Membrane-Bound IL-2 Fusion Protein for IL-2-Independent Treg Maintenance
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Solution Overview
Problem
Treg cells are strictly dependent on IL-2 for survival and activation, which is predominantly secreted by T-effector cells, leading to challenges in maintaining their viability and suppressive activity, especially in environments with low or absent IL-2 concentrations, such as those induced by immune suppressants.
Innovation Solution
A fusion protein comprising a membrane-bound IL-2 (mbIL-2) and a chimeric antigen receptor (CAR) is expressed in Treg cells, allowing them to survive and maintain suppressive activity in low or IL-2-deprived conditions by localizing IL-2 signaling to the cell membrane, thereby bypassing activation of other IL-2-dependent cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Treg cells are maintained in environments with low or absent IL-2 concentrations (e.g., under immune suppressant treatment), then the viability and suppressive activity of Treg cells is improved, but the natural dependence on exogenous IL-2 for survival is worsened
Solution Approach 1:
The patent applies self-service by enabling Treg cells to produce and bind IL-2 autonomously through the membrane-bound IL-2 fusion protein. This eliminates the need for exogenous IL-2 from T-effector cells, allowing Treg cells to maintain their suppressive activity independently in IL-2 deprived environments such as those treated with calcineurin inhibitors.
Solution Approach 2:
The patent merges the IL-2 production function with the Treg cell structure by integrating membrane-bound IL-2 into the cell membrane. This fusion protein combines the IL-2 signaling domain with a transmembrane anchor, enabling the cell to both produce and bind IL-2 locally, thereby resolving the contradiction between independence and functional dependence.
2Reliability
If membrane-bound IL-2 fusion protein is expressed in Treg cells, then the survival of Treg cells in IL-2 deprived conditions is improved, but the complexity of the cellular system is worsened
Solution Approach 1:
The patent segments the IL-2 protein into functional domains: a secretory leader peptide, an IL-2 signaling domain, a linker region, and a transmembrane anchor. This segmentation allows the IL-2 function to be isolated and integrated specifically into the cell membrane rather than requiring complete redesign of the cellular IL-2 production system.
Solution Approach 2:
The membrane-bound IL-2 fusion protein acts as an intermediary between the cell's internal IL-2 production machinery and the external signaling environment. It mediates IL-2 binding and signaling at the cell membrane, simplifying the overall system by providing a dedicated interface that eliminates the need for complex secretory and binding mechanisms.
3Reliability
If Treg cells are activated for suppressive activity against cognate antigen, then the therapeutic efficacy is improved, but the risk of activating non-specific T cells is worsened
Solution Approach 1:
The patent applies local quality by restricting IL-2 binding and signaling to a localized membrane-bound fusion protein specifically expressed on Treg cells. This spatial localization ensures that IL-2 signaling occurs only at the Treg cell surface where the fusion protein is present, preventing systemic activation of non-specific T cells while maintaining therapeutic efficacy against the cognate antigen.
Data Source
AI summary
The present invention relates to a fusion protein that provides for maintenance of regulatory T-cells that are polyclonal, e.g. natural isolated antigen-specific Treg cells, and/or Treg cells generated by introduction of a nucleic acid construct for expression of FOXP3, and/or Treg cells which express a chimeric antigen receptor (CAR), which Treg cells in contact with the cognate antigen are activated for suppressive activity, as well as to Treg cells that express the fusion protein, wherein the Treg cells are polyclonal or the Treg cells express a CAR. The fusion protein comprises or consists of an optional secretory leader peptide, IL-2, preferably a linker peptide, and a membrane-spanning anchor, which fusion protein is also termed membrane-bound IL-2.