Chimeric Receptor Treg Cells for Antigen-Specific Immune Suppression
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Solution Overview
Problem
Current treatments for autoimmune and inflammatory diseases, such as inflammatory bowel disease (IBD) and graft rejection, are limited in effectiveness due to the inability to specifically target and suppress T-effector cell-mediated immune responses at the site of inflammation.
Innovation Solution
The development of an immunoregulatory pharmaceutical composition that utilizes genetically engineered T regulatory cells (Tregs) with chimeric receptors (CRs) specific for target antigens, allowing for antigen-specific activation and suppression of T-effector cells at the site of inflammation, independent of MHC restriction and costimulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional Treg cells are used for treatment, then they can suppress immune responses, but they cannot specifically target and accumulate at the site of inflammation
Solution Approach 1:
The chimeric receptor on Treg cells enables them to detect target antigens at the inflammation site and activate suppressive functions in response to antigen presence, creating a feedback mechanism that directs Treg accumulation and activation precisely where needed
Solution Approach 2:
The patent creates Treg cells with heterogeneous properties - they express chimeric receptors that confer antigen-specific targeting capability, allowing a subset of Tregs to selectively accumulate at inflammation sites while maintaining their suppressive function, rather than treating all Tregs uniformly
2Reliability
If conventional Treg cells are used, then they can suppress T-effector cells, but they require MHC restriction and costimulation which limits their effectiveness
Solution Approach 1:
The chimeric receptor design extracts the antigen recognition function from the conventional TCR-MHC interaction system, using antibody-derived single-chain variable fragments that can bind antigens directly without requiring MHC presentation, thereby eliminating MHC restriction and costimulation requirements
Solution Approach 2:
The patent fundamentally changes the activation parameters of Treg cells by replacing the conventional TCR signaling pathway with chimeric receptor signaling, allowing activation through direct antigen binding without the need for MHC restriction or costimulatory signals
3Reliability
If current treatments are used for autoimmune diseases, then they can provide some symptom relief, but they are limited in effectiveness due to inability to specifically target T-effector cell-mediated responses
Solution Approach 1:
The chimeric receptor acts as an intermediary that bridges the Treg cell and the target antigen, enabling specific recognition and suppression of T-effector cell-mediated responses at the inflammation site while maintaining the therapeutic suppressive function of Tregs
Solution Approach 2:
The patent creates a universal therapeutic approach where Treg cells engineered with chimeric receptors can be applied to treat various autoimmune and inflammatory diseases by targeting different antigens, making the therapy adaptable across multiple disease indications
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
This approach enables site-specific accumulation and activation of Tregs, leading to the production of suppressive cytokines that alleviate symptoms and treat autoimmune and inflammatory conditions by suppressing T-effector cells in an antigen-nonspecific manner, potentially curing or alleviating diseases like IBD.
Implementation Method 1
a cell comprises a chimeric nucleic acid that encodes a chimeric receptor (CR) polypeptide that comprises, expressed in a single, continuous chain, an extracellular recognition region, a transmembrane region and an intracellular signaling region... the extracellular recognition region of the chimeric receptor is specific for the selected target antigen
Implementation Method 2
the intracellular region comprises a combination of T-cell signaling polypeptide moieties which combination of moieties comprises one or more cytoplasmic domains of a costimulatory molecule, and a cytoplasmic T-cell stimulatory domain, and which combination of moieties, upon binding of the extracellular recognition region to the selected target antigen, triggers activation of the Treg cells
Implementation Method 3
which combination of moieties, upon binding of the extracellular recognition region to the selected target antigen, triggers activation of the Treg cells to cause suppression of T-cell mediated immunity
Data Source
Figure 1A~1B
Figure 2
Figure 3
AI summary
A redirected Treg cell is endowed with specificity toward a selected target antigen or ligand. The cell contains a chimeric receptor polypeptide that is expressed in a single, continuous chain, with an extracellular recognition region displayed on the surface of the cell, a transmembrane region and an intracellular signaling region. The extracellular recognition region is specific for the selected target antigen or ligand. The intracellular signaling region includes a combination of T-cell signaling polypeptide moieties, which combination, upon binding of the extracellular recognition region to the selected target antigen or ligand, triggers activation of the redirected Treg cells to cause suppression of T-cell mediated immunity. Such redirected Treg cells may be used to suppress undesired activity of T effector cells thereby mediating an immune or inflammatory response. They are particularly useful in treating T effector cell-mediated diseases, such as inflammatory bowel disease, transplant rejection and GVH disease.