ADR T-Cell Receptors for Selective Activated T-Cell Elimination
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Solution Overview
Problem
Current treatments for unwanted activation of T- and NK-cells in transplant patients and autoimmune conditions are ineffective, leading to immune rejection and immunodeficiency, with a lack of methods to selectively eliminate pathogenic cells.
Innovation Solution
Engineering adoptive T-cells to express chimeric auto/allo-immune defense receptors (ADRs) that target activated pathogenic T and NK cells, allowing for selective elimination while sparing resting cells, and providing these cells with signaling domains for activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If allogeneic cells are used for adoptive transfer, then cell availability and productivity are improved, but immune rejection by host T-cells and NK-cells occurs
Solution Approach 1:
The patent exploits the harmful activation markers (OX40, 4-1BB, CD40L) expressed by pathogenic T-cells and NK-cells to create the ADR system. The ADR is designed to recognize these very markers that indicate cell activation and pathogenicity, converting the harmful immune response indicators into beneficial targeting signals that enable selective elimination of harmful cells while preserving normal cells
Solution Approach 2:
The ADR acts as an intermediary molecule between the therapeutic cells and the pathogenic immune cells. It comprises an extracellular domain that recognizes activation markers on pathogenic cells and an intracellular signaling domain that triggers cytotoxic activity, serving as a bridge that enables selective targeting without requiring direct recognition by the therapeutic cells
2Object-affected harmful factors
If immunosuppressive drugs are used to treat allo-immune reactions, then immune rejection is reduced, but immunodeficiency and susceptibility to infections occur
Solution Approach 1:
The ADR system applies local quality by enabling selective action only against activated pathogenic cells that express specific markers (OX40, 4-1BB, CD40L). Resting normal T-cells and NK-cells that do not express these markers are spared, allowing the system to eliminate harmful immune responses locally at the site of pathogenic activity without causing systemic immunodeficiency
Solution Approach 2:
The system applies partial action by targeting only the subset of immune cells that are activated and expressing pathogenic markers, rather than suppressing the entire immune system. This partial targeting approach eliminates the harmful immune response while preserving the beneficial immune functions of resting cells
3Object-affected harmful factors
If activated pathogenic T-cells are selectively targeted, then allo-immune reactions are controlled, but resting T-cells must be spared to maintain immune function
Solution Approach 1:
The ADR system achieves local quality by differentiating between activated and resting T-cells based on the presence of specific surface markers. The extracellular domain of the ADR is designed to recognize activation markers (OX40, 4-1BB, CD40L) that are only expressed on activated pathogenic cells, ensuring that cytotoxic activity is triggered only against these activated cells while resting cells expressing different marker profiles are spared
Data Source
AI summary
Embodiments of the disclosure concern engineered auto/allo-immune defense receptor (ADR)-expressing T cells that selectively target activated T cells, including pathogenic T cells, to incapacitate them. The chimeric receptors comprise moieties for targeting 4-1BB, 0X40, and CD40L, for example, whose expression is indicative of activated T cells. In particular embodiments, there are methods of preventing or treating conditions associated with activated T cells using adoptive T-cell transfer of cells encoding the ADRs.