Humanized IL-4Rα Transgenic Mice for Therapeutic Evaluation
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Solution Overview
Problem
Current methods for evaluating the pharmacokinetics and pharmacodynamics of therapeutic molecules targeting human IL-4 or IL-4Rα proteins in non-human animals are inadequate due to species-specificity issues, where these molecules do not interact with endogenous IL-4 or IL-4Rα proteins in non-human animals.
Innovation Solution
The development of transgenic non-human animals with humanized IL-4 and/or IL-4Rα genes, allowing these animals to express human or humanized IL-4 and/or IL-4Rα proteins, thereby enabling proper evaluation of therapeutic molecules targeting these proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If therapeutic molecules targeting human IL-4 or IL-4Rα proteins are evaluated in non-human animals with endogenous IL-4 or IL-4Rα proteins, then the evaluation can be performed in standard non-human animal models, but the therapeutic molecules cannot properly interact with the endogenous proteins due to species-specificity issues
Solution Approach 1:
The patent applies parameter changes by humanizing the IL-4 and IL-4Rα genes in non-human animals, specifically changing the species origin of these genes from non-human to human. This allows therapeutic molecules designed for human proteins to properly interact with the target proteins in the animal model, resolving the species-specificity issue while maintaining the advantages of in vivo evaluation
2Measurement precision
If non-human animals with humanized IL-4 and/or IL-4Rα genes are developed, then accurate evaluation of human-specific therapeutic molecules is enabled, but the complexity of creating and maintaining transgenic animal models increases
Solution Approach 1:
The patent applies segmentation by replacing only the specific IL-4 and IL-4Rα genes with human versions in the non-human animal genome, rather than creating fully humanized animals. This targeted gene replacement allows for accurate evaluation of human-specific therapeutics while minimizing the overall complexity compared to complete humanization
Solution Approach 2:
The patent uses non-human animals as an intermediary system that expresses human IL-4 and IL-4Rα proteins. These animals serve as a bridge between in vitro human cell studies and clinical trials in humans, allowing for in vivo pharmacokinetics and pharmacodynamics evaluation of human-specific therapeutics in a living system with human target proteins
Data Source
AI summary
Non-human animals comprising a human or humanized IL-4 and/or IL-4Rα nucleic acid sequence are provided. Non-human animals that comprise a replacement of the endogenous IL-4 gene and/or IL-4Rα gene with a human IL-4 gene and/or IL-4Rα gene in whole or in part, and methods for making and using the non-human animals, are described. Non-human animals comprising a human or humanized IL-4 gene under control of non-human IL-4 regulatory elements is also provided, including non-human animals that have a replacement of non-human IL-4-encoding sequence with human IL-4-encoding sequence at an endogenous non-human IL-4 locus. Non-human animals comprising a human or humanized IL-4Rα gene under control of non-human IL-4Rα regulatory elements is also provided, including non-human animals that have a replacement of non-human IL-4Rα-encoding sequence with human or humanized IL-4Rα-encoding sequence at an endogenous non-human C IL-4Rα locus. Non-human animals comprising human or humanized IL-4 gene and/or IL-4Rα sequences, wherein the non-human animals are rodents, e.g., mice or rats, are provided.