Construction method and application of humanized kdr gene modified animal model

Abstract

The application provides a method for constructing a humanized KDR genetically modified animal model and its application, relating to the technical field of genetic engineering. The humanized KDR genetically modified animal model constructed in the present application can accelerate the research progress in fields related to human KDR gene or protein. Preferably, the present application utilizes homologous recombination gene editing technology to replace the mouse Kdr gene with the human KDR gene on mice with a sound immune system to construct a mouse model capable of interacting with anti-human KDR antibodies, Compared with ordinary mice, this model has realized the humanization of key target molecules and retained a complete immune system, which can be used to screen and evaluate drugs targeting human KDR genes, and is an ideal preclinical drug testing 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

Images