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Acta Neuropathol Commun. 2018 May 31;6(1):43. doi: 10.1186/s40478-018-0543-z.

A common antigenic motif recognized by naturally occurring human VH5-51/VL4-1 anti-tau antibodies with distinct functionalities.

Author information

1
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333, CN, Leiden, the Netherlands. AApetri@its.jnj.com.
2
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, 2333, CN, Leiden, the Netherlands.
3
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA, 92121, USA.
4
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
5
Present address: Janssen R&D US, 3210 Merryfield Row, San Diego, CA, 92121, USA.
6
Proteros Biostructures GmbH, Bunsenstraße 7a, 82152, Planegg, Germany.
7
Janssen Vaccines and Prevention, Janssen Pharmaceutical Companies of Johnson and Johnson, Archimedesweg 6, Leiden, CN, 2333, the Netherlands.
8
Janssen Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium.
9
Molecular and Cellular Pharmacology, Discovery Sciences, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium.
10
Department of Pathology, Amsterdam Neuroscience, VU University Medical Center, De Boelelaan 1117, 1081, HV, Amsterdam, the Netherlands.
11
Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
12
Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA.
13
Department of Neurology, Amsterdam Neuroscience, Academic Medical Center, Meidreefberg 9, 1105, AZ, Amsterdam, the Netherlands.

Abstract

Misfolding and aggregation of tau protein are closely associated with the onset and progression of Alzheimer's Disease (AD). By interrogating IgG+ memory B cells from asymptomatic donors with tau peptides, we have identified two somatically mutated VH5-51/VL4-1 antibodies. One of these, CBTAU-27.1, binds to the aggregation motif in the R3 repeat domain and blocks the aggregation of tau into paired helical filaments (PHFs) by sequestering monomeric tau. The other, CBTAU-28.1, binds to the N-terminal insert region and inhibits the spreading of tau seeds and mediates the uptake of tau aggregates into microglia by binding PHFs. Crystal structures revealed that the combination of VH5-51 and VL4-1 recognizes a common Pro-Xn-Lys motif driven by germline-encoded hotspot interactions while the specificity and thereby functionality of the antibodies are defined by the CDR3 regions. Affinity improvement led to improvement in functionality, identifying their epitopes as new targets for therapy and prevention of AD.

KEYWORDS:

Alzheimer’s disease; Antigenic motif; Monoclonal antibody; Tau protein

PMID:
29855358
PMCID:
PMC5984341
DOI:
10.1186/s40478-018-0543-z
[Indexed for MEDLINE]
Free PMC Article

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