Humanized FcγR Mouse Model for Antibody Evaluation
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Solution Overview
Problem
Current models lack a comprehensive system to accurately reflect human FcγR functions, particularly for low-affinity receptors, hindering the assessment of human antibody therapeutics and immune processes relevant to diseases like RA and SLE.
Innovation Solution
Genetically modified mice are developed to express human low-affinity FcγR genes, lacking endogenous mouse FcγR genes, allowing for the expression of human FcγR α-chains and maintaining a functional mouse FcR γ-chain, thereby mimicking human FcγR functions and facilitating the evaluation of therapeutic antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If genetically modified mice are developed to express human FcγR genes, then the accuracy of modeling human immune responses is improved, but the complexity of the genetic modification process increases
Solution Approach 1:
The patent uses a targeting vector as an intermediary tool to facilitate the genetic modification process. This vector contains the human FcγR genes along with selection markers and homology regions, serving as a mediator to insert human genes into the mouse genome at specific loci. This intermediary approach simplifies the complex process of genetic engineering by providing a pre-packaged system for gene delivery and integration.
Solution Approach 2:
The patent performs preliminary genetic modifications by first knocking out endogenous mouse FcγR genes before introducing human FcγR genes. This preliminary action ensures that the mouse genome is prepared and ready to receive human genes without interference from endogenous genes, streamlining the overall modification process and improving the accuracy of the humanized model.
2Adaptability or versatility
If endogenous mouse FcγR genes are knocked out, then the ability to study human-specific FcγR functions is improved, but the complexity of generating knockout mice increases
Solution Approach 1:
The patent combines the knockout of endogenous mouse FcγR genes with the introduction of human FcγR genes into a single integrated genetic modification strategy. By merging these two operations, the patent eliminates the need for separate knockout and transgenic steps, reducing overall complexity while enabling the study of human-specific FcγR functions in a unified mouse model.
Solution Approach 2:
The targeting vector serves as an intermediary that simultaneously achieves both knockout and gene introduction. The vector design includes regions that facilitate deletion of endogenous genes while also providing the human gene sequence for insertion, making the dual modification process more manageable and less complex than performing these operations separately.
3Adaptability or versatility
If multiple human FcγR genes are co-expressed, then the comprehensiveness of the immune model is improved, but the difficulty of genetic engineering increases
Solution Approach 1:
The patent merges multiple human FcγR genes into a single targeting vector construct, allowing simultaneous introduction of all desired genes into the mouse genome in one genetic modification event. This merging approach prevents the need for multiple separate transgenic introductions, significantly reducing the difficulty of genetic engineering while achieving comprehensive human FcγR expression.
Solution Approach 2:
The targeting vector is designed as a universal platform that can accommodate multiple different human FcγR genes. This multi-functional vector system allows researchers to co-express various human FcγR isoforms and variants within a single genetic modification framework, making the process of creating comprehensive immune models more accessible and less difficult.
Data Source
AI summary
Genetically modified non-human animals and methods and compositions for making and using them are provided, wherein the genetic modification comprises a deletion of the endogenous low affinity FcγR locus, and wherein the mouse is capable of expressing a functional FcRγ-chain. Genetically modified mice are described, including mice that express low affinity human FcγR genes from the endogenous FcγR locus, and wherein the mice comprise a functional FcRγ-chain. Genetically modified mice that express up to five low affinity human FcγR genes on accessory cells of the host immune system are provided.