Protease-Cleavable Linker for Activatable CAR-T Receptors
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Solution Overview
Problem
Current adoptive T cell therapy for cancer faces limitations due to treatment-related toxicities, specificity issues, and off-target effects, particularly in solid tumors, where conventional CAR-T cells target antigens also expressed in healthy tissues, leading to on-target off-tumor toxicities and complex production processes.
Innovation Solution
Development of antigen binding receptors with a protease-cleavable peptide linker connecting a masking moiety, such as a mutated Fc domain, and an antigen binding moiety, which are specifically activated by proteases in the tumor microenvironment, allowing targeted binding to therapeutic antibodies with mutated Fc domains, reducing off-target effects and enhancing tumor specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR-T cells target epithelial tumor antigens, then tumor targeting capability is achieved, but on-target off-tumor toxicities occur due to antigen expression in normal tissues
Solution Approach 1:
The CAR-T cell receptor is designed to be dynamically activated only in the presence of specific proteases (such as cathepsin B) that are overexpressed in the tumor microenvironment. The receptor contains a protease-sensitive linker that cleaves upon encountering the protease, triggering activation. This dynamic activation mechanism ensures that CAR-T cells remain inactive in normal tissues lacking the activating protease, thereby eliminating off-tumor toxicities while maintaining tumor targeting capability.
Solution Approach 2:
The invention applies local quality by confining CAR-T cell activation to specific spatial locations where proteases are present - namely the tumor microenvironment. The protease-sensitive linker ensures that the receptor only becomes active locally where the activating protease is available, creating a localized therapeutic effect that spares normal tissues from unintended activation and toxicity.
2Productivity
If CAR-T cells are activated in response to tumor antigens, then tumor lysis is achieved, but treatment-related toxicities and off-target effects increase
Solution Approach 1:
The invention introduces an intermediary mechanism - the protease-sensitive linker - that mediates between the CAR-T cell receptor and its activation. This linker acts as a gatekeeper that only opens (cleaves) when the activating protease is present, thereby controlling and limiting activation to appropriate contexts. This intermediary layer prevents direct, uncontrolled activation that would lead to toxicities while still allowing productive tumor lysis when the protease is available.
3Reliability
If protease-cleavable peptide linker is used to activate CAR-T cells, then tumor specificity is improved, but device complexity increases
Solution Approach 1:
The CAR-T cell receptor is segmented into distinct functional modules: an extracellular domain for antigen binding, a protease-sensitive linker for activation control, and an intracellular signaling domain for tumor lysis initiation. This segmentation allows each component to perform its specific function independently while maintaining overall system simplicity. The protease-sensitive linker is a small, well-defined peptide sequence that can be easily integrated without requiring complex additional structures.
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 enhances the specificity and safety of CAR-T cell therapy by ensuring activation only in the presence of specific proteases within the tumor microenvironment, reducing toxicity and expanding the range of druggable target antigens, thereby improving the therapeutic index for cancer treatment.
Implementation Method 1
activatable through (a) protease(s). After activation, the antigen binding receptors are targeted to tumor cells by specifically binding to/interacting with the mutated Fc domain of therapeutic antibodies
Data Source
AI summary
The present invention generally relates to activatable antigen binding receptors capable of specific binding to a mutated Fc domain. The antigen binding receptors of the invention are activatable through (a) protease(s). After activation, the antigen binding receptors are targeted to tumor cells by specifically binding to/interacting with the mutated Fc domain of therapeutic antibodies. The invention also relates to transduced immune cells expressing the antigen binding receptors of the invention and/or nucleic acid molecules encoding the antigen binding receptors of the present invention. Further provided are kits comprising such cells and/or nucleic acid molecules in combination with tumor targeting antibodies comprising a mutated Fc domain.