Membrane-Bound IL-10 Cytokines for Antigen-Specific Immune Suppression
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Solution Overview
Problem
Existing Treg-based therapies, particularly those inducing Tr1 cells, face challenges with uncontrolled IL-10 secretion leading to systemic immune suppression and loss of antigen-or tissue-selectivity, posing risks in clinical settings.
Innovation Solution
Development of a chimeric polypeptide comprising a cytokine region, transmembrane region, and signaling region of a T cell costimulatory receptor, specifically membrane-bound IL-10 fused with CD40 or TLR4, to induce Tr1-like cells with controlled IL-10 secretion and enhanced antigen-specific suppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If constitutive IL-10 expression is enforced in CD4 T cells through lentiviral transduction, then Tr1 phenotype and function are generated, but uncontrolled IL-10 secretion occurs leading to systemic immune suppression
Solution Approach 1:
The patent transforms the static constitutive IL-10 expression system into a dynamic regulated system by fusing IL-10 with costimulatory receptors (CD40, CD28, TLR4) that respond to specific stimuli. This allows IL-10 secretion to be dynamically controlled based on antigen presence and T cell activation state, preventing uncontrolled systemic suppression while maintaining Tr1 functionality.
Solution Approach 2:
The patent changes the expression pattern parameter of IL-10 from constitutive (constant) to regulated (stimulus-dependent). By incorporating costimulatory receptor domains, the system shifts IL-10 secretion to occur only under specific conditions such as T cell activation or antigen recognition, thereby controlling the timing and magnitude of anti-inflammatory cytokine release.
2Reliability
If constitutive IL-10 expression is enforced in CD4 T cells, then Tr1 phenotype is generated, but antigen-specificity and tissue-selectivity are lost
Solution Approach 1:
The patent applies local quality by making IL-10 expression dependent on local T cell activation signals and antigen presence. The costimulatory receptor fusion creates a system where IL-10 is produced locally and selectively in response to specific antigenic stimuli rather than being uniformly expressed throughout the body, thereby restoring tissue- and antigen-specificity to the therapeutic cells.
Solution Approach 2:
The system transitions from static constitutive expression to dynamic regulated expression where IL-10 production is activated only when T cells encounter their specific antigen. This dynamic control enables the cells to adapt their cytokine secretion based on the local immunological environment, preserving antigen-specificity while maintaining Tr1 phenotype.
3Object-affected harmful factors
If Tregs are used for suppressing local inflammation, then immunological balance is restored, but uncontrolled IL-10 secretion causes systemic immune suppression
Solution Approach 1:
The patent implements feedback control by coupling IL-10 expression to costimulatory receptor signaling pathways that are activated in response to antigen recognition and T cell activation. This feedback mechanism ensures that IL-10 is produced only when and where T cells are activated by their specific antigens, creating a self-regulating system that suppresses local inflammation without causing systemic immune suppression.
Solution Approach 2:
The system changes the regulatory parameter of IL-10 expression from constitutive to stimulus-dependent. By incorporating costimulatory receptor domains (CD40, CD28, TLR4), the patent creates a feedback loop where IL-10 secretion is controlled by the activation state of the T cell itself, ensuring that anti-inflammatory effects are localized to the site of antigen recognition rather than being systemically distributed.
Data Source
AI summary
Nucleic acid molecules comprising a sequence encoding a chimeric polypeptide comprising a cytokine region comprising at least one single-chain anti-inflammatory cytokine, a transmembrane region and a at least one signaling region comprising an element of a T cell costimulatory receptor of the tumor necrosis factor receptor (TNFR) family are provided. Expression vectors, polypeptides, cells, enriched populations and pharmaceutical compositions are also provided, as are methods for inducing immune suppression and treating a disease, disorder or condition characterized by excessive activity of the immune system.