Engineered CD25 Receptors for Selective Low-Dose IL-2 Signaling
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Solution Overview
Problem
Existing IL-2 therapies induce severe toxicity and off-target effects due to non-specific activation of immune cells, limiting their therapeutic efficacy in cancer and autoimmune treatments.
Innovation Solution
Engineering CD25 proteins with increased affinity for IL-2 and IL-13Rα2 as a surrogate receptor to concentrate IL-2 signaling on target cells, allowing reduced doses of IL-2 to be administered, thereby minimizing toxicity and enhancing selective expansion of engineered cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type IL-2 is administered at therapeutic doses, then immune cell activation and expansion are achieved, but severe toxicity and off-target effects occur
Solution Approach 1:
The patent applies local quality by engineering CD25 proteins with increased affinity for IL-2 specifically on target cells, while leaving other cells with normal CD25 expression. This creates a localized enhancement of IL-2 signaling sensitivity only where needed, allowing therapeutic efficacy while minimizing systemic toxicity. The modified cells become selectively responsive to IL-2 without affecting other immune cells.
Solution Approach 2:
The patent changes the binding affinity parameter of the CD25 protein for IL-2 by introducing specific amino acid mutations. This parameter change increases the sensitivity of engineered cells to IL-2 signaling, enabling effective activation and expansion at lower IL-2 doses, thereby reducing the harmful effects associated with high-dose wild-type IL-2 administration.
2Productivity
If high doses of IL-2 are administered, then expansion of target cells is achieved, but regulatory T cell growth is promoted which blunts efficacy
Solution Approach 1:
The patent creates a localized advantage for engineered target cells by equipping them with high-affinity CD25 proteins, while regulatory T cells retain normal CD25 expression. This ensures that even at lower IL-2 doses, the engineered cells receive sufficient signaling for expansion without preferentially promoting Treg growth, thereby maintaining therapeutic efficacy.
Solution Approach 2:
By changing the affinity parameter of CD25 for IL-2 in engineered cells, the patent enables these cells to achieve effective signaling and expansion at lower IL-2 concentrations. This parameter change prevents the dose-dependent promotion of Treg growth that occurs with wild-type IL-2, as the engineered cells can expand effectively before Tregs are activated.
3Productivity
If IL-2 signaling is enhanced in target cells, then selective expansion is achieved, but complexity of protein engineering increases
Solution Approach 1:
The patent applies local quality by modifying only the CD25 protein component on target cells to have increased IL-2 affinity, while keeping the rest of the cell and signaling pathway unchanged. This focused modification achieves selective expansion without requiring complex multi-component engineering systems.
Solution Approach 2:
The patent achieves selective expansion by changing a single critical parameter - the binding affinity of CD25 for IL-2 - through targeted amino acid mutations. This single parameter change is sufficient to create differential responsiveness to IL-2, avoiding the need for complex multi-parameter engineering.
Data Source
AI summary
Engineered proteins, polynucleotides encoding such proteins, and methods of use thereof are provided, which engineered proteins enhance the sensitivity of a cell to IL-2.