Humanized PD-1 Animal Models for Accurate Immune Response Screening
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Solution Overview
Problem
Traditional drug development methods for immune-related diseases and cancer therapies face challenges due to the inability of conventional animal models to accurately replicate human tumor microenvironments, leading to high failure rates and discrepancies between animal and clinical trial results.
Innovation Solution
The development of genetically modified animals that express human or chimeric PD-1 proteins, allowing for the creation of humanized animal models that mimic human immune responses and facilitate the screening and evaluation of anti-PD-1 antibodies and cancer therapies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional animal models are used for drug screening, then the animal model is easy to obtain and maintain, but the test results do not reflect the real human disease state and interaction at targeting sites
Solution Approach 1:
The patent creates a copy of the human PD-1 gene and integrates it into the mouse genome to replace the endogenous mouse PD-1 gene. This copying approach allows the animal model to express human PD-1 protein, thereby accurately representing human disease states and interactions at targeting sites, while maintaining the overall simplicity of the mouse model system.
2Reliability
If in vitro screening approaches are used, then the screening process is simple and fast, but the body environment (tumor microenvironment, stromal cells, immune cell interaction) cannot be provided
Solution Approach 1:
The patent uses genetically modified animals as an intermediary system between in vitro screening and human clinical trials. The animal model provides a living body environment with tumor microenvironment, stromal cells, and immune cell interactions, while still allowing for systematic drug screening. This intermediary approach bridges the gap between simplified in vitro models and complex human physiology.
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 more complex
Solution Approach 1:
The patent extracts the human PD-1 gene sequence and isolates it for integration into the mouse genome. By taking out only the specific human PD-1 gene rather than introducing entire human immune system components, the approach achieves humanized functionality with minimal genetic modification complexity. This selective extraction strategy maintains drug development efficiency while avoiding excessive complexity.
Data Source
AI summary
The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) programmed cell death protein 1 (PD-1), and methods of use thereof. In one aspect, the animals have an insertion of a sequence encoding a human or humanized programmed cell death protein 1 (PD-1) at an endogenous PD-1 gene locus. This animal model can express a PD-1 protein containing a functional domain of the human PD-1 protein, and can be used as an animal model for developing therapeutics for human diseases and disorders, and assessing the toxicity and/or the efficacy of these human therapeutics.