FcγR Deficient Mice With Human Receptor Locus
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Solution Overview
Problem
There is a need for non-human animal models that co-express multiple human FcRs, particularly low affinity FcRs, to study human immune responses and develop therapies for autoimmune diseases and anti-tumor treatments, as well as to test human antibody pharmaceuticals effectively.
Innovation Solution
Genetically modify non-human animals, such as mice, by deleting endogenous low affinity FcγR genes and replacing them with human FcγR genes, enabling expression of functional human FcγR receptors on various immune cells, thereby mimicking human immune functions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If endogenous murine FcγR genes are deleted and replaced with human FcγR genes, then the ability to study human immune responses and test human antibody pharmaceuticals is improved, but the complexity of genetic modification and breeding required is increased
Solution Approach 1:
The patent creates a copy of the human FcγR gene cluster and inserts it into the murine genome at the endogenous FcγR locus. This copying approach allows the mouse to express human FcγR receptors while maintaining the genomic context and regulatory elements, providing a reliable model for studying human immune responses without requiring complex multi-gene modifications throughout the genome.
Solution Approach 2:
The patent changes the species origin parameter of the FcγR genes from murine to human by deleting endogenous murine FcγR genes and replacing them with human FcγR genes. This parameter change enables the animal model to more accurately reflect human immune system behavior, particularly in response to human therapeutic antibodies, while the structured replacement process manages the complexity through targeted genetic engineering.
2Adaptability or versatility
If multiple human FcγR genes are co-expressed, then the utility for studying human disease therapies and pharmaceutical development is improved, but the difficulty of achieving functional expression of all receptors is increased
Solution Approach 1:
The patent achieves multi-functionality by co-expressing multiple human FcγR genes (FcγRI, FcγII, FcγIII, and FcγIV) within a single animal model. The shared constant regions and common signaling pathways allow these different receptors to function together in a coordinated manner, enabling the study of various human immune responses and disease therapies using one versatile model system rather than multiple separate models.
Solution Approach 2:
The patent merges multiple human FcγR gene sequences into a single integrated genomic construct that replaces the murine FcγR locus. This combining approach allows all human FcγR variants to be co-expressed from a unified genetic architecture, simplifying the achievement of functional expression compared to introducing multiple separate transgenes, while maintaining the ability to study diverse human immune functions.
3Reliability
If endogenous FcγR genes are deleted, then the ability to study ADCC processes with human antibodies is improved, but the impact on overall immune system function is increased
Solution Approach 1:
The patent uses the endogenous murine FcR γ-chain as an intermediary component that can pair with both murine and human FcγR α-chains. This intermediary approach allows the deletion of endogenous FcγR genes while preserving the ability to form functional receptor complexes, as the murine γ-chain serves as a bridge that enables human FcγR α-chains to function properly in the murine immune system context.
Solution Approach 2:
The patent applies local quality by selectively deleting only the FcγR α-chain genes while preserving the FcR γ-chain genes in the murine genome. This localized modification approach allows the study of ADCC processes with human antibodies by removing the interfering murine α-chains, while the preserved γ-chains continue to support overall immune system function and enable proper receptor complex formation.
Data Source
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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 FcyR 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 FcyR genes from the endogenous FcyR 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.