Universal CAR T Cell Therapy with Protease-Sensitive Linker
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Solution Overview
Problem
Current cancer immunotherapies face challenges in targeting antigens uniquely expressed on tumor tissue without affecting normal cells, and generating TCR or antibodies specific to each patient's unique tumor neoantigens is difficult and costly.
Innovation Solution
Development of a universal CAR T cell therapy system using a binding molecule with a recognition domain linked to a protection domain, where the recognition domain is masked by a protease-sensitive or pH-sensitive polymer, allowing activation only at tumor sites by local proteases or acidic pH, enabling targeted immune responses without off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are used to target tumor antigens, then immune responses against tumors are generated, but off-target activation affecting normal cells occurs
Solution Approach 1:
A protease-sensitive linker peptide serves as an intermediary between the targeting moiety and the effector domain. This linker is cleaved by tumor-associated proteases (such as MMPs or cathepsins) to activate the CAR T cell only at the tumor site, preventing off-target activation against normal cells while maintaining tumor-specific immune responses
Solution Approach 2:
The system exploits parameter changes in the tumor microenvironment, specifically the presence of elevated protease activity or acidic pH conditions. The protease-sensitive linker changes its cleavage state in response to these parameter changes, enabling selective activation of CAR T cells only in the tumor environment where proteases are overexpressed
2Adaptability or versatility
If TCR or antibodies are generated for each patient's unique tumor neoantigens, then patient-specific tumor targeting is achieved, but the process becomes difficult and costly
Solution Approach 1:
The patent employs universal CAR T cell constructs that can target any tumor expressing specific proteases (such as MMPs or cathepsins), which are commonly overexpressed across multiple tumor types. This universal approach eliminates the need to generate patient-specific TCRs or antibodies for each neoantigen, while still achieving tumor-specific targeting through the protease-sensitive linker mechanism
Solution Approach 2:
The system utilizes the universal parameter of protease overexpression in the tumor microenvironment across different cancer types. By designing CAR T cells with protease-sensitive linkers that respond to this universal parameter change, the therapy achieves adaptability to various tumors without requiring complex patient-specific antigen characterization and TCR/antibody generation
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 allows for specific tumor targeting with CAR T cells, generating immune responses against tumors without prior knowledge of neoantigens, reducing off-target activation and making the therapy more patient-specific and cost-effective.
Implementation Method 1
the recognition domain is masked by a protease-sensitive or pH-sensitive polymer, allowing activation only at tumor sites by local proteases or acidic pH
Implementation Method 2
the recognition domain is masked by a protease-sensitive or pH-sensitive polymer, allowing activation only at tumor sites by local proteases or acidic pH
Data Source
AI summary
The present invention provides universal immunotherapy compositions useful for targeted treatment of cancers and other immune disorders.