Humanized GITR Animal Models for Accurate Drug Screening
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Solution Overview
Problem
Current drug development for immune-related diseases and cancers faces challenges due to the inability of traditional in vitro and in vivo screening methods to accurately replicate human tumor microenvironments, leading to high failure rates and discrepancies between animal and human clinical trial results.
Innovation Solution
Development of genetically modified animal models that express human or chimeric glucocorticoid-induced TNFR-related protein (GITR), allowing for the study of GITR function and the evaluation of anti-GITR antibodies in a human-relevant context, facilitating drug screening and development.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional in vitro screening approaches are used, then the screening process is simple and fast, but the results cannot accurately reflect human disease states and show high failure rates in clinical trials
Solution Approach 1:
The patent introduces a humanized animal model as an intermediary system between in vitro screening and human clinical trials. This model expresses human GITR protein and can be engrafted with human tumor cells, serving as a bridge that provides more physiologically relevant testing results while avoiding the limitations of both simple cell culture and direct human trials
Solution Approach 2:
The patent changes the biological parameters of the test subject by creating animals with humanized immune systems that express human GITR protein. This parameter change allows the model to respond to anti-GITR antibodies in a manner more similar to human patients, thereby improving the predictive value of preclinical studies
2Ease of manufacture
If conventional experimental animals are used for in vivo pharmacological tests, then the animal models are easy to maintain and cost-effective, but the test results do not reflect real human disease states and show significant discrepancies from clinical trial outcomes
Solution Approach 1:
The patent applies local quality by selectively humanizing specific components of the animal model - specifically the GITR protein and optionally tumor cells - while maintaining the rest of the animal system as conventional. This targeted approach provides human-relevant data where needed while preserving the practical advantages of conventional animal models
3Reliability
If humanized animal models expressing human GITR are developed, then the accuracy of drug testing is improved and clinical trial predictive value is enhanced, but the complexity of model creation and maintenance increases
Solution Approach 1:
The patent segments the humanization process into manageable components: first creating animals with human GITR expression, then optionally adding human tumor cell engraftment. This segmentation allows for stepwise validation and optimization, reducing the overall complexity by breaking down the challenging task of creating a fully humanized model into separate, controllable stages
Data Source
AI summary
The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) glucocorticoid-induced TNFR-related protein (GITR), and methods of use thereof.