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Construction method and application of TIM3 humanized mouse model

A construction method and humanized technology, applied in the field of TIM3 gene modified humanized animal model construction, can solve the problem of incomplete trial of antibodies to humans

Active Publication Date: 2019-11-26
GEMPHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to species differences, the immune checkpoint antibodies screened in mice are not fully tested in humans

Method used

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  • Construction method and application of TIM3 humanized mouse model
  • Construction method and application of TIM3 humanized mouse model
  • Construction method and application of TIM3 humanized mouse model

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1TI

[0033] Example 1 TIM3 Humanized Mouse Model Establishment

[0034] The present invention uses homologous recombination and embryonic stem cell technology to replace human HAVCR2 with mouse Havcr2 gene on mouse ES cells with C57BL / 6 background and BALB / c background, so as to construct a mouse model that can express human TIM3. And by mating with PD1 humanized mice with independent property rights, a dual-human mouse model that can express human TIM3 and PD1 was obtained.

[0035] 1. Determine the replacement region of the human fragment and the inserted human sequence

[0036] According to the structure and function of human TIM3, the extracellular region and transmembrane region encoded by the human HAVCR2 gene were selected to replace the extracellular region and transmembrane region encoded by the mouse Havcr2 gene, and the intracellular region of the mouse was retained. The amino acid sequence of the extracellular region encoded by the HAVCR2 gene (Aa: 1-225) is shown in S...

Embodiment 2B

[0069] Example 2 Human-derived TIM3 expression and immune system verification in BALB / c-hTIM3 and B6-hTIM3 mice

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PUM

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Abstract

The invention provides a method for preparing a TIM3 humanized animal mode based on a gene modification technology. The method comprises the following steps of: replacing an extracellular region and atransmembrane region coded by a mouse source Havcr2 gene with an extracellular region and a transmembrane region coded by a human source HAVCR2 gene on a mouse with a sound immune system; reserving an intracellular region of the mouse Havcr2 gene; and constructing a mouse model capable of interacting with an anti-human source TIM3 monoclonal antibody. Compared with common mice, the model realizesthe humanization transformation of key target molecules, retains the complete immune system, can be used for screening and evaluating drugs aiming at human genes, and is an ideal pre-clinical drug test model.

Description

technical field [0001] The invention belongs to the field of animal genetic engineering and genetic modification, and in particular relates to a method for constructing a TIM3 gene modified humanized animal model based on gene editing technology. Background technique [0002] Cancer immunotherapy is a treatment that uses the body's own immune system to attack cancer cells. The confrontation between the immune system and cancer cells is a dynamic process of a long-term game, both head-on and intertwined. The immune cells of a healthy body can discover and kill most cancerous cells, but under the induction of various innate or acquired factors, the immune system will lose its absolute advantage, and even be "rebelled" by cancer cells, becoming a key factor in the occurrence and development of cancer. a member. [0003] There are many types of tumor immunotherapy, but most of them essentially use T cells to exert anti-tumor effects, including cytokine stimulation, small molec...

Claims

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Application Information

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IPC IPC(8): C12N15/85A01K67/027A61K49/00
CPCA01K67/0275A01K2227/105A01K2267/0331A61K49/0008C12N15/85
Inventor 高翔琚存祥赵静吴丹张明坤侯欢欢
Owner GEMPHARMATECH CO LTD
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