6H06

FAB CBTAU-22.1 IN COMPLEX WITH TAU PEPTIDE V1088-5

6H06 の概要

• エントリーDOI: 10.2210/pdb6h06/pdb
• 分子名称: HUMAN FAB ANTIBODY FRAGMENT OF CBTAU-22.1, HUMAN FAB ANTIBODY FRAGMENT OF HCBTAU-22.1, Microtubule-associated protein tau, ... (5 entities in total)
• 機能のキーワード: fab, tau peptide, complex, immune system
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 203703.04

構造登録者

Juraszek, J.,Steinbacher, S. (登録日: 2018-07-06, 公開日: 2018-07-25, 最終更新日: 2024-11-13)

主引用文献

van Ameijde, J.,Crespo, R.,Janson, R.,Juraszek, J.,Siregar, B.,Verveen, H.,Sprengers, I.,Nahar, T.,Hoozemans, J.J.,Steinbacher, S.,Willems, R.,Delbroek, L.,Borgers, M.,Dockx, K.,Van Kolen, K.,Mercken, M.,Pascual, G.,Koudstaal, W.,Apetri, A.
Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser422containing epitope on pathological tau.
Acta Neuropathol Commun, 6:59-59, 2018

PubMed Abstract: Aggregation of tau protein and spreading of tau aggregates are pivotal pathological processes in a range of neurological disorders. Accumulating evidence suggests that immunotherapy targeting tau may be a viable therapeutic strategy. We have previously described the isolation of antibody CBTAU-22.1 from the memory B-cell repertoire of healthy human donors. CBTAU-22.1 was shown to specifically bind a disease-associated phosphorylated epitope in the C-terminus of tau (Ser) and to be able to inhibit the spreading of pathological tau aggregates from P301S spinal cord lysates in vitro, albeit with limited potency. Using a combination of rational design and random mutagenesis we have derived a variant antibody with improved affinity while maintaining the specificity of the parental antibody. This affinity improved antibody showed greatly enhanced potency in a cell-based immunodepletion assay using paired helical filaments (PHFs) derived from human Alzheimer's disease (AD) brain tissue. Moreover, the affinity improved antibody limits the in vitro aggregation propensity of full length tau species specifically phosphorylated at position 422 produced by employing a native chemical ligation approach. Together, these results indicate that in addition to being able to inhibit the spreading of pathological tau aggregates, the matured antibody can potentially also interfere with the nucleation of tau which is believed to be the first step of the pathogenic process. Finally, the functionality in a P301L transgenic mice co-injection model highlights the therapeutic potential of human antibody dmCBTAU-22.1.

PubMed: 30001207
DOI: 10.1186/s40478-018-0562-9

実験手法

X-RAY DIFFRACTION (2.63 Å)