Humanized TNFR2 Mouse Model for Drug Screening
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Solution Overview
Problem
Conventional drug development methods using in vitro screening and conventional experimental animals fail to accurately reflect human disease states due to the lack of a suitable body environment and differences between human and animal genetics, leading to high failure rates in drug development and clinical trials.
Innovation Solution
Development of a genetically modified animal model that expresses human or chimeric TNFR2, allowing for the study of TNFR2 function and the evaluation of anti-TNFR2 antibodies, which can be used in drug screening and cancer therapy, reducing the gap between animal and human test results.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional experimental animals are used for in vivo pharmacological testing, then the test results can be obtained, but the results do not accurately reflect human disease states and targeting site interactions
Solution Approach 1:
The patent creates a humanized mouse model by replacing the endogenous mouse TNFR2 gene with the human TNFR2 gene, copying the human receptor's binding and signaling characteristics into the animal model. This allows the mouse to accurately reflect human disease states and drug responses at the TNFR2 targeting site, resolving the discrepancy between animal test results and human clinical outcomes.
2Ease of manufacture
If in vitro screening approaches are used, then the screening process is simple, but the body environment (tumor microenvironment, stromal cells, extracellular matrix, immune cell interaction) cannot be provided
Solution Approach 1:
The humanized mouse serves as an intermediary system that bridges in vitro simplicity and in vivo complexity. It provides the complete body environment including tumor microenvironment, stromal cells, extracellular matrix, and immune cell interactions while maintaining the human TNFR2 target for drug screening, thus enabling comprehensive drug evaluation that reflects actual human physiological conditions.
3Productivity
If humanized animal models are developed, then the efficiency of new drug development is improved and cost is reduced, but the genetic modification process becomes complex
Solution Approach 1:
The patent segments the genetic modification process into distinct steps: (1) preparing the human TNFR2 gene expression construct, (2) introducing the construct into mouse embryonic stem cells, (3) injecting the modified stem cells into mouse embryos, and (4) generating and characterizing the humanized mouse line. This segmentation makes the complex process more manageable and reproducible, improving drug development efficiency while maintaining genetic modification accuracy.
Data Source
AI summary
The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) TNFR2, and methods of use thereof.