Engineered Treg With MBP-Specific TCR for Autoimmune CNS Targeting
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Solution Overview
Problem
Current treatments for autoimmune and inflammatory central nervous system (CNS) diseases, such as multiple sclerosis, primarily suppress the immune system generally, failing to specifically target and manage local immune responses, leading to ongoing disease progression and significant toxicity in treatments like stem cell transplantation.
Innovation Solution
Engineering regulatory T cells (Tregs) with specific T cell receptors (TCRs) capable of binding to myelin basic protein (MBP), using retroviral transfer of MBP-TCR and FOXP3 genes into Tregs to suppress autoimmune responses in the CNS, with the TCRs comprising specific α and β chains and additional cysteine residues for enhanced stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If general immune system suppression is used to treat autoimmune CNS diseases, then immune-mediated damage is reduced, but specificity is lost and systemic side effects occur
Solution Approach 1:
The patent applies local quality by engineering Tregs with antigen-specific TCRs that target only CNS-associated antigens (MBP, PLP, MOG) rather than suppressing the entire immune system. This localized approach suppresses autoimmune responses specifically in the CNS while preserving systemic immune function, thereby reducing off-target side effects.
Solution Approach 2:
The patent changes the parameter of Treg specificity by modifying the TCR repertoire through genetic engineering. By introducing TCR genes specific to CNS antigens and optimizing CDR3 sequences, the Tregs acquire enhanced antigen recognition capability, transforming them from polyclonal to antigen-specific suppressors.
2Object-affected harmful factors
If bone marrow transplantation with immunosuppressive drugs is used, then immune system is reset, but toxicity and risk increase substantially
Solution Approach 1:
The patent extracts the essential function of immune reset (suppressing autoimmune responses) without requiring aggressive myelo-ablative conditioning. By directly engineering Tregs with antigen-specific TCRs and transferring them systemically, the therapy achieves immune modulation without the toxicities of bone marrow transplantation.
Solution Approach 2:
The patent creates a simplified copy of the immune reset function by transferring engineered Tregs rather than performing full bone marrow transplantation. These engineered Tregs replicate the protective effect of a reset immune system by providing antigen-specific suppression without requiring destruction and regeneration of the entire hematopoietic system.
3Adaptability or versatility
If exogenous TCRs are expressed in Tregs, then antigen specificity is achieved, but expression success is unpredictable
Solution Approach 1:
The patent changes the structural parameters of the TCR by optimizing the CDR3 sequences and adding cysteine residues at specific positions (48 in alpha chain, 57 in beta chain). These modifications enhance stability and expression levels, transforming unpredictable TCR expression into a reliable process.
Solution Approach 2:
The patent creates a composite TCR structure by combining optimized variable regions with modified constant regions containing additional cysteine residues. This composite design enhances overall TCR stability and expression, ensuring reliable antigen specificity in engineered Tregs.
4Object-affected harmful factors
If current disease-modifying treatments are used, then clinical relapses are reduced, but CNS-specific suppression of immunopathology is not achieved
Solution Approach 1:
The patent applies local quality by engineering Tregs with TCRs specific to CNS antigens (MBP, PLP, MOG) rather than using non-specific immunosuppressants. This enables targeted suppression of autoimmune responses in the CNS while preserving systemic immune function, achieving both relapse reduction and CNS-specific targeting.
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
The engineered Tregs specifically target and suppress autoimmune responses in the CNS, potentially offering a more effective and safer approach to managing diseases like multiple sclerosis by reducing immunopathology without systemic side effects.
Implementation Method 1
by retroviral transfer of MBP-TCR genes into purified Tregs and/or by retroviral transfer of MBP-TCR and forkhead box P3 (FOXP3) genes into conventional CD4+ T cells
Implementation Method 2
The TCR may be capable of specifically binding to a peptide which comprises at least 90% identity to MBP 82-102 (SEQ ID NO: 12) or a fragment thereof when the peptide is presented by a major histocompatibility complex (MHC) molecule
Implementation Method 3
The constant region domains of the α chain and β chain of the TCR may each comprise an additional cysteine residue, enabling the formation of an extra disulphide bond between the α chain and the β chain
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.