Multi-Antigen CAR T-Cell Design Against Antigen Escape
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Solution Overview
Problem
Current chimeric antigen receptor (CAR) T-cell therapies for T-cell malignancies face challenges such as antigen target selection, CAR design, tumor heterogeneity, and immunosuppressive microenvironments, leading to immune escape and limited efficacy, particularly in relapsed B-cell malignancies.
Innovation Solution
Development of engineered T cells with chimeric antigen receptors comprising a signal peptide, antigen recognition domain, hinge region, transmembrane domain, signaling domain, and co-stimulatory domain, utilizing FcER1A, CD19, BCMA, or CD45, with high-efficiency cleavage sites and multiple antigen recognition domains to enhance targeting and overcome immunosuppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If single antigen CAR T cells are used, then initial remission rates are high, but relapse occurs due to antigen escape
Solution Approach 1:
The patent applies multi-functionality by engineering CAR T cells to recognize and bind to multiple different antigens simultaneously (e.g., CD19, CD20, CD22). This allows a single CAR T cell product to target multiple B-cell malignancy antigens, preventing antigen escape and extending remission duration while maintaining high initial remission rates.
2Reliability
If CAR proteins are overexpressed to enhance targeting, then tumor cell recognition improves, but toxicity to cells increases
Solution Approach 1:
The patent applies parameter changes by optimizing the expression level of CAR proteins on T cell surfaces. Instead of maximizing expression, the invention identifies an optimal expression range that provides sufficient tumor cell recognition and binding affinity while avoiding the toxic effects associated with overexpression, thus balancing efficacy and safety.
3Reliability
If CAR T cells are engineered with multiple domains, then targeting capability improves, but design complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the CAR structure into distinct functional domains: an extracellular antigen recognition domain (single-chain variable fragment), a transmembrane domain for membrane anchoring, and an intracellular signaling domain for T cell activation. This modular segmentation allows for systematic design and optimization of each domain's function while managing overall design complexity.
4Device complexity
If scFv is used as the antigen recognition domain, then CAR structure is simplified, but binding affinity and function are limited
Solution Approach 1:
The patent applies parameter changes by optimizing the single-chain variable fragment (scFv) parameters including amino acid sequence selection, length optimization, and structural configuration. These parameter optimizations enhance the binding affinity and functional efficacy of the scFv while maintaining the simplified CAR structure, thus improving reliability without significantly increasing complexity.
Data Source
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AI summary
The present disclosure provides chimeric antigen receptors, compositions, and methods thereof. In one embodiment the present disclosure provides a method of treating autoimmune diseases, asthma, and preventing or mediating organ rejection in a subject.