Humanized CD137 Mouse Models for Accurate Anti-CD137 Antibody Testing
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Solution Overview
Problem
Conventional drug development methods using in vitro screening and conventional experimental animals fail to accurately replicate human disease states due to lack of tumor microenvironment and immune cell interactions, leading to high failure rates and discrepancies in clinical trial results.
Innovation Solution
Development of genetically modified animal models expressing human or chimeric CD137 proteins, allowing for more accurate drug screening and evaluation of anti-CD137 antibodies in a human-like environment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional experimental animals are used for in vivo pharmacological testing, then the test can be performed in a living organism, but the test results cannot reflect the real human disease state and interaction at targeting sites
Solution Approach 1:
The patent creates humanized mouse models by replacing the endogenous mouse CD137 gene with the human CD137 gene, thereby copying human biological characteristics into the animal model. This allows the mouse to express human CD137 protein on its cell surface, enabling accurate testing of anti-CD137 antibodies and evaluation of drug efficacy in a human-relevant biological context.
2Ease of manufacture
If in vitro screening approaches are used, then the screening process is simple and controllable, but the body environment such as tumor microenvironment, stromal cells, extracellular matrix components and immune cell interaction cannot be provided
Solution Approach 1:
The humanized mouse model serves as an intermediary system that bridges in vitro screening and human clinical trials. It provides a living organism with human-specific biological characteristics (human CD137 expression) that enables complex immune cell interactions and tumor microenvironment dynamics to occur in vivo, while still allowing controlled experimental manipulation and measurement.
3Productivity
If humanized animal models are developed, then the efficiency of new drug development is improved and cost is reduced, but the model complexity increases
Solution Approach 1:
The patent focuses on humanizing a specific gene (CD137) rather than attempting to humanize the entire genome. This selective approach maintains the majority of the mouse genome's simplicity and ease of manipulation while introducing only the necessary human characteristics for the specific drug target, thereby balancing model complexity with productivity benefits.
Data Source
AI summary
The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) CD137, and methods of use thereof.