Engineered Immunosuppressive Cell Surface Receptors for Graft Rejection
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Solution Overview
Problem
Current cell therapies, particularly allogeneic therapies, face significant immune rejection issues due to immunogenicity of gene-edited cells, leading to severe side effects and reduced persistence of therapeutic cells, necessitating improved methods to suppress immune rejection without lymphocyte depletion.
Innovation Solution
Development of an immunosuppressive molecule comprising an immunosuppressive protein binding domain, transmembrane domain, and co-stimulatory domain, which binds to multiple immunosuppressive proteins (e.g., NKG2A, TIM3, LAG3, TIGIT, CTLA4, PD1, FasL) to suppress immune cell function and proliferation, thereby reducing immune rejection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If allogeneic therapy is used, then production cost is reduced and waiting time is shortened, but immune rejection reaction occurs
Solution Approach 1:
The patent converts the harmful immune rejection reaction into a beneficial outcome by engineering therapeutic cells to express immunosuppressive molecules. These molecules actively suppress host immune cells, transforming the host's immune system from a harmful force into a controlled environment that supports therapeutic cell persistence and function.
Solution Approach 2:
The patent changes the immunological parameters of therapeutic cells by introducing engineered immunosuppressive molecules with specific binding affinities to multiple immunosuppressive proteins. This parameter change enables the cells to resist immune rejection while maintaining their therapeutic function, resolving the contradiction between allogeneic therapy benefits and immune rejection risks.
2Object-affected harmful factors
If lymphocyte depletion is performed, then immune rejection reaction is reduced, but severe side effects occur
Solution Approach 1:
The patent introduces an intermediary mechanism - engineered immunosuppressive molecules expressed on therapeutic cells - that mediates the suppression of host immune cells. This intermediary approach replaces the harsh lymphocyte depletion method with a targeted, cell-specific immunosuppression strategy that achieves the same goal without the severe side effects of systemic lymphocyte depletion.
3Object-affected harmful factors
If gene editing is used to knock out TCR genes or HLA class I molecules, then graft rejection is reduced, but immunogenicity remains and other immune cells trigger responses
Solution Approach 1:
The patent segments the approach to reducing graft rejection by focusing specifically on enhancing immunosuppressive molecule expression rather than knocking out essential genes like TCR or HLA class I. This segmented strategy maintains the necessary immunogenicity for therapeutic function while selectively suppressing rejection through multiple immunosuppressive pathways (NKG2A, TIM3, LAG3, TIGIT, CTLA4, PD1, FasL).
Data Source
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AI summary
An immunosuppressive molecule comprising an immunosuppressive protein binding domain, a transmembrane domain and a co-stimulatory domain and the molecule does not comprise a primary signaling domain, wherein the immunosuppressive protein is selected from two or more of NKG2A, TIM3, LAG3, TIGIT, CTLA4, PD1 and FasL. An engineered cell expressing the immunosuppressive molecule and a composition comprising the engineered cell. A method for reducing immune rejection using the immunosuppressive molecule.