Cereblon-Based Heterodimerizable CARs for Selective T Cell Activation
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Solution Overview
Problem
Current chimeric antigen receptors (CARs) for T lymphocytes lack selective control over activation, leading to potential off-tumor effects due to the requirement of only a primary signal for activation, which can result in unintended targeting of healthy cells expressing tumor-associated antigens.
Innovation Solution
Design of CARs comprising two polypeptides, one with cereblon and the other with a cereblon-associated protein, which form a heterodimer upon binding a cereblon-binding compound, allowing for selective activation by providing both primary and costimulatory signals, thereby controlling CAR activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CARs use only a primary signal for activation, then the activation response is strong and rapid, but off-tumor effects occur due to lack of selective control
Solution Approach 1:
The CAR activation system is segmented into two separate functional components: a primary signal component (CD3ζ signaling domain) and a costimulatory signal component (CD28 or ICOS domain). These are divided between the first and second polypeptides, requiring both signals to be provided separately - one through antigen binding and the other through cereblon-binding compound binding - thereby achieving selective control while maintaining strong activation response.
2Object-affected harmful factors
If CARs require both primary and costimulatory signals, then selective control and reduced off-tumor effects are achieved, but the activation control mechanism becomes more complex
Solution Approach 1:
The CAR is divided into two separate polypeptides: the first polypeptide contains the antigen-binding domain and primary signaling domain (CD3ζ), while the second polypeptide contains the costimulatory domain (CD28 or ICOS). This segmentation allows independent optimization of each component's function and enables selective activation only when both polypeptides are present and bound to their respective ligands, reducing off-tumor effects.
Solution Approach 2:
The cereblon-binding compound acts as an intermediary molecule that mediates the formation of the heterodimer between the first and second polypeptides. By binding to cereblon in the first polypeptide and facilitating interaction with the cereblon-associated protein in the second polypeptide, the cereblon-binding compound serves as a controlled mediator that enables selective activation only in the presence of the compound, thereby reducing off-tumor effects.
3Reliability
If CARs are designed with heterodimerizable polypeptides, then selective activation control is achieved, but the manufacturing and expression complexity increases
Solution Approach 1:
The CAR construct is segmented into two separate polypeptides that can be expressed independently in the T cells. The first polypeptide is encoded by a first nucleic acid and the second polypeptide by a second nucleic acid, allowing flexible manufacturing and expression strategies. This segmentation enables selective activation through heterodimerization only when both polypeptides are expressed, achieving reliable selective activation.
Solution Approach 2:
The CAR system incorporates dynamic heterodimerization through the cereblon-cereblon-associated protein interaction that is modulated by the cereblon-binding compound. The heterodimer formation is dynamic and reversible, allowing the CAR to transition between active and inactive states based on the presence of the activating compound. This dynamic control mechanism achieves selective activation while maintaining manufacturing flexibility.
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
This approach enables precise activation of CAR-expressing immune cells only in the presence of specific antigens and a cereblon-binding compound, reducing off-tumor effects and enhancing targeted therapy.
Implementation Method 1
the cereblon (or functional portion thereof) of the first polypeptide and cereblon-associated protein (or functional portion thereof) of the second polypeptide bind the cereblon-binding compound resulting in formation of a heterodimer with CAR function
Data Source
AI summary
Provided herein are modified T lymphocytes comprising chimeric receptors and methods thereof.