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IL21R gene humanized non-human animal as well as construction method and application thereof

An IL21R, non-human animal technology, applied in the fields of botanical equipment and methods, biochemical equipment and methods, applications, etc., can solve problems such as gene complexity

Active Publication Date: 2021-03-16
BIOCYTOGEN PHARMACEUTICALS (BEIJING) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the differences in physiology and pathology between animals and humans, coupled with the complexity of genes (genetic factors), how to construct an "effective" humanized animal model for new drug development is still the biggest challenge ( Scheer N, Snaith M, Wolf CR, Seibler J. Generation and utility of genetically humanized mouse models, Drug Discov Today; 18(23-24):1200-11, 2013)

Method used

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  • IL21R gene humanized non-human animal as well as construction method and application thereof
  • IL21R gene humanized non-human animal as well as construction method and application thereof
  • IL21R gene humanized non-human animal as well as construction method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Example 1 Preparation of IL21R Gene Humanized Mice

[0134] In this example, a non-human animal (such as a mouse) is modified so that the non-human animal contains a nucleotide sequence encoding a humanized IL21R protein, and a genetically modified non-human animal capable of expressing a humanized IL21R protein is obtained. . Mouse IL21R gene (NCBI Gene ID: 60504, Primary source: MGI: 1890475, UniProt ID: Q9JHX3, located at position 125202424 to position 125232742 of chromosome 7 NC_000073.7, based on transcript NM_021887.2 and its encoded protein NP_ 068687.1 (SEQ ID NO: 1)) and human IL21R gene (NCBI Gene ID: 50615, Primarysource: HGNC: 6006, UniProt ID: Q9HBE5, located at positions 27402162-27452043 of chromosome 16 NC_000073.7, based on transcript NM_181078. 3 and its encoded protein NP_851564.1 (SEQ ID NO: 2)). Comparison diagram such as figure 1 shown.

[0135] In order to achieve the purpose of the present invention, the gene sequence encoding human IL21R pr...

Embodiment 2

[0157] Example 2 In vivo efficacy verification

[0158] The IL21R humanized mice prepared by this method can be used to evaluate the efficacy of modulators targeting human IL21R. For example, take IL21R humanized mouse homozygote and inoculate mouse colon cancer cell MC38 subcutaneously, and wait until the tumor volume grows to about 100mm 3 Afterwards, they were divided into control group or treatment group according to the tumor volume. The treatment group randomly selected drugs targeting human IL21R X, Y, Z, etc., and the control group was injected with an equal volume of normal saline. Regularly measuring the tumor volume and weighing the body weight of the mice can effectively evaluate the in vivo safety and in vivo drug efficacy of the compound by comparing the changes in the body weight of the mice and the size of the tumor.

Embodiment 3

[0159] Embodiment 3 double gene or multigene humanization mouse

[0160] Using the method or the prepared IL21R gene humanized mice can also prepare double-gene modified or multi-gene modified mouse models. As in the aforementioned Example 1, the embryonic stem cells used for blastocyst microinjection can be selected from mice containing other genetic modifications such as PD-1, PD-L1, CTLA4, OX40, LAG3, TIM3, CD73, or On the basis of humanized IL21R mice, using the isolation of mouse ES embryonic stem cells and gene recombination targeting technology, a mouse model of IL21R and other genetic modifications with double or multiple genes was obtained. The homozygous or heterozygous IL21R mice obtained by this method can also be mated with other genetically modified homozygous or heterozygous mice, and their offspring are screened. According to the law of Mendelian inheritance, there is a certain probability that IL21R gene and other genes can be obtained. Genetically modified d...

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Abstract

The invention provides a construction method of a non-human animal based on IL21R gene humanized modification, a humanized IL21R protein, a humanized IL21R gene, a targeting vector of the IL21R gene and application of the targeting vector in the field of biomedicine. A homologous recombination mode is utilized to introduce a nucleotide sequence of a part of coded human IL21R protein into a non-human animal genome, and the humanized IL21R protein can be normally expressed in the body of the non-human animal. The non-human animal can be used for human IL21R signal mechanism research and drug screening of inflammation, tumors and autoimmune diseases, and has important application value for research and development of new drugs of immune targets.

Description

technical field [0001] The invention belongs to the field of animal genetic engineering and genetic modification, and in particular relates to a non-human animal with humanized IL21R gene, its construction method and its application in the field of biomedicine. Background technique [0002] The full name of IL21R is interleukin 21 receptor. It is a type I transmembrane receptor protein, mainly expressed in spleen, thymus, lymph nodes and peripheral blood lymphocytes. IL21R is a complex composed of IL-21R subunit and γc, in which IL-21R subunit is the ligand recognition binding site, and γc is the signal transduction unit. IL-21R has a wide range of biological functions. After binding its ligand IL-21, it activates the JAKs-STATs signaling pathway, stimulates the proliferation of T cells and NK cells, regulates the survival and differentiation of B cells and dendritic cells, and thus participates in The body's innate and adaptive immunity. As a new type of immunoregulatory...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/85C07K14/715A01K67/027C12N15/12C12N5/10A61K49/00
CPCA01K67/0271A01K67/0278A01K2227/105A01K2267/0331A01K2267/0387A61K49/0008C07K14/7155C12N15/8509C12N2800/107
Inventor 吕锐利尚诚彰聂琰晖
Owner BIOCYTOGEN PHARMACEUTICALS (BEIJING) CO LTD