Humanized Mouse Cytokine Model for In Vivo Immunotherapy Assessment
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Solution Overview
Problem
There is a need for robust humanized mouse models that allow for the engraftment of human hematopoietic stem cells and human tumor xenografts to study the interactions between the human immune system and cancer in vivo.
Innovation Solution
Genetically-modified, immunodeficient mice are engineered to express human stem cell factor (hSCF), human granulocyte-macrophage colony-stimulating factor (hGM-CSF), human interleukin-3 (hIL-3), and human colony-stimulating factor 1 (hCSF1), which support the engraftment of human hematopoietic stem cells and tumor cells, allowing for the assessment of anti-tumor activity of test substances.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If genetically-modified mice are engineered to express multiple human cytokines (hSCF, hGM-CSF, hIL-3, hCSF1) to support human hematopoietic stem cell engraftment, then the reliability of the humanized mouse model is improved, but the device complexity increases
Solution Approach 1:
The patent segments the complex task of creating a humanized mouse model by introducing multiple human cytokine genes (hSCF, hGM-CSF, hIL-3, hCSF1) separately into the mouse genome. Each cytokine gene is inserted at specific loci to support different aspects of human hematopoietic stem cell engraftment and function, allowing systematic construction of the humanized model.
Solution Approach 2:
The genetically-modified mouse model serves multiple functions simultaneously: it supports human hematopoietic stem cell engraftment, enables tumor xenograft formation, and allows assessment of immunotherapy efficacy. The multi-cytokine expression system creates a universal platform that can evaluate various test substances across different cancer types and immunotherapies.
2Reliability
If human tumor cells are administered to immunodeficient mice to form xenografts, then the ability to assess anti-tumor activity is improved, but the measurement precision of immune system interactions is worsened
Solution Approach 1:
The patent applies local quality by creating localized human immune cell populations within specific tissues and organs of the mouse host. Human hematopoietic stem cells engraft and differentiate into human immune cells in specific microenvironments, allowing study of immune-tumor interactions at localized sites while maintaining overall mouse physiology.
Solution Approach 2:
The patent uses human hematopoietic stem cells as intermediaries to bridge the mouse host system and human tumor cells. These stem cells differentiate into human immune cells that mediate the interactions with human tumors, enabling indirect study of human immune system responses to cancer in an in vivo setting.
3Reliability
If multiple human cytokine genes are introduced into mouse genome, then the engraftment of human hematopoietic stem cells is improved, but the manufacturing precision of the genetic modification decreases
Solution Approach 1:
The patent employs preliminary action by using targeted gene insertion methods to pre-establish specific genomic loci for cytokine gene integration before introducing human hematopoietic stem cells. The genetic modifications are performed in advance to create a prepared host environment that optimally supports subsequent human cell engraftment and cytokine production.
Solution Approach 2:
The patent creates copies of human cytokine genes (hSCF, hGM-CSF, hIL-3, hCSF1) and inserts them into the mouse genome. These genetic copies enable the mouse to produce human cytokines that mimic the human physiological environment, supporting human hematopoietic stem cell engraftment without requiring actual human tissue transplantation.
Data Source
AI summary
A method of identifying anti-tumor activity of a test substance is provided along with a genetically-modified, immunodeficient mouse and methods of use, wherein the genetically-modified, immunodeficient mouse enables in vivo investigation of the interactions between the human immune system and human cancer.