Humanized CD94 NKG2A Mouse Models for Drug Screening
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Conventional drug development methods using wild-type mice are inadequate for screening and evaluating drugs targeting human CD94 or NKG2A due to significant differences in protein sequences, leading to high failure rates and discrepancies between preclinical and clinical trial results.
Innovation Solution
Development of genetically modified animal models that express human CD94 or chimeric CD94 and NKG2A proteins, allowing for the creation of humanized models that can interact with human antibodies and recognize MHC class I molecules, facilitating drug screening and evaluation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If wild-type mice are used for drug screening, then the experimental model is simple and easy to maintain, but the test results do not reflect the real human disease state due to significant sequence differences between human and mouse CD94/NKG2A proteins
Solution Approach 1:
The patent applies parameter changes by modifying the genetic sequence parameters of the mouse model. Specifically, the mouse CD94 and NKG2A gene sequences are replaced with human CD94 and NKG2A gene sequences, changing the protein sequence identity from approximately 55% and 42% to 100% match with human proteins. This sequence parameter change enables human antibodies to recognize the target proteins in the animal model, thereby improving the reliability of drug screening while maintaining the simplicity of the mouse model system.
2Reliability
If humanized animal models are developed to express human CD94 and NKG2A proteins, then the accuracy of drug screening is improved, but the complexity of model development increases
Solution Approach 1:
The patent applies the extraction principle by isolating and replacing only the specific gene sequences responsible for the antigenic differences. Instead of creating a fully humanized animal model, the invention extracts the human CD94 and NKG2A gene sequences and inserts them into the mouse genome at the corresponding loci. This targeted extraction and replacement approach achieves the necessary human protein expression while minimizing the overall complexity of model development.
Solution Approach 2:
The patent applies segmentation by dividing the genome modification into specific targeted regions. The humanization process is segmented to affect only the CD94 and NKG2A gene loci, leaving the rest of the mouse genome unchanged. This segmented approach allows for precise genetic modification that achieves the desired protein expression without the complexity of comprehensive humanization.
3Quantity of substance
If conventional animal models are used, then the cost of research and development is lower, but the failure rate of drug development is higher due to discrepancies between preclinical and clinical trial results
Solution Approach 1:
The patent applies parameter changes by modifying the genetic sequence parameters of the mouse model. Specifically, the mouse CD94 and NKG2A gene sequences are replaced with human CD94 and NKG2A gene sequences, changing the protein sequence identity from approximately 55% and 42% to 100% match with human proteins. This sequence parameter change enables human antibodies to recognize the target proteins in the animal model, thereby improving the reliability of drug screening while maintaining the simplicity of the mouse model system.
Data Source
AI summary
The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) CD94 and/or NKG2A, and methods of use thereof.