Humanized Rodent Models for Antibody Pharmacokinetic Testing
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Solution Overview
Problem
Conventional rodent models are inadequate for predicting the safety, efficacy, and dosing of complex therapeutic agents like antibodies and Fc fusion proteins in humans due to differences in pharmacokinetic properties and immune responses compared to humans.
Innovation Solution
Genetically modified rodents are developed to express human Fc regions and Fc receptors, reducing anti-human immune responses and mimicking human Fc interactions, allowing for more accurate testing of human therapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional rodent models are used for testing therapeutic agents, then the testing cost is low and the model is simple, but the predictive accuracy for human therapeutic responses is poor
Solution Approach 1:
The patent applies local quality by selectively humanizing specific components of the rodent immune system rather than creating a fully human model. The rodents express human Fc receptors and human immunoglobulin constant regions in specific tissues where these components naturally occur, while maintaining rodent physiology elsewhere. This targeted approach improves predictive accuracy for Fc-mediated therapeutic responses without the complexity and cost of fully humanized models.
Solution Approach 2:
The patent creates a composite biological model that combines rodent and human biological components. The rodents possess a hybrid immune system with rodent variable regions for antigen recognition and human constant regions and Fc receptors for effector functions. This composite structure allows the model to exhibit both rodent handling advantages and human-like responses to therapeutic antibodies, resolving the contradiction between simplicity and predictive accuracy.
2Measurement precision
If larger animals like non-human primates are used for testing, then the predictive accuracy for human responses is high, but the testing cost is high and suitable disease models are not available
Solution Approach 1:
The patent changes the biological parameters of the rodent model by introducing human Fc receptor genes and human immunoglobulin constant region genes. This parameter modification allows small rodents to exhibit pharmacokinetic and pharmacodynamic properties similar to humans, achieving high predictive accuracy at low cost. The parameter change transforms the rodent from a poor predictor to a reliable model without requiring expensive primate facilities.
3Ease of manufacture
If rodents are used for testing complex therapeutic agents, then the testing cost is low and the model is simple, but the pharmacokinetic properties differ significantly from humans
Solution Approach 1:
The patent applies preliminary action by genetically modifying the rodents to express human Fc receptors and human immunoglobulin constant regions before administering the therapeutic agents. This pre-adaptation ensures that the rodents' immune systems are primed to interact with human therapeutics in a human-like manner, eliminating the need for costly post-hoc corrections and improving pharmacokinetic predictability while maintaining cost efficiency.
Data Source
AI summary
Provided herein are methods and compositions related to the in vivo testing of therapeutic agents comprising a human Fc in genetically modified rodents (e.g., the testing of the pharmacokinetic and/or pharmacodynamic properties of such a therapeutic agent in genetically modified rodents). In some embodiments the genetically modified rodents express antibodies comprising a human Fc (e.g., a human IgG1 Fc, a human IgG4 Fc). In some embodiments, the rodents express fully human antibodies (i.e., antibodies having human heavy chains and human light (γ or κ) chains). In certain embodiments the genetically modified rodents comprise one or more Fc receptors with a human extracellular domain (e.g., a Neonatal Fc Receptor (FcRn), a β-2-microglobulin polypeptide (β2M), a Fc ε receptor 1 α (FcεR1α), a Fc γ receptor 1 alpha (FcγR1a), a Fc gamma receptor 2a (FcγR2a), a Fc gamma receptor 2b (FcγR2b), a Fc gamma receptor 3a (FcγR3a), a Fc gamma receptor 3b (FcγR3b), a Fc gamma receptor 2c (FcγR2c)). The transmembrane and cytoplasmic domain of such receptors can be human or non-human (e.g., rodent).