Humanized CD28 Animal Models for Reliable Immune Screening
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Solution Overview
Problem
Traditional drug development methods for immune-related diseases and cancers rely on in vitro screening and conventional animal models, which fail to replicate the human body environment and tumor microenvironment, leading to high failure rates and discrepancies between animal and clinical trial results.
Innovation Solution
Development of genetically modified animal models expressing human or chimeric CD28 proteins, allowing for the study of CD28 function, antibody screening, and drug evaluation in a more human-relevant context.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional animal models are used for in vivo pharmacological testing, then the complexity of the model is low and ease of manufacture is high, but the reliability of test results is poor due to species differences and inability to replicate human body environment
Solution Approach 1:
The patent applies local quality by selectively humanizing specific components of the animal model - introducing human CD28 gene and human B7-1/B7-2 proteins at specific loci - while maintaining the rest of the animal genome as conventional. This allows the model to have human-relevant immune interaction capabilities at the target site while retaining animal physiology elsewhere, thus improving reliability without requiring complete humanization of the entire organism.
Solution Approach 2:
The patent uses an intermediary approach by creating a chimeric model where human immune proteins (CD28, B7-1, B7-2) are introduced into an animal system. This intermediary model serves as a bridge between conventional animal models and human subjects, allowing pharmacological testing in an in vivo environment that more closely mimics human immune responses without requiring full humanization.
2Reliability
If in vitro screening approaches are used for drug development, then the cost and time investment are low, but the reliability of results is poor due to inability to provide body environment such as tumor microenvironment and immune cell interaction
Solution Approach 1:
The patent creates an intermediary in vivo model that combines animal physiology with human immune proteins, serving as a middle ground between simple in vitro screening and expensive clinical trials. This model provides the body environment (tumor microenvironment, immune cell interactions) that in vitro systems lack, while being more cost-effective and faster than full human clinical trials.
Solution Approach 2:
The patent changes key parameters of the testing system by introducing human CD28 and human B7-1/B7-2 proteins into the animal model. This parameter change enables the model to respond to anti-CD28 antibodies in a human-relevant manner, improving the predictive value of drug screening results while maintaining the practical advantages of animal modeling.
3Reliability
If complete humanization of animal models is performed, then the reliability of human antibody screening is maximized, but the complexity of model preparation and cost increase significantly
Solution Approach 1:
The patent applies local quality by selectively humanizing only the necessary components - CD28 receptor and B7-1/B7-2 ligands - rather than completely humanizing the entire animal model. This targeted approach achieves sufficient reliability for human antibody screening while keeping model preparation complexity and costs manageable.
Solution Approach 2:
The patent uses partial action by introducing only the specific human proteins needed for CD28 pathway research rather than complete humanization. This partial humanization provides adequate reliability for screening anti-CD28 antibodies and studying human immune responses without the excessive complexity and cost of full humanization.
Data Source
AI summary
The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) CD28, and methods of use thereof.