Humanized Mouse PBMC Model for CRS Toxicity Prediction
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Solution Overview
Problem
Current methods for predicting cytokine release syndrome (CRS) in humans, such as in vivo animal models and in vitro whole-blood assays, fail to accurately determine immunotoxicity, leading to unforeseen severe reactions as seen in the TGN1412 trial, due to interspecies differences and limitations in modeling human immune responses.
Innovation Solution
A method using irradiated immunodeficient mice engrafted with human peripheral blood mononuclear cells (PBMCs) to administer immunomodulatory drugs, measuring cytokine concentrations of IFN-γ and IL-10 to predict CRS severity, with thresholds indicating potential human responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional in vivo animal models (rodent and non-human primate) are used for toxicity testing, then the testing can be performed with existing models, but the genomic responses do not accurately mimic human immune responses leading to false predictions
Solution Approach 1:
The patent uses human stem cells as an intermediary to bridge the gap between traditional animal models and human responses. By engrafting human stem cells that differentiate into human immune cells within immunodeficient animals, the model creates a hybrid system that maintains the physiological context of an in vivo animal model while producing human-specific genomic responses to immunomodulatory drugs.
Solution Approach 2:
The patent fundamentally changes the biological parameters of the test model by replacing rodent or primate immune systems with human immune cells derived from stem cells. This parameter change transforms the model from one that produces non-human genomic responses to one that accurately mimics human immune responses, thereby improving predictive accuracy for human toxicity.
2Reliability
If human stem cells are grafted into non-human mammals for testing, then human immune responses can be modeled, but the method requires obtaining bone marrow from patients and waiting for stem cell growth and differentiation which is time-consuming and invasive
Solution Approach 1:
The patent performs preliminary actions by harvesting and preparing human stem cells from healthy donors in advance, before the actual toxicity testing begins. The stem cells are cultured and differentiated into immune cells ex vivo, and then engrafted into immunodeficient animals, thereby eliminating the need to wait for stem cell growth during the testing process and reducing the overall time required.
Solution Approach 2:
The patent creates a copy of the human immune system within the animal model by engrafting human stem cells that differentiate into human immune cells. This copied immune system responds to immunomodulatory drugs in the same manner as a human immune system would, providing accurate predictive data without requiring direct testing in human patients.
3Ease of operation
If in vitro whole-blood or PBMC assays are used, then the testing is simpler and faster, but the assays cannot model the systemic response to potential drug toxicity
Solution Approach 1:
The patent merges the advantages of both in vitro and in vivo approaches by combining human stem cells (providing human-specific responses) with an in vivo animal model (providing systemic physiological context). The resulting humanized animal model maintains the simplicity and ethical benefits of in vitro testing while adding the critical dimension of systemic response modeling that in vitro assays cannot provide.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method provides a reliable in vivo model for predicting CRS severity in humans by correlating mouse cytokine levels with human responses, enabling safer dosage determination and toxicity assessment of immunomodulatory drugs.
Implementation Method 1
providing an immunodeficient mouse, said mouse is irradiated with 75-125 cGy X-ray
Data Source
AI summary
Humanized mouse models and methods are provided for determining whether administration of an immunomodulatory drug likely elicits a severe cytokine release syndrome in a human. Humanized mouse models and methods are also provided for determining the immunotoxicity in a human of a drug candidate or of drug combinations.