Modular CAAR Recognition for Targeting Diverse Autoantigens
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Solution Overview
Problem
Current chimeric autoantibody receptor (CAAR)-T cell therapies are limited in their ability to recognize and target autoreactive immune cells, particularly those with post-translational modifications or nucleic acids, and lack flexibility in specificity and efficacy, failing to address multiple autoantigens and T cells in autoimmune diseases.
Innovation Solution
A fragmented CAAR system is introduced, where the signaling and recognition portions are separated into distinct constructs, allowing for flexible and adjustable therapies by administering separate recognition components and enabling the immune system to perform logical computations based on multiple targets, including T cells and cells with non-conventional autoantigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If traditional CAAR-T cells are used to target autoreactive immune cells, then selective depletion of autoreactive B cells is achieved, but the therapy cannot recognize T cells or cells with post-translational modifications
Solution Approach 1:
The CAAR construct is divided into separate modular components: an extracellular recognition domain (which can be swapped to target different autoantigens or MHC-peptide complexes) and an intracellular signaling domain. This segmentation allows the therapy to be adapted for different cell types (B cells, T cells, or cells with post-translational modifications) while maintaining reliable selective depletion through proper signaling domain pairing.
2Adaptability or versatility
If traditional CAAR constructs with fixed specificity are used, then the therapy can be manufactured with defined targets, but it lacks flexibility to adapt to individual patient needs or multiple autoantigens
Solution Approach 1:
The CAAR system incorporates dynamic elements through its modular design, allowing the recognition domain to be changed based on patient-specific autoantigens or disease progression. The system can be dynamically adapted by swapping extracellular domains while maintaining the core signaling architecture, enabling personalized therapy without requiring complete reconstruction of the CAR construct.
Solution Approach 2:
The intracellular signaling domain serves as a universal component that can pair with multiple different extracellular recognition domains targeting various autoantigens or MHC-peptide complexes. This multi-functionality allows a single signaling domain design to support multiple therapeutic applications across different autoimmune diseases and patient populations.
3Adaptability or versatility
If conventional CAAR designs are used, then the structure is simple and manufacturable, but the therapy cannot perform logical computations or target multiple antigens simultaneously
Solution Approach 1:
The CAAR is segmented into distinct functional modules that can be independently configured to perform logical operations. By separating recognition domains from signaling domains and introducing intermediary binding domains, the system can implement logic gates (AND, OR, NOT) where specific combinations of bound antigens trigger or inhibit signaling, enabling complex decision-making at the cellular level.
Solution Approach 2:
Intermediary binding domains are introduced as mediators between the extracellular recognition elements and intracellular signaling pathways. These intermediary domains can be conditionally activated or deactivated based on the presence of specific antigen combinations, enabling logical computation by controlling whether the signaling cascade is initiated or blocked.
Data Source
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Figure 2
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AI summary
Chimeric autoantibody receptors (CAARs) can include separate signaling and recognition constructs that are able to bind ligands that target autoantigens made of conventional amino acids, non-conventional amino acids, carbohydrates, or nucleic acids. Additionally, the present disclosure describes cells modified to express such constructs and the use of such constructs and/or cells in the treatment of autoimmune disease.