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Alzheimer's Research & Therapy
Published in: Alzheimer's Research & Therapy 1/2020

01-12-2020 | Alzheimer's Disease | Research

Effector function of anti-pyroglutamate-3 Aβ antibodies affects cognitive benefit, glial activation and amyloid clearance in Alzheimer’s-like mice

Authors: Helen Crehan, Bin Liu, Martin Kleinschmidt, Jens-Ulrich Rahfeld, Kevin X. Le, Barbara J. Caldarone, Jeffrey L. Frost, Thore Hettmann, Birgit Hutter-Paier, Brian O’Nuallain, Mi-Ae Park, Marcelo F. DiCarli, Inge Lues, Stephan Schilling, Cynthia A. Lemere

Published in: Alzheimer's Research & Therapy | Issue 1/2020

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Abstract

Background

Pyroglutamate-3 Aβ (pGlu-3 Aβ) is an N-terminally truncated and post-translationally modified Aβ species found in Alzheimer’s disease (AD) brain. Its increased peptide aggregation propensity and toxicity make it an attractive emerging treatment strategy for AD. We address the question of how the effector function of an anti-pGlu-3 Aβ antibody influences the efficacy of immunotherapy in mouse models with AD-like pathology.

Methods

We compared two different immunoglobulin (Ig) isotypes of the same murine anti-pGlu-3 Aβ mAb (07/1 IgG1 and 07/2a IgG2a) and a general N-terminal Aβ mAb (3A1 IgG1) for their ability to clear Aβ and protect cognition in a therapeutic passive immunotherapy study in aged, plaque-rich APPSWE/PS1ΔE9 transgenic (Tg) mice. We also compared the ability of these antibodies and a CDC-mutant form of 07/2a (07/2a-k), engineered to avoid complement activation, to clear Aβ in an ex vivo phagocytosis assay and following treatment in APPSLxhQC double Tg mice, and to activate microglia using longitudinal microPET imaging with TSPO-specific 18F-GE180 tracer following a single bolus antibody injection in young and old Tg mice.

Results

We demonstrated significant cognitive improvement, better plaque clearance, and more plaque-associated microglia in the absence of microhemorrhage in aged APPSWE/PS1ΔE9 Tg mice treated with 07/2a, but not 07/1 or 3A1, compared to PBS in our first in vivo study. All mAbs cleared plaques in an ex vivo assay, although 07/2a promoted the highest phagocytic activity. Compared with 07/2a, 07/2a-k showed slightly reduced affinity to Fcγ receptors CD32 and CD64, although the two antibodies had similar binding affinities to pGlu-3 Aβ. Treatment of APPSLxhQC mice with 07/2a and 07/2a-k mAbs in our second in vivo study showed significant plaque-lowering with both mAbs. Longitudinal 18F-GE180 microPET imaging revealed different temporal patterns of microglial activation for 3A1, 07/1, and 07/2a mAbs and no difference between 07/2a-k and PBS-treated Tg mice.

Conclusion

Our results suggest that attenuation of behavioral deficits and clearance of amyloid is associated with strong effector function of the anti-pGlu-3 Aβ mAb in a therapeutic treatment paradigm. We present evidence that antibody engineering to reduce CDC-mediated complement binding facilitates phagocytosis of plaques without inducing neuroinflammation in vivo. Hence, the results provide implications for tailoring effector function of humanized antibodies for clinical development.
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Metadata
Title
Effector function of anti-pyroglutamate-3 Aβ antibodies affects cognitive benefit, glial activation and amyloid clearance in Alzheimer’s-like mice
Authors
Helen Crehan
Bin Liu
Martin Kleinschmidt
Jens-Ulrich Rahfeld
Kevin X. Le
Barbara J. Caldarone
Jeffrey L. Frost
Thore Hettmann
Birgit Hutter-Paier
Brian O’Nuallain
Mi-Ae Park
Marcelo F. DiCarli
Inge Lues
Stephan Schilling
Cynthia A. Lemere
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Alzheimer's Research & Therapy / Issue 1/2020
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/s13195-019-0579-8

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