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Method for treating infectious diseases by NK (natural killer) targeted immune checkpoints

A technology for immune checkpoints and infectious diseases, applied in the direction of immunoglobulin, chemical instruments and methods, antiviral agents, etc., can solve the problems of limited treatment effect, inability to effectively protect patients from re-infection, and high price

Active Publication Date: 2019-06-04
INST PASTEUR OF SHANGHAI CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the limitations faced by DAA drugs include: (1) drug resistance; (2) DAA drugs, like the traditional ribavirin / peg-interferon combination therapy, cannot effectively protect against re-infection and have entered chronic infection The treatment effect of patients in the later period is limited; (3) the types of DAA drugs are currently less and expensive, which significantly increases the economic burden of patients

Method used

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  • Method for treating infectious diseases by NK (natural killer) targeted immune checkpoints
  • Method for treating infectious diseases by NK (natural killer) targeted immune checkpoints
  • Method for treating infectious diseases by NK (natural killer) targeted immune checkpoints

Examples

Experimental program
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Effect test

Embodiment 1

[0075] Example 1. Establishment and Confirmation of HCV Mouse Model

[0076] During the course of HCV infection, acute HCV infection is characterized by a marked delay in the T cell response. In a previous study, human CD81 and OCLN liver-specific double transgenic mice (C / O-Tg mice) have been constructed on the ICR mouse background, which are able to support chronic HCV infection and mimic chronic hepatitis C. Immune tolerance, steatosis, liver fibrosis, liver cirrhosis and other disease processes (Chen J, Zhao Y, Zhang C, Chen H, Feng J, et al.2014.Persistenthepatitis C virus infections and hepatopathological manifestations in immune-competent humanized mice . Cell research 24:1050).

[0077] This mouse model of HCV infection was first replicated and validated. HCV (J399EM, 1mL, TCID 50 =2x10 7 ) to C / O-Tg mice and wild-type littermate control mice for tail vein infusion. Detection of HCV genome copy number in mouse liver at different time points after HCV infusion indi...

Embodiment 2

[0078] Example 2. T cell immune checkpoint blockade has no effect on HCV chronic infection

[0079] Since it is generally believed that CD8+ T cells play an important role in the process of virus infection and clearance, we first detected the expression of CD8+ T immune checkpoint molecules during HCV infection. It was found that after infection of mice with HCV, the T cell immune checkpoint molecule PD-1 ( figure 2 A) and Tim-3 ( figure 2 B) Upregulation with the establishment of chronic infection. Based on this, it was tested whether targeting T cell immune checkpoint molecules could inhibit this chronic infection process. However, if figure 2 C and figure 2 As shown in the results of D, no matter whether the PD-1 blocking antibody (clone number G4, self-produced by the hybridoma) or the combined use of PD-1 and Tim-3 blocking antibodies (clone number BE0115, purchased from BioXcell) were used alone, all Cannot effectively promote virus clearance. The above results...

Embodiment 3

[0080] Example 3. Depletion of NK cells leads to persistent infection of HCV

[0081] The effect of HCV infection on NK cell function was subsequently examined. Hepatic NK cell depletion during HCV infection was examined by an in vitro NK function assay. The results showed that the IFN-γ secretory ability and CD107a degranulation level of liver NK cells of HCV-infected C / O-Tg mice stimulated by target cell Yac-1 increased within 4 days after HCV infusion, which then decreased rapidly to baseline levels similar to uninfected liver NK cells ( image 3 A). Further studies showed upregulation of NK-activating receptors Ly49D, Ly49H and NKG2D within 4 days after HCV infusion ( image 3 B). These results demonstrate transient liver infiltration and activation of NK cells in response to HCV infection. However, these activated receptors decreased in hepatic NK cells 4 days after HCV infusion, whereas the expression of immune checkpoint molecules KLRG1, NKG2A, and TIGIT increased ...

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Abstract

The invention relates to a method for preventing or treating infectious diseases in subjects. The method comprises the step of applying an NK immune checkpoint molecule antagonist or expression inhibitor to subjects. The invention also relates to the NK immune checkpoint molecule antagonist or expression inhibitor and an application of a pharmaceutical composition comprising the NK immune checkpoint molecule antagonist or expression inhibitor in treatment of infectious diseases.

Description

technical field [0001] The present disclosure relates to the field of immunotherapy. In particular, the present disclosure relates to methods of preventing or treating infectious diseases by targeting NK cell immune checkpoints. The present disclosure also relates to the use of the NK cell immune checkpoint molecule antagonist or expression inhibitor and the pharmaceutical composition comprising the same in the treatment of infectious diseases. technical background [0002] Infectious diseases caused by viral infections including human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) are prevalent worldwide. People of different genders, ages and races have different susceptibility to the above viruses. For example, according to the statistics of the World Health Organization, about 185 million people (about 3% of the total population) are infected with HCV (Mohd Hanafiah, K., et al., Global epidemiology of hepatitis C virus infection: New ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K39/395A61P31/14A61P31/20A61P31/18A61K31/7088
CPCA61P31/20A61P31/18A61P31/14A61K45/06A61K31/713A61K31/497A61K31/403A61K31/4709A61K31/7072A61K31/7068A61K31/4178C07K16/2803C07K2317/76A61K2039/505A61K2300/00A61K31/7056
Inventor 唐宏张超陈海荣
Owner INST PASTEUR OF SHANGHAI CHINESE ACADEMY OF SCI
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