoluble A?, whilst chGantenerumab and mC2 did not. 3D6 caused a significant increase in the levels of pro-inflammatory cytokines IL-1? and TNF?, and an associated increase in microglial expression of CD11B and CD68. chGantenerumab increased pro-inflammatory cytokines and microglial activation, but minimal changes in CD68, as an indicator of phagocytosis. Injection of mC2 did not cause any significant inflammatory changes. Our results demonstrate that the ability of an antibody to clear plaques and induce inflammation is dependent on the epitope and affinity of the antibody.

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Accepted/In Press date: 25 September 2015
e-pub ahead of print date: 3 October 2015
Published date: November 2015
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 390372
URI: http://eprints.soton.ac.uk/id/eprint/390372
ISSN: 0001-6322
PURE UUID: 74f15e71-e591-469c-8ff8-f2a31523a902
ORCID for J. Teeling: ORCID iD orcid.org/0000-0003-4004-7391

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Date deposited: 31 Mar 2016 14:38
Last modified: 21 Nov 2021 02:55

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Contributors

Author: J.P. Fuller
Author: J. Stavenhagen
Author: S. Christensen
Author: Fredrik Kartberg
Author: M. Glennie
Author: J. Teeling ORCID iD

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