Polypeptide and use thereof in anti-glomerular basement membrane disease

An amino acid and hydrophobic amino acid technology, applied in the field of immunotherapy, can solve serious problems, lack of specific treatment plan, high cost and other problems

Active Publication Date: 2020-10-27
PEKING UNIV FIRST HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is currently no specific treatment for this disease
In addition, plasmapheresis and immunosuppressive therapy have many problems as existing treatment methods: the former can only clear circulating autoantibodies and is expensive, while the latter can cause serious adverse reactions

Method used

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  • Polypeptide and use thereof in anti-glomerular basement membrane disease
  • Polypeptide and use thereof in anti-glomerular basement membrane disease
  • Polypeptide and use thereof in anti-glomerular basement membrane disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1. Design and synthesis of polypeptides

[0039] Identification of core epitopes

[0040] Studies have shown that the α3-P14 peptide (α3 127-148 : TDIPPCPHGWISLWKGFSFIMF; SEQ ID NO: 1) includes an antigenic epitope recognized by T cells and is closely related to the development of anti-GBM disease (Hu SY, et al., supra). Immunization of animals with α3-P14 peptide can induce anti-GBM disease, and the identification of key amino acids related to pathogenicity in α3-P14 peptide shows that when tryptophan at position 136 (W136) in α3-P14 peptide , isoleucine at position 137 (I137), leucine at position 139 (L139), tryptophan at position 140 (W140) or phenylalanine at position 143 (F143) are mutated, Immune animals no longer get sick. It can be seen that the motif WIxLWxxF composed of the above amino acids is the key amino acid motif for the α3-P14 peptide to induce anti-GBM disease.

[0041] In addition, a key site in the α3-P14 peptide that binds to the HLA-D...

Embodiment 2

[0049] Example 2. Pathogenicity Research of Polypeptides

[0050] The pathogenicity of modified m-P14 polypeptides against GBM disease was first investigated. Refer to the previous establishment method of anti-GBM rat animal model (Hu SY et al.J.Cell.Mol.Med.Vol 21, No 9,2017pp.2117-2128), detect α3-P14 polypeptide and m-P14 polypeptide Whether anti-GBM disease can be induced after immunization of animals. Briefly, WistarKyoto (WKY) rats (female, 4 week age, each group n=6). Immunization was performed with a single rear footpad injection at a dose of 200 μg / kg of the polypeptide. The negative control group was injected with PBS only. Hematuria samples were collected before immunization and weekly after immunization. Animals were sacrificed at the end of the 6th week after immunization, and kidney tissues were collected for pathological observation.

[0051] The results showed that, two weeks after immunization, antibodies against corresponding immunogens were produced in...

Embodiment 3

[0053] Example 3.m-P14 polypeptide prevents and treats the effect of anti-GBM disease

[0054] This example studies the effect of m-P14 polypeptide in the prevention and treatment of anti-GBM disease.

[0055] experimental design

[0056] All WKY rats were injected with α3-P14 polypeptide into the rear foot pad once (day 0) to induce anti-GBM disease, and the dose was 200 μg / kg subcutaneously. After immunization, the rats were divided into prevention group (treatment started from day 0), treatment group (treatment started after the hematuria / proteinuria symptoms of anti-GBM disease appeared in experimental rats), disease group (no intervention after immunization), and At the same time, a negative control group (only injected with PBS) was set up, with 6 animals in each group. For specific experimental procedures, see Figure 4 .

[0057] Prevention group: divided into high-dose group (30 mg / kg / time) and low-dose group (10 mg / kg / time) according to the dosage of m-P14 poly...

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Abstract

The invention provides a modified polypeptide capable of effectively preventing and treating an anti-glomerular basement membrane (anti-GBM) disease. The invention further provides a nucleotide sequence for coding the polypeptide, a carrier, a composition containing the polypeptide or the carrier and use of the composition in prevention and treatment of the anti-GBM disease.

Description

technical field [0001] The present disclosure relates to the field of immunotherapy. In particular, the disclosure relates to a modified polypeptide and its use in the prevention and treatment of anti-glomerular basement membrane (anti-GBM) disease. [0002] technical background [0003] Anti-glomerular basement membrane (anti-glomerular basement membrane, anti-GBM) disease is a group of autoimmune diseases characterized by the appearance of anti-GBM antibodies in the circulation and / or the deposition of antibodies in organs. Kidney involvement often manifests as crescentic nephritis, which has an acute onset and rapid progression, and can develop into end-stage renal disease in a short period of time. It is the glomerulonephritis with the worst prognosis. Lung involvement often manifests as pulmonary hemorrhage, or even fatal massive hemoptysis, which is a critical illness in internal medicine. Currently, there is no specific treatment for this disease. In addition, plasm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/78C12N15/12A61K38/39A61P13/12A61P37/02
CPCC07K14/78A61P13/12A61P37/02A61K38/00
Inventor 赵明辉崔昭贾晓玉史悦
Owner PEKING UNIV FIRST HOSPITAL
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