Construction method and application of humanized KDR gene modified animal model

Abstract

The invention provides a construction method and application of a humanized KDR gene modified animal model, and relates to the technical field of gene engineering. The humanized KDR gene modified animal model constructed by the method can accelerate the research progress of the fields related to human KDR gene or protein. Preferably, by utilizing a homologous recombination gene editing technologyis utilized, on a mouse with the healthy immune system, a mouse-derived Kdr gene is replaced with a human KDR gene, and a mouse model capable of interacting with an anti-human KDR antibody is constructed; and compared with a common mouse, the model realizes humanized modification of key target molecules, retains the complete immune system, can be used for screening and evaluating drugs for the human KDR gene, and is a very ideal preclinical drug test model.

Description

technical field [0001] This application relates to the technical field of genetic engineering, in particular to a method for constructing a humanized KDR genetically modified animal model and its application. Background technique [0002] Cancer is a major public health problem facing the world, and the incidence and mortality of human cancer are still rising. With increasing aging and population growth, cancer is expected to become the leading cause of death in the 21st century, and cancer has become a heavy burden on public health care. [0003] Angiogenesis is a necessary step in the development of tumors: during tumor growth, when the diameter of the tumor is >2mm, the diffusion in the tissue alone cannot obtain the required nutrients and oxygen, and new angiogenesis is required to provide cancer cells Provide nutrients and oxygen supply for the growth and expansion of cancer cells. In 1971, Folkman et al. proposed that the growth and metastasis of solid tumors depe...

AI Technical Summary

Problems solved by technology

Because the developed human-derived target drugs cannot recognize the target molecules of animals, the contradiction that animals cannot be used for drug efficacy and pharmacological and toxicological evaluation is particularly prominent in macromolecular antibody drugs, because macromolecular antibody drugs may only recognize the target molecules produced by A target site composed of several amino acids, and a difference of one amino acid in the target molecule between animals and humans may cause the drug not to recognize the target in the animal, which in turn affects the subsequent drug evaluation, prolongs the development cycle, and increases the Certainty

The amino acid sequence identity of human and mouse KDR proteins is only 85%, and the amino acid identity of the extracellular region is even lower, only 79.9% (the extracellular region is the main action region of antibody macromolecular drugs targeting the KDR target), This difference in amino acid sequence caused the marketed ramucirumab targeting the KDR target to fail to recognize the mouse Kdr protein, and it was impossible to use the mouse to conduct research on the efficacy, toxicity, and safety of ramucirumab. Evaluation

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