Membrane-Bound IL-10 Treg Engineering for Stable Tr1 Phenotype

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Solution Overview

Problem

Existing Treg-based therapies fail to adequately recruit, induce, or engineer sufficient numbers of stable Tr1 phenotype Tregs, which are crucial for clinical efficacy and safety in treating autoimmune diseases and immune system disorders.

Innovation Solution

Genetically reprogram CD4 T cells to express membrane-bound IL-10 (mem-IL10) using a nucleic acid molecule encoding a homodimeric IL-10 linked to a transmembrane-intracellular stretch, optionally through a flexible hinge, delivered via viral vectors, to confer a stable Tr1 phenotype.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If Tregs are used to suppress local inflammation and restore immunological balance, then therapeutic efficacy is improved, but the limited availability and instability of Tr1 phenotype Tregs worsen the feasibility of treatment

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidnumber of stable Tr1 phenotype Tregs

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The invention changes the phenotypic parameters of Tregs by genetically reprogramming them to express membrane-bound IL-10, thereby converting them into stable Tr1 phenotype cells. This parameter change (from natural Treg phenotype to engineered Tr1 phenotype) directly addresses the scarcity and instability issues of natural Tr1 cells while maintaining their therapeutic immunosuppressive function

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The genetically reprogrammed Tregs express membrane-bound IL-10 that provides autocrine signaling to maintain their own Tr1 phenotype stability. This self-service mechanism ensures continuous phenotypic stability without requiring external support, enabling the cells to self-maintain their therapeutic properties in vivo

Inventive Principle:

Principle #25Self-service

2Stability of the object's composition

If membrane-bound IL-10 is expressed on Tregs to stabilize Tr1 phenotype, then phenotype stability is improved, but the complexity of genetic reprogramming worsens the manufacturing process

Engineering Contradiction:

ImproveTr1 phenotype stabilityVSAvoidgenetic reprogramming complexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The invention uses a universal genetic reprogramming approach that can be applied to any Treg cell source (autologous or allogeneic) to confer Tr1 phenotype. The membrane-bound IL-10 construct serves multiple functions: it stabilizes the Tr1 phenotype, provides autocrine signaling, and can be delivered through standard viral vector systems, making the process universally applicable rather than requiring cell-specific complex procedures

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The invention introduces membrane-bound IL-10 as an intermediary molecule that mediates the stabilization of Tr1 phenotype. Rather than directly manipulating multiple genetic pathways to achieve phenotype stability, the membrane-bound IL-10 acts as a mediator that signals to maintain the desired phenotype, simplifying the genetic reprogramming requirement to a single functional element

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentEP3768699B1Genetically reprogrammed tregs expressing membrane-bound il-10

Publication Date: 2025.11.12 GAVISH GALILEE BIO APPL

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Figure 3A~3B

AI summary

A nucleic acid molecule comprising a nucleotide sequence encoding a homodimeric IL-10 linked to a transmembrane-intracellular stretch, optionally through a flexible hinge, is provided as well as a mammalian regulatory T cell (Treg) comprising and expressing the nucleic acid molecule and uses thereof.