Humanized PD-L1 Mouse Model for Immune Therapy Testing
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current systems lack effective in vivo models for determining the therapeutic potential of new therapies targeting autoimmunity, cancer, and infectious diseases, particularly in modulating immune responses, as cells can evade immune surveillance through cell surface polypeptides like PD-L1, hindering the development of effective treatments.
Innovation Solution
Engineering non-human animals with a humanized CD274 gene expressing a PD-L1 polypeptide, combining human and non-human portions, to create improved in vivo systems for identifying and developing therapeutics that up-regulate anti-tumor and anti-microbial immunity, allowing for the targeting of PD-L1 or its binding partners.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If non-human animals are used as in vivo systems, then the ability to study immune responses is improved, but the relevance to human therapeutic efficacy is reduced
Solution Approach 1:
The patent applies local quality by humanizing specific regions of the PD-L1 protein (extracellular domain) while maintaining rodent background. This allows the animal to serve as a whole in vivo system while having human-relevant properties in the critical immune interaction region, thus improving both in vivo capability and therapeutic relevance simultaneously
Solution Approach 2:
The patent creates a composite biological system by combining human PD-L1 protein sequences with rodent genomic background and regulatory elements. This composite approach enables the animal to exhibit human-relevant immune modulation properties while maintaining the practical advantages of rodent in vivo systems for therapeutic development
2Reliability
If human PD-L1 protein is expressed in non-human animals, then the functional relevance to human immunity is improved, but the animal's natural immune response characteristics are altered
Solution Approach 1:
The patent modifies only the extracellular domain of PD-L1 (residues 1-131) while maintaining rodent intracellular domains and regulatory mechanisms. This localized humanization preserves the natural immune response characteristics of the rodent while introducing human-relevant surface properties for immune interaction
Solution Approach 2:
The patent segments the PD-L1 protein into human and rodent portions, with the human extracellular domain interacting with PD-1 receptors and the rodent intracellular domain maintaining endogenous signaling pathways. This segmentation allows simultaneous achievement of human relevance and preservation of natural immune profile
3Object-generated harmful factors
If cells express PD-L1 to evade immune surveillance, then tumor growth is promoted, but therapeutic intervention becomes more difficult
Solution Approach 1:
The patent converts the harmful immune evasion mechanism (PD-L1 expression) into a beneficial therapeutic target by expressing human PD-L1 in rodent animals. This allows therapeutic agents targeting PD-L1 to be developed and tested in a whole in vivo system, transforming the evasion mechanism into a controllable therapeutic target
Solution Approach 2:
The humanized rodent animal serves as an intermediary system between human cancer biology and therapeutic development. The animal expresses human PD-L1 on tumor cells, enabling testing of PD-L1 targeting therapies in a whole in vivo context while maintaining relevance to human disease
Data Source
AI summary
Non-human animals, methods and compositions for making and using the same, are provided, wherein said non-human animals comprise a humanization of a Cluster of Differentiation 274 (CD274) gene. Such non-human animals may be described, in some embodiments, as having a genetic modification to an endogenous CD274 gene so that said non-human animals express a Programmed cell death ligand 1 (PD-L1) polypeptide that includes a human portion and an endogenous portion (e.g., a non-human portion).