Ctla4 Pdcd1 Mouse Model for Immune Checkpoint Adverse Events
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Solution Overview
Problem
Current animal models do not faithfully recapitulate the immune-related adverse events and autoimmunity associated with checkpoint blockade therapies, such as myocarditis and type I diabetes, making it difficult to screen for effective mitigating agents.
Innovation Solution
A mouse model with a heterozygous loss-of-function Ctla4 gene and a homozygous loss-of-function Pdcd1 gene is developed, which exhibits autoimmunity resembling the adverse events seen in human patients, allowing for the screening of candidate agents to mitigate these conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If checkpoint blockade therapy is used to treat cancer, then tumor response is improved, but immune-related adverse events and autoimmunity occur
Solution Approach 1:
The patent creates a mouse model that copies the genetic alterations caused by checkpoint blockade therapy (heterozygous Ctla4 loss and homozygous Pdcd1 loss) to reproduce the autoimmune pathology in a controlled system, enabling study of adverse events without exposing patients to harmful effects
2Reliability
If existing animal models are used, then basic immune function is maintained, but they do not faithfully recapitulate checkpoint blockade-induced autoimmunity
Solution Approach 1:
The patent modifies the genetic parameters of the mouse model by introducing specific loss-of-function alleles (heterozygous Ctla4 and homozygous Pdcd1) to change the immune regulation parameters, thereby enabling the model to faithfully recapitulate the specific autoimmunity caused by checkpoint blockade therapy
3Device complexity
If no animal model exists for checkpoint blockade autoimmunity, then basic research is simplified, but screening for mitigating agents becomes impossible
Solution Approach 1:
The mouse model performs self-service by spontaneously developing the autoimmune pathology relevant to checkpoint blockade therapy, eliminating the need for complex experimental induction procedures while enabling direct screening of mitigating agents in a physiologically relevant context
Data Source
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AI summary
Provided herein are mice that are heterozygous knock outs for Ctla4 and homozygous knockouts for Pdcd1 (Ctla4 +/- Pdcd1 -/- mice), which may suffer from autoimmunity, including myocarditis and insulin-dependent diabetes mellitus. Also provided are methods of using such mice to screen for therapeutic agents that mitigate immune-related adverse events.