Immunodeficient Mouse With Fcgr2b Deletion for Human ADCC Evaluation
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Solution Overview
Problem
Existing immunodeficient mice, such as NOG mice, exhibit antibody-dependent cellular cytotoxicity (ADCC) activity from mouse immune cells, complicating the evaluation of human antibody responses and limiting the engraftment of human cells, particularly human NK cells, which are essential for evaluating ADCC activity.
Innovation Solution
A genetically modified immunodeficient mouse is developed by introducing mutations into the IL-2 receptor γ chain gene and disabling FcgR expression, combined with the introduction of the human IL-15 gene to enable higher engraftment of human cells, particularly human NK cells, and evaluate ADCC activity using these cells as effector cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If FcgR is expressed in the immunodeficient mouse, then ADCC activity from mouse immune cells is activated, but this complicates the evaluation of human antibody responses and limits human cell engraftment
Solution Approach 1:
The patent removes FcgR expression from the mouse system by deleting the Fcgr2b gene, thereby extracting the harmful ADCC activity component. This allows human antibody responses to be evaluated without interference from mouse immune cell activity.
Solution Approach 2:
The patent changes the genetic parameter of the mouse by introducing mutations in the IL-2 receptor γ chain gene and deleting the Fcgr2b gene, fundamentally altering the immune system's capability to perform ADCC while maintaining other necessary immune functions for human cell engraftment.
2Quantity of substance
If human cells are engrafted in NOG mice, then human cell analysis is enabled, but engraftment rate is limited due to mouse immune system activity
Solution Approach 1:
The patent extracts the harmful immune rejection mechanism by deleting FcgR expression and disabling IL-2 receptor γ chain, thereby removing the mouse immune system's ability to recognize and reject human cells through ADCC pathways.
Solution Approach 2:
The patent creates a composite genetic structure combining multiple modifications: IL-2 receptor γ chain mutation, Fcgr2b gene deletion, and human IL-15 gene introduction, resulting in an immunodeficient mouse with enhanced human cell compatibility.
3Measurement precision
If mouse FcgR is present, then mouse immune cells can eliminate foreign substances, but this prevents accurate evaluation of human antibody-dependent cancer suppression
Solution Approach 1:
The patent extracts the confounding variable of mouse FcgR-mediated immunity by deleting the Fcgr2b gene, thereby isolating the human antibody's effect on cancer cells without mouse immune system interference.
Solution Approach 2:
The patent introduces human IL-15 as an intermediary cytokine that supports human NK cell function and engraftment, creating a human-centric immune environment within the mouse host for accurate antibody evaluation.
Data Source
AI summary
An object of the present invention is to provide an immunodeficient mouse which is capable of eliminating effects of immune cells from the immunodeficient mouse against human antibodies and in which human cells are engrafted at high level.Deletion of a mouse FcgR gene from an NOG mouse results in a mouse that does not exhibit antibody-dependent cellular cytotoxic activity on tumors, and in the mouse, human cells can be engrafted at significantly higher level than that in the NOG mouse. Furthermore, by introducing the human IL-15 gene into the mouse and engrafting a human NK cell in the mouse, only human NK cells become effector cells to enable evaluation of ADCC activity.