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01-11-2015 | Original Paper

Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N-truncated Abeta in sporadic Alzheimer disease cases and mouse models

Authors: Yvonne Bouter, Jose Socrates Lopez Noguerola, Petra Tucholla, Gabriela A. N. Crespi, Michael W. Parker, Jens Wiltfang, Luke A. Miles, Thomas A. Bayer

Published in: Acta Neuropathologica | Issue 5/2015

Abstract

Solanezumab and Crenezumab are two humanized antibodies targeting Amyloid-β (Aβ) which are currently tested in multiple clinical trials for the prevention of Alzheimer’s disease. However, there is a scientific discussion ongoing about the target engagement of these antibodies. Here, we report the immunohistochemical staining profiles of biosimilar antibodies of Solanezumab, Crenezumab and Bapineuzumab in human formalin-fixed, paraffin-embedded tissue and human fresh frozen tissue. Furthermore, we performed a direct comparative immunohistochemistry analysis of the biosimilar versions of the humanized antibodies in different mouse models including 5XFAD, Tg4-42, TBA42, APP/PS1KI, 3xTg. The staining pattern with these humanized antibodies revealed a surprisingly similar profile. All three antibodies detected plaques, cerebral amyloid angiopathy and intraneuronal Aβ in a similar fashion. Remarkably, Solanezumab showed a strong binding affinity to plaques. We also reaffirmed that Bapineuzumab does not recognize N-truncated or modified Aβ, while Solanezumab and Crenezumab do detect N-terminally modified Aβ peptides Aβ4–42 and pyroglutamate Aβ3–42. In addition, we compared the results with the staining pattern of the mouse NT4X antibody that recognizes specifically Aβ4–42 and pyroglutamate Aβ3–42, but not full-length Aβ1–42. In contrast to the biosimilar antibodies of Solanezumab, Crenezumab and Bapineuzumab, the murine NT4X antibody shows a unique target engagement. NT4X does barely cross-react with amyloid plaques in human tissue. It does, however, detect cerebral amyloid angiopathy in human tissue. In Alzheimer mouse models, NT4X detects intraneuronal Aβ and plaques comparable to the humanized antibodies. In conclusion, the biosimilar antibodies Solanezumab, Crenezumab and Bapineuzumab strongly react with amyloid plaques, which are in contrast to the NT4X antibody that hardly recognizes plaques in human tissue. Therefore, NT4X is the first of a new class of therapeutic antibodies.

https://clinicaltrials.gov. Accessed 1 July 2015

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Title: Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N-truncated Abeta in sporadic Alzheimer disease cases and mouse models
Authors: Yvonne Bouter
Jose Socrates Lopez Noguerola
Petra Tucholla
Gabriela A. N. Crespi
Michael W. Parker
Jens Wiltfang
Luke A. Miles
Thomas A. Bayer
Publication date: 01-11-2015
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 5/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-015-1489-x

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Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N-truncated Abeta in sporadic Alzheimer disease cases and mouse models

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Keynote webinar | Spotlight on medication adherence

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Other articles of this Issue 5/2015

Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43

PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

PDCD10 (CCM3) regulates brain endothelial barrier integrity in cerebral cavernous malformation type 3: role of CCM3-ERK1/2-cortactin cross-talk

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies