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CN-115925987-B - Antigen polypeptide based on beta-amyloid modification and application thereof

CN115925987BCN 115925987 BCN115925987 BCN 115925987BCN-115925987-B

Abstract

The invention discloses an antigen polypeptide based on beta-amyloid modification and application thereof, wherein the antigen polypeptide comprises A, B, C components, wherein a component a of a component A is a beta-amyloid monomer amino acid fragment or a combination of a plurality of amino acid fragments, a component B of a component B is a small molecular compound capable of being combined with a beta-amyloid monomer or oligomer, and a component C of a component C is a coupling carrier protein. The modified antigen peptide provided by the invention can be used for targeting a lamellar region of beta-amyloid to block the abnormally folded beta-amyloid to form a toxic oligomer, and the antibody generated by antigen immunization can specifically identify beta-amyloid oligomer and polymer combined by a small molecular compound, namely a targeting immune complex, so that the beta-amyloid oligomer and the polymer can be effectively cleared, and finally, beta-amyloid pathological abnormality of AD can be prevented and slowed down from preventing beta-amyloid monomer aggregation and clearing beta-amyloid aggregate in multiple dimensions, and the effect of preventing and treating AD can be generated.

Inventors

  • TAN JUN
  • MO LING
  • LI SONG
  • ZI DAN
  • ZHENG XIAOJIANG

Assignees

  • 安域生物科技(杭州)有限公司

Dates

Publication Date
20260505
Application Date
20220902
Priority Date
20220228

Claims (10)

  1. 1. The antigen polypeptide based on betA-amyloid modification is characterized by comprising A, B, C, wherein the A, B, C is connected in A C-A-B mode, wherein A is CKLVFFA, B is curcumin, C is hemocyanin, the C-terminal carboxyl of A is connected with the hydroxyl of B through an ester bond, the N-terminal of A is connected with sulfhydryl, the amino on the C surface is connected with maleimide group, and A is connected with the maleimide group of C through the N-terminal sulfhydryl.
  2. 2. Use of an antigenic polypeptide based on beta-amyloid modification as claimed in claim 1 for the manufacture of a medicament for the prevention and/or treatment of alzheimer's disease.
  3. 3. Use of an antigenic polypeptide based on modification of beta-amyloid according to claim 1 for the preparation of a vaccine for alzheimer's disease.
  4. 4. The method of claim 3, wherein the vaccine further comprises an adjuvant, and wherein the adjuvant is Freund's adjuvant.
  5. 5. Use of an antigen polypeptide based on beta-amyloid modification according to claim 1 for the preparation of a product for detecting aβ oligomers or polymers.
  6. 6. Use of an antigenic polypeptide based on beta-amyloid modification as claimed in claim 1 for the manufacture of a product for early risk assessment screening for alzheimer's disease, disease diagnosis or auxiliary diagnosis.
  7. 7. An alzheimer's disease vaccine comprising a β -amyloid modification-based antigenic polypeptide as defined in claim 1 and an adjuvant.
  8. 8. The alzheimer's vaccine of claim 7, wherein the adjuvant is freund's adjuvant.
  9. 9. An alzheimer's disease targeted immune complex comprising a vaccine, wherein the vaccine comprises a β -amyloid modification-based antigen polypeptide and an adjuvant, wherein the antigen polypeptide is as defined in claim 1.
  10. 10. The alzheimer's disease targeted immune complex of claim 9, further comprising a small molecule compound, said small molecule compound being one of curcumin, desmethoxycurcumin, bisdesmethoxycurcumin, homotaurine, 3-sulfopropionic acid, epigallocatechin gallate, brazilin, gossypin, oleuropein aglycone, quercetin, resveratrol, rosmarinic acid, 6-shogaol, tanshinone, vitamin a, vitamin B 12 , vitamin D 2 , vitamin D 3 , vitamin K 3 .

Description

Antigen polypeptide based on beta-amyloid modification and application thereof Technical Field The invention relates to the technical field of biopharmaceuticals, in particular to an antigen polypeptide based on beta-amyloid modification and application thereof. Background Alzheimer's Disease (AD), also known as Alzheimer's disease, is a neurodegenerative disease with a long disease course, and is characterized clinically by cognitive and memory impairment caused by synaptic and neuronal loss. Data statistics show that the incidence rate of senile dementia of the aged 60 to 80 years old is about 4%, and the incidence rate of the aged over 80 years old is as high as 20% -40%. According to the latest reports of the world health organization, more than 5000 million dementia patients worldwide have been reported, and this figure is expected to be more than 1.5 million by 2050. The cost of therapeutic care, etc. caused by AD is estimated to increase to $ 2 trillion by 2030, causing significant economic burden and pressure to the patient's home and society. At present, several medicines for treating AD on the market can only relieve symptoms to a certain extent and cannot achieve the effect of radical treatment, and aiming at the current situation that China gradually steps into the aging society, the research and treatment level of the Alzheimer disease of China needs to be improved. The main hypothesis of AD pathogenesis is the amyloid cascade hypothesis, which considers that the hydrolysis of Amyloid Precursor Protein (APP) in the brain of AD patients to produce excessive β -amyloid (aβ) is the main cause of neurotoxicity, and that aβ can also cause Tau protein hyperphosphorylation to produce neurofibrillary tangles, ultimately leading to synaptic injury and neuronal loss. Therefore, approaches with aβ as a therapeutic target are a hotspot in the current development of anti-AD drugs and vaccines. Immunotherapy of AD is largely divided into immunotherapy against aβ and tau. Since various variants and aggregates of aβ (aβ40, aβ42, aβ35, aβ oligomers, aβ pre-fiber oligomers, aβ fibers, aβ plaque deposits) are substances of the body itself, the use of a purely endogenous aβ polypeptide or protein as an antigen causes autoimmune reactions in the body, and tends to induce a sub-population Th1 cell reaction of CD 4T cells, leading to adverse reactions such as inflammation. In addition, immunization of the body with aβ as an antigen may also cause adverse reactions to cerebral microhemorrhages, which may be caused by excessive clearance of aβ from the resulting immune reaction. After the first application of human fibrotic aβ42 polypeptides to immunize AD transgenic mice and achieve a certain effect in 1999, numerous phase I clinical studies have also achieved preliminary good responses, but subsequent clinical phase II experiments have developed meningitis resulting from an autoimmune response to T cells, and subsequent entry into the clinical study stage with the option of active immunization vaccines targeting the B lymphocyte epitope aβ1-15 of aβ42 peptide can still develop side effects and ultimately lead to termination of the experiment. At present, other AD vaccines under development cannot achieve the therapeutic effect of improving the cognitive ability, probably because antibodies generated after immunization of the vaccines cannot effectively block abnormal folding of Abeta to form oligomers with larger toxicity on synaptic functions and neurons, so that the cognitive ability cannot be improved. Therefore, both active immunotherapy and passive immunotherapy or prevention of AD should require that the induced high level antibodies specifically block the abnormal folding of aβ to form toxic aβ oligomers, reduce the level of aβ oligomers in the brain, protect the neuronal synaptic function and cognitive ability, and thus produce an effective immunoprophylaxis. Disclosure of Invention In order to overcome the defects in the background art, the invention provides an antigen polypeptide modified based on beta-amyloid and application of the antigen polypeptide in preventing and treating Alzheimer's disease, wherein the antigen polypeptide not only can induce organisms to produce antibodies and prevent Abeta monomer from gathering, but also can be matched with a small molecular compound to remove Abeta aggregate, thereby preventing and slowing down Abeta pathological abnormality of Alzheimer's disease and realizing the prevention and treatment of Alzheimer's disease. The specific technical scheme is as follows: The invention provides an antigen polypeptide based on beta-amyloid modification, which comprises A, B, C components connected in any sequence through a connecting bond or a connecting group; The component A is formed by combining m components a, the component B is formed by combining n components B, the component C is formed by combining k components C, the component a is a beta-amyloid protein monomer amin