TSHR Chimeric Autoantigen Receptor for Selective B-Cell Depletion
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Solution Overview
Problem
Current treatments for autoimmune thyroid diseases like Graves' disease, such as antithyroid drugs and therapeutic antibodies, face limitations in efficacy and safety, and existing CAR T cell therapies target all B cells, leading to immune deficits.
Innovation Solution
A chimeric autoantigen receptor (CAAR) targeting the extracellular domain of the thyroid-stimulating hormone receptor (TSHR) is developed, lacking specific segments to specifically deplete auto-reactive B cells, comprising a signal peptide, extracellular domain, hinge region, transmembrane domain, and intracellular signaling domains, encoded by a nucleic acid molecule and delivered via a lipid nanoparticle.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR T cell therapies target all B cells, then autoantibody production is reduced, but immune deficits occur
Solution Approach 1:
The CAAR targets a specific local epitope (extracellular domain of TSHR) on B cells rather than pan-B cell markers, enabling selective depletion of autoantibody-producing cells while preserving other immune functions. This local specificity resolves the contradiction by achieving targeted therapy without broad immune suppression.
Solution Approach 2:
The chimeric receptor is segmented into distinct functional domains: extracellular binding domain (specificity), transmembrane domain (anchoring), and intracellular signaling domain (activation). This segmentation allows independent optimization of each function, particularly the epitope recognition domain that enables selective targeting of TSHR-autoreactive B cells.
2Reliability
If pan-suppression is used to disrupt autoimmune stimulation, then autoantibody production is inhibited, but risk of infection increases
Solution Approach 1:
Instead of pan-suppression, the CAAR implements local quality by targeting only TSHR-autoreactive B cells through specific epitope recognition. This selective approach inhibits autoantibody production against TSHR while leaving other immune pathways intact, thereby reducing infection risk associated with broad immunosuppression.
Solution Approach 2:
The invention converts the harmful non-specific immune suppression into a beneficial specific targeting mechanism. The chimeric receptor uses the harmful autoantibodies' own specificity (binding to TSHR) as the basis for therapeutic action, turning the disease mechanism against itself through epitope-specific recognition.
3Reliability
If therapeutic antibodies are used to target TSHR, then autoimmune stimulation is reduced, but safety risks remain
Solution Approach 1:
The CAAR acts as an intermediary mechanism that bridges the gap between therapeutic targeting and safety. By using autologous T cells expressing the chimeric receptor, the system achieves specific TSHR targeting through endogenous immune cells rather than exogenous antibodies, reducing safety risks associated with therapeutic antibody administration.
Solution Approach 2:
The therapy employs the patient's own T cells as effectors, making the system self-service. The autologous T cells express the chimeric receptor and mediate their own therapeutic action, eliminating the need for external therapeutic antibodies and their associated safety risks while maintaining specific TSHR targeting.
4Reliability
If antithyroid drugs are used to treat GD, then thyroid hormone production is reduced, but relapse occurs upon discontinuation
Solution Approach 1:
The CAAR therapy provides continuous useful action by establishing long-lived memory T cells that maintain specific surveillance and destruction of TSHR-autoreactive B cells. This continuous immune memory ensures sustained control of autoantibody production, eliminating the relapse problem associated with discontinuous antithyroid drug treatment.
Solution Approach 2:
The therapy rushes through the treatment course by directly targeting and eliminating the root cause (autoreactive B cells) rather than managing symptoms through hormone suppression. This direct approach to pathogen elimination provides durable cure-like outcomes, skipping the need for long-term medication maintenance.
Data Source
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AI summary
A chimeric protein comprising an extracellular domain of human thyroid-stimulating hormone receptor (TSHR), said domain lacking a C-terminal segment comprising at least the segment from amino acid residue 301 to 413 of TSHR.