CAR-Treg Fusion Protein for Targeted HvG Rejection Suppression
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Solution Overview
Problem
Current treatments for Host-versus-Graft (HvG) disease, which occurs in transplant recipients, are inadequate in suppressing the host's immune response against the transplant, particularly when the transplant expresses MHC class I molecules like HLA-A*02 or SLA-01*0401, leading to cytotoxic rejection.
Innovation Solution
A fusion protein, specifically a chimeric antigen receptor (CAR) is expressed in regulatory T-cells (Tregs) that are HLA-A*02 or SLA-01*0401 negative, comprising a single-chain variable fragment antibody domain (scFv), a hinge, a transmembrane domain, and intracellular signaling domains, enabling targeted suppression of cytotoxic T-cells against the transplant.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used to suppress host immune response against transplant, then immune rejection occurs, but the treatments are inadequate in suppressing cytotoxic T-cell responses
Solution Approach 1:
The patent introduces CAR-expressing regulatory T-cells as intermediary cells that specifically recognize and suppress cytotoxic T-cells targeting the transplant. These engineered Tregs act as mediators between the host immune system and the transplant, providing targeted suppression of harmful cytotoxic responses while preserving overall immune function.
Solution Approach 2:
The patent modifies regulatory T-cells by introducing chimeric antigen receptor (CAR) genes, changing their parameter of antigen specificity. This transforms ordinary Tregs into specialized cells that can recognize specific transplant antigens (HLA-A*02 or SLA-01*0401) and exert targeted suppressive effects, overcoming the inadequacy of conventional treatments.
2Reliability
If CAR-expressing Tregs are used to suppress cytotoxic T-cell responses, then immune rejection is reduced, but the treatment requires in vitro expansion which complicates the process
Solution Approach 1:
The patent performs preliminary genetic modification of regulatory T-cells ex vivo to express CAR receptors, equipping them with specific antigen recognition capability before adoptive transfer. This preliminary action ensures that the transferred cells are immediately functional and can rapidly suppress cytotoxic T-cell responses without requiring further in vitro expansion, thereby reducing process complexity.
3Adaptability or versatility
If conventional immunosuppression is used, then general immune response is suppressed, but it cannot specifically target cytotoxic T-cells against the transplant
Solution Approach 1:
The patent endows regulatory T-cells with localized specificity by equipping them with chimeric antigen receptors that recognize only specific transplant antigens (HLA-A*02 or SLA-01*0401). This creates local quality in the immune suppression - the Tregs exert suppressive effects specifically at the interface between host immune cells and transplant cells expressing the target antigen, rather than causing global immunosuppression.
Solution Approach 2:
The patent fundamentally changes the parameter of antigen specificity in regulatory T-cells by introducing CAR genes. This transforms non-specific Tregs into highly specific cells that can distinguish between self and transplant antigens, enabling adaptable and targeted immune suppression that conventional immunosuppressants cannot achieve.
Data Source
AI summary
A fusion protein for use in the treatment of HvG disease in a patient having received a transplant, for use in suppressing the host's immune response directed against the transplant. The fusion protein is adapted for use in suppressing the immune rejection of a transplant which contains or expresses HLA-A*02 or SLA-01*0401 in a recipient patient who is negative for HLA-A*02 or SLA-01*0401, i.e. the patient prior to transplantation does not express HLA-A*02 or SLA-01*0401. The fusion protein is a chimeric antigen receptor (CAR), which upon expression in regulatory T-cells (Treg) causes a specific suppressor activity of the regulatory T-cells in the presence of HLA-A*02 or SLA-01*0401.