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Humanized cytokine animal model, preparation method and application

A humanized, non-human animal technology, applied in the field of biomedicine, can solve problems such as defects in the development and function of human cells, inability to screen and evaluate drug efficacy and defects in ordinary mice

Active Publication Date: 2020-06-19
BIOCYTOGEN JIANGSU CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Since the IL-6 protein of rodents such as mice and human IL-6 protein have about 41% identity (Identities) in amino acid sequence, and IL-6R (Identities) 53%, generally speaking, human IL-6 or Antibodies to IL-6R protein cannot recognize mouse IL-6 or IL-6R, that is, in the process of drug development related to IL-6 and IL-6R targets, ordinary mice cannot be used to screen and evaluate human IL-6R 6 and the efficacy of IL-6R drugs
In addition, in immunodeficient mice such as NOD-Prkdc scid IL-2rγ null In mice, although the immune function of such mice is severely deficient, there is almost no rejection of human cells and tissues, a small amount of cells can form tumors (depending on cell line or cell type), and there is no leakage of B lymphocytes , is the most suitable tool mouse for human cell or tissue transplantation, and has been widely used in the development of new humanized mouse models. After hematopoietic stem cells, there are defects in the development and function of human cells (Watanabe Yet al., Int Immunol. 2009Jul; 21(7):843-58)

Method used

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  • Humanized cytokine animal model, preparation method and application
  • Humanized cytokine animal model, preparation method and application
  • Humanized cytokine animal model, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0199] Example 1 IL-6 Gene Humanized Mice

[0200] Mouse IL-6 gene (NCBI Gene ID: 16193, Primary source: MGI: 96559, UniProt ID: P08505, located at positions 30013114 to 30019975 of chromosome 5 NC_000071.6) and human IL-6 gene (NCBI Gene ID: 3569 , Primary source: HGNC: 6018, UniProt ID: P05231, located at positions 22725889 to 22732002 of chromosome 7 NC_000007.14), given that human IL-6 and mouse IL-6 have multiple subtypes or transcripts, such as figure 1 The gene schematic diagram shown demonstrates the inclusion of figure 1A: mouse transcript NM_031168.2 (SEQ ID NO: 1) and its encoded protein NP_112445.1 (SEQ ID NO: 2), figure 1 B: mouse transcript NM_001314054.1 (SEQ ID NO: 3) and its encoded protein NP_001300983.1 (SEQ ID NO: 4), figure 1 C: human transcript NM_000600.4 (SEQ ID NO: 5) and its encoded protein NP_000591.1 (SEQ ID NO: 6), figure 1 D: Human transcript NM_001318095.1 (SEQ ID NO: 7) and its encoded protein NP_001305024.1 (SEQ ID NO: 8).

[0201] In order...

Embodiment 2

[0263] Example 2 IL-6R Gene Humanized Mice

[0264] Mouse IL-6R gene (NCBI Gene ID: 16194, Primary source: MGI: 105304, UniProtID: P08505, located at positions 89869324 to 89913196 of chromosome 3 NC_000069.6) and human IL-6R gene (NCBI Gene ID: 3570, Primary source: HGNC: 6019, UniProt ID: P08887, located at positions 154405193 to 154469450 of chromosome 1 NC_000001.11), given that human IL-6R and mouse IL-6R have multiple subtypes or transcripts, such as Figure 13 The gene schematic diagram shown is based on mouse transcript NM_010559.3 (SEQ ID NO: 59) and its encoded protein NP_034689.2 (SEQ ID NO: 60), human transcript NM_000565.3 (SEQ ID NO: 61) and its encoded protein Take protein NP_000556.1 (SEQ ID NO: 62) as an example.

[0265] In order to achieve the purpose of the present invention, the gene sequence encoding human IL-6R protein can be introduced into the endogenous mouse IL-6R locus, so that the mouse expresses human IL-6R protein. For example, mouse embryonic ...

Embodiment 3

[0294] Example 3 Reconstitution of the human immune system in IL-6 humanized mice

[0295] Using the IL-6 humanized mouse (B-NDG background) prepared in Example 1 as a tool can transplant human CD34+ cells and realize the reconstruction of the human immune system. Umbilical cord blood stem cells injected into the tail vein of mice after myeloablation by irradiation. Plasma samples were collected and tested at various times after transplantation. The results showed that IL-6 humanized mice (B-NDG background) had higher human peripheral blood engraftment than wild-type controls, and the percentage of differentiation was closer, containing some mature B cells.

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Abstract

The invention relates to a humanized gene modification inhuman animal, in particular to an animal model expressing humanized IL-6R and / or IL-6 protein. In some examples, an inhuman animal expressing the humanized IL-6R and / or IL-6 and subjected to genetic modification also has an immunodeficiency phenotype, and / or contains more humanized cytokine of IL3, GM-CSF and the like. The invention also provides a construction method of the humanized inhuman animal containing IL-6R and / or IL-6 gene modification, and an application of the construction method to the field of biopharmaceutical.

Description

technical field [0001] This application relates to a method for establishing a humanized genetically modified animal model and its application, specifically, to a method for constructing a genetically modified animal model based on humanized IL-6R and / or IL-6 and its application in the field of biomedicine application. Background technique [0002] Experimental animal disease models are indispensable research tools for the study of the etiology and pathogenesis of human diseases, the development of prevention technologies and the development of drugs. However, due to the differences in the physiological structure and metabolic system between animals and humans, traditional animal models cannot well reflect the real conditions of the human body. It is an urgent need for the biomedical industry to establish disease models in animals that are closer to the physiological characteristics of humans . [0003] With the continuous development and maturity of genetic engineering te...

Claims

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Application Information

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IPC IPC(8): C12N15/85C12N15/90C12N15/113C12N15/62A01K67/027A61K49/00
CPCA01K67/0276A01K67/0278A01K2207/15A01K2217/072A01K2217/075A01K2227/105A01K2267/0325A01K2267/0368A61K49/0008C07K14/5412C07K14/7155C07K2319/00C12N15/1136C12N15/1138C12N15/8509C12N15/907C12N2800/107C12N2310/20
Inventor 沈月雷张美玲姚佳维郭朝设郭雅南白阳黄蕤赵磊尚诚彰
Owner BIOCYTOGEN JIANGSU CO LTD
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