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

被引：17

作者：

Apetri, Adrian ^{[1
]}

Crespo, Rosa ^{[1
]}

Juraszek, Jarek ^{[1
]}

Pascual, Gabriel ^{[2
]}

Janson, Roosmarijn ^{[1
]}

Zhu, Xueyong ^{[5
]}

Zhang, Heng ^{[5
]}

Keogh, Elissa ^{[2
]}

Holland, Trevin ^{[2
]}

Wadia, Jay ^{[2
,11
]}

Verveen, Hanneke ^{[1
]}

Siregar, Berdien ^{[1
]}

Mrosek, Michael ^{[6
]}

Taggenbrock, Renske ^{[1
]}

Ameijde, Jeroenvan ^{[1
]}

Inganas, Hanna ^{[1
]}

van Winsen, Margot ^{[1
]}

Koldijk, Martin H. ^{[1
]}

Zuijdgeest, David ^{[12
]}

Borgers, Marianne ^{[3
]}

Dockx, Koen ^{[4
]}

Stoop, Esther J. M. ^{[1
]}

Yu, Wenli ^{[5
]}

Brinkman-van der Linden, Els C. ^{[1
]}

Ummenthum, Kimberley ^{[7
]}

van Kolen, Kristof ^{[3
]}

Mercken, Marc ^{[3
]}

Steinbacher, Stefan ^{[6
]}

de Marco, Donata ^{[3
]}

Hoozemans, Jeroen J. ^{[7
]}

Wilson, Ian A. ^{[5
,8
]}

Koudstaal, Wouter ^{[1
]}

Goudsmit, Jaap ^{[1
,9
,10
]}

机构：

[1] Johnson & Johnson, Janssen Pharmaceut Co, Janssen Prevent Ctr, Archimedesweg 6, NL-2333 CN Leiden, Netherlands

[2] Johnson & Johnson, Janssen Pharmaceut Co, Janssen Prevent Ctr, 3210 Merryfield Row, San Diego, CA 92121 USA

[3] Johnson & Johnson, Janssen Pharmaceut Co, Janssen Neurosci Discovery, Turnhoutseweg 30, B-2340 Beerse, Belgium

[4] Johnson & Johnson, Janssen Pharmaceut Co, Discovery Sci, Mol & Cellular Pharmacol, Turnhoutseweg 30, B-2340 Beerse, Belgium

[5] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA

[6] Proteros Biostruct GmbH, Bunsenstr 7a, D-82152 Planegg, Germany

[7] Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam Neurosci, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands

[8] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[9] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA

[10] Acad Med Ctr, Amsterdam Neurosci, Dept Neurol, Meidreefberg 9, NL-1105 AZ Amsterdam, Netherlands

[11] Janssen R&D US, 3210 Merryfield Row, San Diego, CA 92121 USA

[12] Johnson & Johnson, Janssen Pharmaceut Co, Janssen Vaccines & Prevent, Archimedesweg 6, NL-2333 CN Leiden, Netherlands

来源：

ACTA NEUROPATHOLOGICA COMMUNICATIONS | 2018年 / 6卷

基金：

英国医学研究理事会;

关键词：

Alzheimer's disease; Tau protein; Monoclonal antibody; Antigenic motif; PAIRED HELICAL FILAMENTS; MICROTUBULE-ASSOCIATED PROTEIN; ALZHEIMERS-DISEASE; IN-VITRO; PROPAGATION; PRINCIPLES; PHOSPHORYLATION; IMMUNOTHERAPY; RELEVANCE; PATHOLOGY;

D O I：

10.1186/s40478-018-0543-z

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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)4-1antibodies.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-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.

引用

页数：17

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