Engineered IL-2 Agonists for Selective NK and T-Cell Activation

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Solution Overview

Problem

Existing interleukin-2 (IL2) therapies face challenges in selectively stimulating cytolytic CD8+ T cells and NK cells while minimizing activation of immunosuppressive regulatory T cells, leading to potential off-target effects and safety concerns.

Innovation Solution

Engineered IL2 polypeptides with amino acid substitutions in the IL2Rβ binding region 2 reduce binding to IL2Rβ, enhancing stimulation of NK cells and T effector cells while providing improved safety and durable immune modulation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If wild-type IL2 is used to stimulate immune cells, then strong immune activation is achieved, but off-target effects and safety concerns occur due to non-selective activation

Engineering Contradiction:

Improveselectivity of immune cell stimulationVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by making specific amino acid substitutions only in the IL2Rβ binding region 2 of the IL2 protein, while maintaining the rest of the protein structure and function intact. This localized modification allows selective binding to IL2Rβ with reduced affinity, thereby achieving selective stimulation of NK cells and T effector cells while minimizing activation of regulatory T cells, thus resolving the contradiction between strong immune activation and off-target effects

Inventive Principle:

Principle #3Local quality

2Productivity

If IL2 binds to IL2Rβ with high affinity, then effective immune stimulation is achieved, but activation of immunosuppressive regulatory T cells occurs

Engineering Contradiction:

Improveimmune cell stimulation effectivenessVSAvoidimmunosuppressive activity

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the binding affinity parameter of IL2 to IL2Rβ through amino acid substitutions in binding region 2. The engineered IL2 polypeptides exhibit reduced binding affinity to IL2Rβ compared to wild-type IL2, which shifts the balance of immune cell activation. This parameter change enables effective stimulation of cytolytic CD8+ T cells and NK cells while reducing activation of regulatory T cells, thereby resolving the contradiction between stimulation effectiveness and immunosuppressive activity

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20250326813A1Engineered interleukin-2 receptor beta reduced-binding agonist

Publication Date: 2025.10.23 ELPIS BIOPHARMACEUTICALS

AI summary

Provided herein are engineered IL2 polypeptides IL2Rβ reduced-binding agonists and fusion proteins thereof. Also provided are methods of modulating an immune response by administering an engineered IL2 polypeptide reduced-binding agonist or a fusion protein thereof.