Chimeric T-Cell Modulators for In Vivo CAR Expression
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Solution Overview
Problem
Current methods for modulating T cell responses are limited in their specificity and efficiency, particularly in activating T cells to target cancer cells, as they rely on epitope-specific T cell receptor binding and costimulatory protein interactions that are not always sufficient for effective cancer treatment.
Innovation Solution
A chimeric molecule comprising a T-cell modulatory multimeric polypeptide (TMMP) and a nucleic acid component encoding a chimeric antigen receptor (CAR) that binds to cancer-associated antigens, allowing T cells to express the CAR on their surface and enhance their cytotoxic activity against cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current methods for modulating T cell responses are used, then T cell activation can be achieved through epitope-specific TCR binding and costimulatory protein interactions, but the specificity and efficiency for targeting cancer cells is insufficient
Solution Approach 1:
The patent combines a T-cell modulatory multimeric polypeptide (TMMP) that provides epitope-specific TCR binding with a nucleic acid component encoding a chimeric antigen receptor (CAR) in a single chimeric molecule. This merging allows simultaneous delivery of both T cell activation signals and CAR expression instructions to target T cells, thereby improving both the specificity through dual recognition mechanisms and the efficiency of cancer cell targeting
2Reliability
If in vitro modification of T cells is performed to express CAR, then CAR expression on T cell surface is achieved, but the process complexity and time required increases
Solution Approach 1:
The chimeric molecule is designed to be taken up by target T cells autonomously, where the T cells themselves perform the function of incorporating the nucleic acid component and expressing the CAR on their surface. This self-service mechanism eliminates the need for complex in vitro modification procedures, reducing process complexity while ensuring reliable CAR expression
3Reliability
If only epitope-specific TCR binding is used for T cell activation, then T cell specificity is maintained, but the activation signal is insufficient for effective cancer treatment
Solution Approach 1:
The chimeric molecule performs multiple functions: the TMMP component provides epitope-specific TCR binding for specificity, while the nucleic acid component encodes a CAR that provides additional targeting capability and activation signaling. This multi-functionality ensures both T cell specificity is maintained and the activation signal is sufficiently strong for effective cancer treatment
Data Source
AI summary
The present disclosure provides a chimeric molecule comprising: a) a T-cell modulatory multimeric polypeptide (TMMP); and b) a nucleic acid component, where the nucleic acid component comprises a nucleic acid comprising a nucleotide sequence encoding a chimeric antigen receptor (CAR) comprising an antibody that binds a cancer-associated antigen. The TMMP binds to and activates a target T cell; the nucleic acid component is taken up by the target T cell such that the target T cell expresses the CAR on its surface. The present disclosure provides methods of making the chimeric molecule. The present disclosure provides treatment methods comprising administering the chimeric molecule.