6h0e | pdb_00006h0e
FAB dmCBTAU-22.1 IN COMPLEX WITH TAU PEPTIDE V1088-23
Structural highlights
Disease[TAU_MOUSE] May be involved in the pathogenesis of cytoplasmic inclusions (as Mallory bodies) in livers of mice chronically intoxicated with Griseofulvin or DDC (3,5-diethoxycarbonyl-2,4-dihydrocollidine), a model for human alcoholic hepatitis. Alteration of Tau (abnormal phosphorylation and cross-linking) could contribute to Mallory bodies formation and disturbance of microtubule function in alcoholic liver disease. Function[TAU_MOUSE] Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity. The C-terminus binds axonal microtubules while the N-terminus binds neural plasma membrane components, suggesting that tau functions as a linker protein between both. Axonal polarity is predetermined by tau localization (in the neuronal cell) in the domain of the cell body defined by the centrosome. The short isoforms allow plasticity of the cytoskeleton whereas the longer isoforms may preferentially play a role in its stabilization. Publication Abstract from PubMedAggregation 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(422)) 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. Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser(422) containing epitope on pathological tau.,van Ameijde J, Crespo R, Janson R, Juraszek J, Siregar B, Verveen H, Sprengers I, Nahar T, Hoozemans JJ, Steinbacher S, Willems R, Delbroek L, Borgers M, Dockx K, Van Kolen K, Mercken M, Pascual G, Koudstaal W, Apetri A Acta Neuropathol Commun. 2018 Jul 12;6(1):59. doi: 10.1186/s40478-018-0562-9. PMID:30001207[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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