RT Journal Article
SR Electronic
T1 Common antigenic motif recognized by human VH5-51/VL4-1 tau antibodies with distinct functionalities
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 287003
DO 10.1101/287003
A1 Adrian Apetri
A1 Rosa Crespo
A1 Jarek Juraszek
A1 Gabriel Pascual
A1 Roosmarijn Janson
A1 Xueyong Zhu
A1 Heng Zhang
A1 Elissa Keogh
A1 Trevin Holland
A1 Jay Wadia
A1 Hanneke Verveen
A1 Berdien Siregar
A1 Michael Mrosek
A1 Renske Taggenbrock
A1 Jeroen van Ameijde
A1 Hanna Inganäs
A1 Margot van Winsen
A1 Martin H. Koldijk
A1 David Zuijdgeest
A1 Marianne Borgers
A1 Koen Dockx
A1 Esther J.M. Stoop
A1 Wenli Yu
A1 Els C. Brinkman-van der Linden
A1 Kimberley Ummenthum
A1 Kristof van Kolen
A1 Marc Mercken
A1 Stefan Steinbacher
A1 Donata de Marco
A1 Jeroen J. Hoozemans
A1 Ian A. Wilson
A1 Wouter Koudstaal
A1 Jaap Goudsmit
YR 2018
UL http://biorxiv.org/content/early/2018/03/22/287003.abstract
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 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.