CAR T Cells with Intermediate Affinity for Selective Targeting
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Solution Overview
Problem
Current CAR T-cell therapies face challenges in specifically targeting cancer cells while minimizing off-target effects on normal tissues due to potential expression of target antigens in non-diseased tissues, leading to unwanted cytotoxicity.
Innovation Solution
Development of CAR T cells with intermediate antigen affinity, allowing selective cytotoxic activity only upon multivalent binding to cells with high antigen expression, and adjusting CAR expression levels to reduce off-target cytotoxicity, using transgenic cells with CARs having a dissociation constant (Kd) between 5 nM and 500 nM, and administering these cells to selectively target cells with elevated antigen expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells with high antigen affinity are used, then cytotoxic activity against target cells is improved, but off-target effects on normal tissues increase
Solution Approach 1:
The patent applies parameter changes by adjusting the dissociation constant (Kd) of the CAR antigen-binding domain to an intermediate range (5-500 nM). This parameter optimization allows the CAR T cells to achieve sufficient cytotoxic activity against high antigen-expressing tumor cells while reducing binding to and damage of normal cells with lower antigen expression levels.
2Productivity
If CAR expression level is increased, then targeting efficiency is improved, but off-target cytotoxicity increases
Solution Approach 1:
The patent optimizes the CAR expression level parameter to achieve an intermediate state that balances targeting efficiency and safety. By controlling the density of CAR molecules on the T cell surface, the system achieves effective targeting of high antigen-expressing cells while the intermediate expression level prevents excessive binding to normal cells, thereby reducing off-target cytotoxicity.
Data Source
AI summary
Chimeric antigen receptors (CARs) and CAR-expressing T cells are provided that can specifically target cells that express an elevated level of a target antigen. Likewise, methods for specifically targeting cells that express elevated levels of antigen (e.g., cancer cells) with CAR T-cell therapies are provided.