Humanized Fcα Receptor Mouse Model for IgA Therapeutic Testing
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Solution Overview
Problem
Current mouse models lack an Fcα receptor, making them unsuitable for predicting the pharmacokinetic and pharmacodynamic properties of IgA-based therapeutic agents in humans, as these agents exhibit different behaviors in mice compared to humans due to the absence of an Fcα receptor for binding IgA antibodies.
Innovation Solution
Genetically modified mice expressing a human or humanized Fcα receptor are developed, allowing for the testing of human IgA antibodies and Fc fusion proteins, which mimic human Fcα receptor expression and interaction, enabling more accurate prediction of therapeutic agent properties in humans.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If wild type mice are used for testing IgA-based therapeutic agents, then the testing is simple and inexpensive, but the pharmacokinetic and pharmacodynamic properties do not predict human responses accurately due to absence of FcαR
Solution Approach 1:
The patent introduces a human FcαR transgene as an intermediary element into the mouse genome, specifically targeting the LRC locus. This transgene acts as a mediator that bridges the gap between mouse physiology and human therapeutic response, enabling accurate prediction of human pharmacokinetic and pharmacodynamic properties while maintaining the simplicity of mouse models.
Solution Approach 2:
The patent modifies the genetic parameters of the mouse model by inserting human FcαR coding sequences into the LRC locus. This parameter change transforms the mouse from lacking FcαR expression to expressing human FcαR on relevant cell surfaces, thereby changing the physiological parameters to better reflect human responses to IgA-based therapeutics.
2Reliability
If genetically modified mice expressing human FcαR are developed, then accurate prediction of human therapeutic properties is achieved, but the manufacturing and genetic modification complexity increases
Solution Approach 1:
The patent performs preliminary genetic modification by inserting the human FcαR transgene into the LRC locus of mouse embryonic stem cells or fertilized eggs before breeding. This preliminary action ensures that all subsequent generations of mice inherit the human FcαR expression capability, establishing a reliable testing system in advance rather than requiring individual mouse modification.
Solution Approach 2:
The patent copies the human FcαR gene sequence and inserts it into the mouse genome at a specific locus. This copying of the human receptor gene into the mouse genetic framework creates a reliable model that replicates human FcαR function, enabling accurate prediction of human therapeutic responses while using the simpler mouse platform.
3Measurement precision
If larger animal models are used instead of mice, then more accurate human response prediction may be achieved, but the cost and size requirements increase
Solution Approach 1:
The patent changes the key parameter of FcαR expression in the mouse model by introducing the human FcαR transgene. This parameter change enables small mice to accurately predict human therapeutic responses, eliminating the need to scale up to larger animal models while maintaining prediction accuracy.
Solution Approach 2:
The human FcαR transgene serves as an intermediary that allows small mouse models to capture human pharmacokinetic and pharmacodynamic properties. This intermediary element enables accurate human response prediction in a compact mouse platform, avoiding the need for larger, more expensive animal models.
Data Source
AI summary
Provided herein are methods and compositions related to mice that express human or humanized Foot receptors (FcaR) from an FcaR locus positioned in the mouse leukocyte receptor complex (LRC). In certain embodiments, such mice are useful for in vivo testing of therapeutic agents comprising a human IgA Fc (e.g., the testing of the pharmacokinetic and/or pharmacodynamic properties of such therapeutic agents and dosing regimens). Also provided herein are methods of using such mice, cells from such mice, methods of making such mice, and ES cells comprising the same genetic modifications as such mice. Provided herein are methods and compositions related to mice that express human or humanized Foot receptors (FcaR) from an FcaR locus positioned in the mouse leukocyte receptor complex (LRC). In certain embodiments, such mice are useful for in vivo testing of therapeutic agents comprising a human IgA Fc (e.g., the testing of the pharmacokinetic and/or pharmacodynamic properties of such therapeutic agents and dosing regimens). Also provided herein are methods of using such mice, cells from such mice, methods of making such mice, and ES cells comprising the same genetic modifications as such mice.