A common antigenic motif recognized by naturally occurring human V H 5-51/V L 4-1 anti-tau antibodies with distinct functionalities

Adrian Apetri, Rosa Crespo, Jarek Juraszek, Gabriel Pascual, Roosmarijn Janson, Xueyong Zhu, Heng Zhang, Elissa Keogh, Trevin Holland, Jay Wadia, Hanneke Verveen, Berdien Siregar, Michael Mrosek, Renske Taggenbrock, Jeroenvan Ameijde, Hanna Inganäs, Margot van Winsen, Martin H. Koldijk, David Zuijdgeest, Marianne Borgers & 13 others Koen Dockx, Esther J. M. Stoop, Wenli Yu, Els C. Brinkman-van der Linden, Kimberley Ummenthum, Kristof van Kolen, Marc Mercken, Stefan Steinbacher, Donata de Marco, Jeroen J. Hoozemans, Ian A. Wilson, Wouter Koudstaal, Jaap Goudsmit

Research output: Contribution to journalArticleAcademicpeer-review

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 V H 5-51/V L 4-1 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 V H 5-51 and V L 4-1 recognizes a common Pro-X n -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.
LanguageEnglish
Article number43
Pages43
JournalActa Neuropathologica Communinications
Volume6
Issue number1
DOIs
Publication statusPublished - 2018

Cite this

Apetri, Adrian ; Crespo, Rosa ; Juraszek, Jarek ; Pascual, Gabriel ; Janson, Roosmarijn ; Zhu, Xueyong ; Zhang, Heng ; Keogh, Elissa ; Holland, Trevin ; Wadia, Jay ; Verveen, Hanneke ; Siregar, Berdien ; Mrosek, Michael ; Taggenbrock, Renske ; Ameijde, Jeroenvan ; Inganäs, Hanna ; van Winsen, Margot ; Koldijk, Martin H. ; Zuijdgeest, David ; Borgers, Marianne ; Dockx, Koen ; Stoop, Esther J. M. ; Yu, Wenli ; Brinkman-van der Linden, Els C. ; Ummenthum, Kimberley ; van Kolen, Kristof ; Mercken, Marc ; Steinbacher, Stefan ; de Marco, Donata ; Hoozemans, Jeroen J. ; Wilson, Ian A. ; Koudstaal, Wouter ; Goudsmit, Jaap. / A common antigenic motif recognized by naturally occurring human V H 5-51/V L 4-1 anti-tau antibodies with distinct functionalities. In: Acta Neuropathologica Communinications. 2018 ; Vol. 6, No. 1. pp. 43.
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title = "A common antigenic motif recognized by naturally occurring human V H 5-51/V L 4-1 anti-tau antibodies with distinct functionalities",
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 V H 5-51/V L 4-1 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 V H 5-51 and V L 4-1 recognizes a common Pro-X n -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.",
author = "Adrian Apetri and Rosa Crespo and Jarek Juraszek and Gabriel Pascual and Roosmarijn Janson and Xueyong Zhu and Heng Zhang and Elissa Keogh and Trevin Holland and Jay Wadia and Hanneke Verveen and Berdien Siregar and Michael Mrosek and Renske Taggenbrock and Jeroenvan Ameijde and Hanna Ingan{\"a}s and {van Winsen}, Margot and Koldijk, {Martin H.} and David Zuijdgeest and Marianne Borgers and Koen Dockx and Stoop, {Esther J. M.} and Wenli Yu and {Brinkman-van der Linden}, {Els C.} and Kimberley Ummenthum and {van Kolen}, Kristof and Marc Mercken and Stefan Steinbacher and {de Marco}, Donata and Hoozemans, {Jeroen J.} and Wilson, {Ian A.} and Wouter Koudstaal and Jaap Goudsmit",
year = "2018",
doi = "10.1186/s40478-018-0543-z",
language = "English",
volume = "6",
pages = "43",
journal = "Acta Neuropathologica Communinications",
issn = "2051-5960",
publisher = "BioMed Central",
number = "1",

}

Apetri, A, Crespo, R, Juraszek, J, Pascual, G, Janson, R, Zhu, X, Zhang, H, Keogh, E, Holland, T, Wadia, J, Verveen, H, Siregar, B, Mrosek, M, Taggenbrock, R, Ameijde, J, Inganäs, H, van Winsen, M, Koldijk, MH, Zuijdgeest, D, Borgers, M, Dockx, K, Stoop, EJM, Yu, W, Brinkman-van der Linden, EC, Ummenthum, K, van Kolen, K, Mercken, M, Steinbacher, S, de Marco, D, Hoozemans, JJ, Wilson, IA, Koudstaal, W & Goudsmit, J 2018, 'A common antigenic motif recognized by naturally occurring human V H 5-51/V L 4-1 anti-tau antibodies with distinct functionalities', Acta Neuropathologica Communinications, vol. 6, no. 1, 43, pp. 43. https://doi.org/10.1186/s40478-018-0543-z, https://doi.org/10.1186/s40478-018-0543-z

A common antigenic motif recognized by naturally occurring human V H 5-51/V L 4-1 anti-tau antibodies with distinct functionalities. / Apetri, Adrian; Crespo, Rosa; Juraszek, Jarek; Pascual, Gabriel; Janson, Roosmarijn; Zhu, Xueyong; Zhang, Heng; Keogh, Elissa; Holland, Trevin; Wadia, Jay; Verveen, Hanneke; Siregar, Berdien; Mrosek, Michael; Taggenbrock, Renske; Ameijde, Jeroenvan; Inganäs, Hanna; van Winsen, Margot; Koldijk, Martin H.; Zuijdgeest, David; Borgers, Marianne; Dockx, Koen; Stoop, Esther J. M.; Yu, Wenli; Brinkman-van der Linden, Els C.; Ummenthum, Kimberley; van Kolen, Kristof; Mercken, Marc; Steinbacher, Stefan; de Marco, Donata; Hoozemans, Jeroen J.; Wilson, Ian A.; Koudstaal, Wouter; Goudsmit, Jaap.

In: Acta Neuropathologica Communinications, Vol. 6, No. 1, 43, 2018, p. 43.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - A common antigenic motif recognized by naturally occurring human V H 5-51/V L 4-1 anti-tau antibodies with distinct functionalities

AU - Apetri, Adrian

AU - Crespo, Rosa

AU - Juraszek, Jarek

AU - Pascual, Gabriel

AU - Janson, Roosmarijn

AU - Zhu, Xueyong

AU - Zhang, Heng

AU - Keogh, Elissa

AU - Holland, Trevin

AU - Wadia, Jay

AU - Verveen, Hanneke

AU - Siregar, Berdien

AU - Mrosek, Michael

AU - Taggenbrock, Renske

AU - Ameijde, Jeroenvan

AU - Inganäs, Hanna

AU - van Winsen, Margot

AU - Koldijk, Martin H.

AU - Zuijdgeest, David

AU - Borgers, Marianne

AU - Dockx, Koen

AU - Stoop, Esther J. M.

AU - Yu, Wenli

AU - Brinkman-van der Linden, Els C.

AU - Ummenthum, Kimberley

AU - van Kolen, Kristof

AU - Mercken, Marc

AU - Steinbacher, Stefan

AU - de Marco, Donata

AU - Hoozemans, Jeroen J.

AU - Wilson, Ian A.

AU - Koudstaal, Wouter

AU - Goudsmit, Jaap

PY - 2018

Y1 - 2018

N2 - 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 V H 5-51/V L 4-1 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 V H 5-51 and V L 4-1 recognizes a common Pro-X n -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.

AB - 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 V H 5-51/V L 4-1 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 V H 5-51 and V L 4-1 recognizes a common Pro-X n -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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/29855358

U2 - 10.1186/s40478-018-0543-z

DO - 10.1186/s40478-018-0543-z

M3 - Article

VL - 6

SP - 43

JO - Acta Neuropathologica Communinications

T2 - Acta Neuropathologica Communinications

JF - Acta Neuropathologica Communinications

SN - 2051-5960

IS - 1

M1 - 43

ER -