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CX3CR1 gene humanized non-human animal as well as construction method and application thereof

A technology of non-human animals and construction methods, applied in the fields of botanical equipment and methods, biochemical equipment and methods, applications, etc., capable of solving problems such as genetic complexity

Active Publication Date: 2021-03-26
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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  • CX3CR1 gene humanized non-human animal as well as construction method and application thereof
  • CX3CR1 gene humanized non-human animal as well as construction method and application thereof
  • CX3CR1 gene humanized non-human animal as well as construction method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Example 1 Preparation of CX3CR1 Gene Humanized Mice

[0138] In this example, a non-human animal (such as a mouse) is transformed so that the non-human animal contains a nucleotide sequence encoding a humanized CX3CR1 protein, and a genetically modified non-human animal capable of expressing a humanized CX3CR1 protein is obtained. . Mouse CX3CR1 gene (NCBI Gene ID: 13051, Primary source: MGI: 1333815, UniProt ID: Q9Z0D9, located at position 119877749 to position 119897362 of chromosome 9 NC_000075.7, based on transcript NM_009987.4 and its encoded protein NP_034117 .3 (SEQ ID NO: 1)) and human CX3CR1 gene (NCBI Gene ID: 1524, Primarysource: HGNC: 2558, UniProt ID: P49238, located at position 39263494-39281735 of chromosome 3 NC_000003.12, based on transcript NM_001337 .4 and its encoded protein NP_001328.1 (SEQ ID NO: 2)). Comparison diagram such as figure 1 shown.

[0139] In order to achieve the purpose of the present invention, the gene sequence encoding human CX...

Embodiment 2

[0161] Example 2 In vivo efficacy verification

[0162] The CX3CR1 humanized mice prepared by this method can be used to evaluate the efficacy of regulators targeting human CX3CR1. For example, take a homozygous CX3CR1 humanized mouse 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 CX3CR1 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

[0163] Embodiment 3 double gene or multigene humanization mouse

[0164] Using the method or the prepared CX3CR1 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 CX3CR1 mice, using the isolation of mouse ES embryonic stem cells and gene recombination targeting technology, a double-gene or multi-gene modified mouse model of CX3CR1 and other gene modifications was obtained. The homozygous or heterozygous CX3CR1 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 the CX3CR1 gene and other genes can be obtained. Genetically...

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Abstract

The invention provides a construction method of a CX3CR1 gene humanized non-human animal. The nucleotide sequence for encoding a human CX3CR1 protein is introduced into a non-human animal genome in ahomologous recombination manner, the humanized CX3CR1 protein can be normally expressed in the animal body, the animal body can be used as an animal model for human CX3CR1 signal mechanism research and tumor and immune disease drug screening, and the important application value is realized on the research and development of new drugs of immune targets. The invention also provides a humanized CX3CR1 protein, a humanized CX3CR1 gene, a targeting vector of the CX3CR1 gene, the non-human animal obtained with the construction method and an application of the non-human animal in the field of biological medicines.

Description

technical field [0001] The invention belongs to the field of animal genetic engineering and genetic modification, and in particular relates to a CX3CR1 gene humanized non-human animal, its construction method and its application in the field of biomedicine. Background technique [0002] CX3CR1 (C-X3-C motif chemokine receptor 1), also known as V28, is a chemokine receptor, belongs to 7 transmembrane proteins, and is a member of G protein receptors. CX3CR1 is mainly expressed in monocytes, macrophages, DC cells, T cells, NK cells, microglia and so on. According to the different binding sites of chemokine receptors and chemokines, they are divided into four categories: CX3CR1, CXCR1-CXCR5, XCR1, CCR1-CCR9. In peripheral blood, CX3CR1 is mostly located on the cell membrane of monocytes and leukocytes, and it is not only involved in the chemotaxis of cells, but also related to the adhesion of cells. It is a dynamic and changeable process that inflammatory cells reach the infla...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/12C12N15/85C07K14/715A01K67/027A61K49/00
CPCA01K67/0278A01K2207/15A01K2217/072A01K2227/105A01K2267/0331A01K2267/0368A01K2267/0387A61K49/0008C07K14/7158C12N15/8509
Inventor 吕锐利张赞
Owner BIOCYTOGEN PHARMACEUTICALS (BEIJING) CO LTD
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