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Recombinant Tau epitope chimeric polymer antigen as well as preparation method and application thereof

A polymer and epitope technology, applied in the fields of biopharmaceuticals and genetic engineering, can solve the problems of not achieving the therapeutic effect of improving cognitive ability, not directly targeting Tau molecules, and not being able to effectively neutralize oligomers

Active Publication Date: 2020-01-14
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These completed clinical trials have not achieved the therapeutic effect of improving cognitive ability. The possible reason is that these vaccines mainly produce non-specific antibodies against Aβ oligomers after immunization, and cannot effectively neutralize the effects on synaptic function and neurons. More toxic oligomers (Meli G, et al., Nature Communications, 2014; 5(5):3867.), so that cognitive ability cannot be improved
[0004] Current active immunization vaccines targeting Aβ do not directly target the Tau molecule to address Tau-associated pathological symptoms

Method used

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  • Recombinant Tau epitope chimeric polymer antigen as well as preparation method and application thereof
  • Recombinant Tau epitope chimeric polymer antigen as well as preparation method and application thereof
  • Recombinant Tau epitope chimeric polymer antigen as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1. Construction of recombinant prokaryotic expression vector and expression and purification of recombinant Tau epitope chimeric multimer antigen in Escherichia coli

[0070] 1. Design and synthesis of 6×(Tau2-18-Th) and 12×(Tau2-18-Th) genes

[0071] According to codon degeneracy, 6 copies of tandem 6×(Tau2-18-Th) genes (see SEQID No.1) and 12 copies of tandem 12×(Tau2-18-Th) genes (see SEQ ID No.2), directly synthesized and cloned into pMD18-T(TaKaRa)T vector named pMD18-6×(Tau2-18-Th) and pMD18-12×(Tau2-18-Th), encoding 6× (Tau2-18-Th) and 12×(Tau2-18-Th) (see SEQ ID No.3 and SEQ ID No.4 for the amino acid sequence), each Tau2-18-Th is connected with a GS flexible peptide ( figure 1 Middle A). In each Tau2-18-Th molecule, Tau2-18 is the phosphatase-activating domain (PAD) of Tau protein, and the polypeptide Tau2-18 molecule can be used as the B cell epitope of this chimeric multimeric antigen , the sequence is AEPRQEFEVMEDHAGTY; Th (AKFVAAWTLKAAA-GS-QYIKAN...

Embodiment 2

[0082] Example 2. Recombinant Tau epitope chimeric multimer antigen induces normal mice to produce a high level of Th2 anti-Tau2-18 antibody response

[0083] Using the recombinant Tau epitope chimeric multimeric antigen protein 6×(Tau2-18-Th) and 12×(Tau2-18-Th) expressed and purified in Example 1 as the immunogen, namely subunit vaccine, to immunize mice , to detect its immunogenicity. The specific method is as follows: C57 / BL6 mice (8 weeks old, female, SPF level, Experimental Animal Center of Military Medical Research Institute) were randomly divided into 3 groups, 8 mice in each group, immunized with 10 μg recombinant protein, and the control group (Control) Immunize with PBS without recombinant protein, and immunize four times in total. Before immunization, the antigen was diluted to a final concentration of 10% (V / V) aluminum adjuvant (Alhydrogel TM , Brenntag Biosector, Frederikssund, Denmark). Intramuscular injection of 100 μl per mouse was used for immunization. F...

Embodiment 3

[0087] Example 3. Recombinant Tau epitope chimeric multimer antigen subunit vaccine induced high level of anti-Tau2-18 antibody after immunization of 3×Tg AD model mice

[0088] The present invention further evaluates the immunogenicity and immunotherapeutic effect of the recombinant Tau epitope chimeric multimer antigen subunit vaccine by 3×Tg AD model mice (for the scheme, see figure 1 Middle D). The specific scheme is as follows. The AD model mice are 3×Tg AD model mice, which are knocked in the presenilin protein PS1 M146V Genetic mice containing Tau were microinjected P301L and APP Swe Constructed a pathological model mouse of AD capable of expressing these three proteins. The disease course of this model mouse will show a certain degree of progression with the growth of the age of the mouse, and it will occur at the age of 6 months. Intracellular Aβ deposition, the pathological characteristics of synaptosomal Tau can be observed at the age of 9 months, compared with o...

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Abstract

The invention discloses a recombinant Tau epitope chimeric polymer antigen as well as a preparation method and an application thereof. The invention provides the recombinant Tau epitope chimeric polymer antigen, which is a basic unit of 6 or 12 tandem phosphatase activation domains of Tau protein and two helper T cell epitopes Th. The recombinant 6 / 12*(Tau2-18-Th) chimeric antigen disclosed by theinvention can generate a high-level Th2 type anti-Tau2-18 antibody after being used for immunizing common and model mice in a low-dose and few-time manner, T cell immune response aiming at Tau2-18 isnot generated, the pathological level of A beta (including soluble oligomers) and Tau (including total Tau and phosphorylated Tau) in the brain of the mouse model is reduced, the related synaptic protein level is increased, and the learning and memory ability is improved. Therefore, a recombinant chimeric epitope vaccine targeting Tau2-18 is a new direction of AD novel vaccine research, which hasgreat potential and application prospect in prevention of Alzheimer's disease.

Description

technical field [0001] The invention relates to the technical fields of biopharmaceuticals and genetic engineering, in particular to recombinant Tau epitope chimeric multimer antigen, its preparation method and application. Background technique [0002] Alzheimer's disease (AD), also known as senile dementia, is a chronic long-term neurodegenerative senile disease, the main clinical feature of which is cognitive and memory impairment caused by the loss of synapses and neurons. The neuroinflammatory plaques caused by the deposition of β-amyloid protein in the brain tissue and the neurofibrillary tangles caused by the phosphorylation of Tau protein are the two main pathological features in AD. In recent years, there have been more than 50 million dementia patients worldwide. The rising incidence has caused great economic burden and pressure on the patients' families and society. With the aging of society, Alzheimer's The level of research and treatment of silent disease needs...

Claims

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Application Information

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IPC IPC(8): C07K19/00C12N15/62C12N15/70A61K39/00A61P25/28A61P25/00
CPCA61K39/0007A61P25/00A61P25/28C07K7/08C07K14/33C07K14/4711C07K2319/00C12N15/70
Inventor 余云舟杨志新王荣陆健昇
Owner ACADEMY OF MILITARY MEDICAL SCI
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