Hypoimmunogenic Cell Engineering for Allogeneic Persistence
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Solution Overview
Problem
The vigorous host-versus-graft immune response against histoincompatible cells prevents the expansion and persistence of allogeneic cells in cell-based therapies, limiting their efficacy in treating various disorders.
Innovation Solution
Engineered cells with reduced expression of MHC class I and/or MHC class II molecules and increased expression of CD47, achieving a threshold level or higher, to evade immune detection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If allogeneic cells are used for cell-based therapy, then ease of manufacturing and quality control are improved, but host-versus-graft immune response prevents expansion and persistence of the cells
Solution Approach 1:
The patent applies parameter changes by modifying the expression levels of specific surface molecules on allogeneic cells. By reducing MHC class I and/or class II expression and increasing CD47 expression, the cells acquire hypoimmunogenic properties that allow them to evade host immune detection while maintaining manufacturing advantages
Solution Approach 2:
The patent converts the harmful host-versus-graft immune response into a benefit by engineering cells with hypoimmunogenic characteristics. The high CD47 expression mimics 'do not eat me' signals to macrophages, while reduced MHC expression minimizes T cell recognition, effectively turning the immune system's attack mechanism into a tolerance mechanism
2Object-affected harmful factors
If MHC class I and/or class II expression is reduced to evade immune detection, then immune recognition is decreased, but cell visibility to immune system may be compromised
Solution Approach 1:
The patent applies local quality by differentially modifying specific molecular characteristics of the cell surface while maintaining others. Rather than uniformly altering all cell surface properties, it specifically reduces MHC class I and/or class II expression while independently increasing CD47 expression, creating localized immunomodulatory effects
3Reliability
If CD47 expression is increased to prevent phagocytosis, then immune evasion is improved, but cell identity and regulation may be altered
Solution Approach 1:
The patent applies partial or excessive action by achieving sufficient immune evasion through moderate increases in CD47 expression rather than complete suppression of all immune pathways. The engineered cells express CD47 at elevated but physiologically reasonable levels, providing adequate protection against phagocytosis without causing excessive immunomodulation
Data Source
AI summary
Disclosed herein are engineered cells and/or hypoimmunogenic cells including engineered cells and/or hypoimmunogenic stem cells, engineered cells and/or hypoimmunogenic cells differentiated therefrom, and/or engineered cells and/or hypoimmunogenic CAR-T cells (primary or differentiated from engineered and/or hypoimmunogenic stem cells) and related methods of their use and generation comprising regulatable reduced expression of one or more MHC class I and/or MHC class II human leukocyte antigen molecules and regulatable overexpression of CD47. Provided herein are cells further exhibiting reduced expression of T-cell receptors.