Multi-CAR Engineered Cells Targeting T-Cell Malignancies
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Solution Overview
Problem
Current chimeric antigen receptor (CAR) therapies for T-cell malignancies face challenges such as antigen target selection, CAR design, and tumor heterogeneity, leading to immune escape and limited efficacy, particularly in T-cell malignancies with poorer outcomes compared to B-cell malignancies.
Innovation Solution
Development of engineered cells expressing multiple chimeric antigen receptors (CARs) with distinct antigen recognition domains, signal peptides, hinge regions, transmembrane domains, co-stimulatory domains, and signaling domains, allowing for simultaneous targeting of multiple antigens to enhance tumor recognition and reduce immune escape.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If single antigen CAR therapy is used, then treatment simplicity is maintained, but immune escape occurs leading to relapse
Solution Approach 1:
The patent combines multiple CAR units with different antigen recognition domains into a single engineered cell, creating a multi-CAR T cell that can simultaneously target multiple antigens. This merging approach prevents immune escape by ensuring that tumor cells must lose multiple antigens simultaneously to evade detection, thereby improving treatment reliability without requiring separate infusions of different CAR therapies
Solution Approach 2:
The engineered cell is designed with multi-functionality by incorporating multiple CAR units that recognize different antigens. This universal design allows a single cell population to target various tumor-associated antigens, making the therapy more robust against antigen heterogeneity and escape mechanisms while maintaining a unified treatment approach
2Reliability
If multiple CAR units are expressed in a single cell, then immune escape is reduced, but CAR design complexity increases
Solution Approach 1:
The patent segments the multi-CAR construct into distinct modular units, each containing an antigen recognition domain, hinge region, transmembrane domain, and signaling domain. These segmented modules can be independently designed and assembled, facilitating systematic optimization of each CAR unit while maintaining overall construct manageability and enabling standardized manufacturing approaches
Solution Approach 2:
The patent optimizes key parameters of the multi-CAR construct including signal peptide sequences for enhanced surface expression, hinge region compositions for improved antigen binding, and signaling domain configurations for optimized T cell activation. These parameter changes improve treatment durability while maintaining design through systematic optimization rather than arbitrary complexity
3Measurement precision
If CAR surface expression is increased, then tumor recognition sensitivity improves, but cellular toxicity increases
Solution Approach 1:
The patent systematically optimizes the signal peptide sequences to achieve optimal CAR surface expression levels that maximize tumor recognition sensitivity while avoiding the toxic effects of overexpression. This parameter optimization ensures sufficient antigen binding capacity without causing cellular stress or dysfunction
Solution Approach 2:
The patent employs different hinge region compositions for different CAR units within the same cell, allowing each CAR to be locally optimized for its specific antigen target. This local quality approach enables tailored expression levels and binding affinities for each antigen recognition domain, improving overall sensitivity while distributing expression burden to reduce toxicity
Data Source
AI summary
The present invention relates to compositions and methods relating to chimeric antigen receptor (CAR) polypeptides and methods relating thereto. In one embodiment, the present invention relates to engineered cells having chimeric antigen receptor polypeptides directed to at least two targets. In another embodiment, the present invention relates to engineered cells having chimeric antigen receptor polypeptides and an enhancer moiety.