Application of huGEMM PD-1 mouse to evaluation of drug effects and immune-related side effects of in-vivo humanized PD-1 antibody

Abstract

The invention relates to the technical field of biological medicines, in particular to an application of a huGEMM PD-1 mouse to evaluation of drug effects and immune-related side effects of an in-vivohumanized PD1 antibody. A human non-small cell lung cancer model HCC827 is inoculated in an NCG mouse, spleen cells from a huGEM hPD-1 mouse are utilized after modeling succeeds, and are are input into the NCG mouse with severe immunodeficiency for immune reconstruction, and the drug effect and irAE of a humanized PD-1 / PD-L1 antibody drug can be evaluated at the same time by utilizing a humanizedtumor and a mouse immune system carrying a human target. Good application prospects are realized.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to the application of huGEMM PD-1 mice in the evaluation of the efficacy and immune-related side effects of human PD-1 antibodies in vivo. [0002] technical background [0003] With the deepening of basic research and clinical trials in the field of tumor immunity in recent years, the clinical application of immune checkpoint inhibitors (Immune Checkpoint Inhibitor, ICI) such as PD-1, CTLA-4 has achieved good therapeutic effects, PD- 1 Antibody drugs such as nivolumab and atezolizumab have been approved by the FDA for the first-line treatment of melanoma, lung cancer, kidney cancer and other cancers; PD-L1 antibody drug atezolizumab has been approved for the treatment of localized tumors that do not respond to platinum-based chemotherapy Advanced or metastatic urothelial carcinoma. However, according to the current clinical data, only a part of patients (less than 40%) respond ...

AI Technical Summary

Problems solved by technology

[0005] The tumor model and immune system involved in the syngeneic mouse model are both of murine origin, so there is no GvHD (Graft-verse Host Diase), but because only the mouse surrogate antibody of human PD-1 / PD-L1 antibody can be detected ( surrogate antibody), which indirectly reflects the potential efficacy and safety of human PD-1 / PD-L1 through the similarity between the immune systems, so it cannot really evaluate the therapeutic effect of the human drug to be tested

The GEMM mouse model can effectively simulate and establish the tumor microenvironment. However, due to its long-term tumor occurrence and known tumor mutations, the tumor heterogeneity is low and the immunogenicity is weak. At the same time, only mouse-derived substitutions can be tested. Antibodies, preclinical applications are subject to some limitations

HuGEMM mice carry human-derived target gene knock-in, such as huGEMM-hPD-1 mice, which can be directly used to detect human-derived antibody drugs. Both the immune system and tumor models are derived from mice, and at the same time, they are affected by the PD-L1 target The limitations of humanized genetically modified mouse tumor cells cannot be used to detect human CDX or PDX tumor models carrying natural PD-L1 high expression

Humanized immune reconstitution mice based on CDX and PDX carry human tumor models and humanized immune systems, but because PBMCs from different donors and CDX / PDX tumors will have different degrees of allogeneic rejection, it has caused batches of There are great differences between times and between PBMC donors, and sometimes even the weight loss of mice is too serious to be successfully modeled; in addition, due to the lack of human immune cells in mice to maintain cell expansion, differentiation, maturation, Migrated cytokines and chemokines can only partially rebuild the immune system, and the functions of immune cells such as NK cells and macrophages are affected, which cannot simulate the clinically occurring immune-related side effects caused by the activation of myeloid cells

Images