Antigen-Specific Treg Engineering for CNS Autoimmunity
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Solution Overview
Problem
Current treatments for autoimmune and inflammatory central nervous system diseases, such as multiple sclerosis, primarily suppress the immune system generally, failing to specifically target and manage local immune responses associated with disease onset and progression, and lack antigen-specific suppression of immunopathology.
Innovation Solution
Engineering regulatory T cells (Tregs) by transferring specific T cell receptors (TCRs) to generate antigen-specific Tregs that can bind to myelin basic protein (MBP), allowing for targeted suppression of autoimmune responses in the central nervous system.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If general immune system suppression is used to treat autoimmune CNS diseases, then immune responses are reduced, but the treatment lacks specificity and causes systemic side effects
Solution Approach 1:
The patent applies local quality by engineering Tregs with antigen-specific TCRs (MBP-specific) that target only the specific autoimmune pathology in the CNS. This creates a localized, specific immune modulation rather than general suppression, allowing the treatment to act precisely where needed (in the CNS against MBP-specific pathogenic T cells) without affecting other immune functions systemically.
Solution Approach 2:
The patent segments the immune system by isolating and engineering a specific subset of T cells (Tregs) with a particular antigen specificity (MBP-TCR). This segmentation allows selective modulation of the specific pathogenic pathway without affecting other immune responses, thereby achieving treatment effectiveness while avoiding systemic side effects.
2Reliability
If bone marrow transplantation with cytostatics and immunosuppressive drugs is performed, then immune suppression is achieved, but the procedure requires aggressive myelo-ablative conditioning with substantial toxicity and risk
Solution Approach 1:
The patent extracts the essential immune suppression function from the complex and toxic bone marrow transplantation procedure. By isolating and engineering Tregs ex vivo with specific TCRs, the invention removes the need for aggressive myelo-ablative conditioning and extensive immunosuppressive drug regimens, achieving the therapeutic effect through a simplified, less toxic approach.
Solution Approach 2:
The engineered Tregs function as a targeted, self-limiting therapeutic agent that delivers immune suppression precisely where needed without requiring the long-term, high-dose immunosuppression and bone marrow reconstitution of transplantation. The Tregs provide localized control and can be administered without the substantial toxicity and risk associated with myelo-ablative conditioning.
3Reliability
If TCRs with high affinity for self antigen are used in Tregs, then antigen-specific suppression is enhanced, but TCR expression in Tregs may be less efficient
Solution Approach 1:
The patent applies parameter changes by selecting and engineering TCRs with optimized affinity parameters for MBP. The inventors identified TCRs that balance sufficient binding affinity to MBP-peptide/MHC complexes (to ensure effective recognition and suppression of pathogenic T cells) with expression efficiency in Tregs. This optimization of the affinity parameter resolves the contradiction between suppression efficiency and ease of manufacture.
Data Source
AI summary
The present invention relates to an engineered regulatory T cell (Treg) comprising a T cell receptor (TCR) which is capable of specifically binding to a myelin basic protein (MBP) peptide or variant or fragment thereof when the peptide is presented by a major histocompatibility complex (MHC) molecule. The present invention further relates to methods for providing an engineered Treg and to methods and uses of said engineered Treg and vectors and kits of vectors encoding said Treg.