Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser422 containing epitope on pathological tau

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...

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Bibliographic Details
Published in:Acta neuropathologica communications 2018-07, Vol.6 (1), p.1-14, Article 59
Main Authors: van Ameijde, Jeroen, Crespo, Rosa, Janson, Roosmarijn, Juraszek, Jarek, Siregar, Berdien, Verveen, Hanneke, Sprengers, Imke, Nahar, Tariq, Hoozemans, Jeroen J, Steinbacher, Stefan, Willems, Roland, Delbroek, Lore, Borgers, Marianne, Dockx, Koen, Van Kolen, Kristof, Mercken, Marc, Pascual, Gabriel, Koudstaal, Wouter, Apetri, Adrian
Format: Article
Language:English
Subjects:
Aggregation
Alzheimer's disease
Analysis
Antigenic determinants
Biosensors
Genetic engineering
Health aspects
Immunoglobulins
Immunotherapy
Interferometry
Intervention
Kinetics
Monoclonal antibodies
Monoclonal antibody
Nervous system diseases
Neurons
Nucleation
Pathology
Peptides
Phosphorylation
Propagation
Proteins
Tau
Transgenic animals
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Summary: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.sup.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. Keywords: Tau, Nucleation, Aggregation, Phosphorylation, Monoclonal antibody, Intervention
ISSN:2051-5960
2051-5960
DOI:10.1186/s40478-018-0562-9