Engineered IL2 Polypeptides for Selective Immune Activation

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Solution Overview

Problem

Current IL2-based therapies activate both effector T cells and immunosuppressive regulatory T cells, which can hamper anti-cancer responses due to the activation of T regulatory cells.

Innovation Solution

Engineered IL2 polypeptides with specific amino acid substitutions in the IL2Rβ binding region enhance binding to IL2Rβ, increasing stimulation of NK cells and effector T cells while reducing binding to IL2Rα, thereby modulating the immune response to preferentially activate effector cells over regulatory T cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If wild-type IL2 is used to activate effector T cells and NK cells, then anti-cancer immune response is enhanced, but regulatory T cells are also activated which hamper the anti-cancer response

Engineering Contradiction:

Improveanti-cancer immune responseVSAvoidimmunosuppressive regulatory T cell activation

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by making specific amino acid substitutions at positions 81, 83, and 94 in the IL2 molecule, which are located in the IL2Rβ binding region. These localized changes selectively enhance binding to IL2Rβ (expressed on effector cells) while reducing binding to IL2Rα (expressed on regulatory T cells), thereby achieving differential immune cell activation without affecting the overall molecular structure

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent changes the binding parameters of IL2 by introducing amino acid substitutions that modify the dissociation constant (KD) for different receptor subtypes. The engineered IL2 exhibits at least 10-fold greater KD for IL2Rβ compared to wild-type IL2, while showing reduced binding to IL2Rα, thus altering the interaction parameters to achieve selective immune cell activation

Inventive Principle:

Principle #35Parameter changes

2Productivity

If IL2 binds to IL2Rα to activate regulatory T cells, then Treg expansion occurs, but this reduces effector T cell and NK cell anti-cancer activity

Engineering Contradiction:

Improveeffector T cell and NK cell proliferationVSAvoidT regulatory cell immunosuppression

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent extracts the harmful effect by removing the ability of IL2 to bind effectively to IL2Rα through amino acid substitutions in the IL2Rβ binding region. By eliminating or reducing the interaction with IL2Rα, the patent prevents regulatory T cell activation while preserving and enhancing binding to IL2Rβ for effector cell stimulation

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent inverts the normal IL2 binding profile by reversing the selectivity: instead of binding both IL2Rα and IL2Rβ as wild-type IL2 does, the engineered IL2 is designed to preferentially bind IL2Rβ while avoiding IL2Rα, thus inverting the activation pattern from Treg-dominant to effector cell-dominant

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentUS20230002466A1Engineered interleukin-2 receptor beta agonists

Publication Date: 2023.01.05 ELPIS BIOPHARMACEUTICALS

AI summary

Provided herein are engineered IL2 polypeptides and fusion proteins thereof. Also provided are methods of modulating an immune response by administering an engineered IL2 polypeptide or a fusion protein thereof. The engineered IL2 polypeptides and fusion proteins thereof demonstrate increased binding to IL2Rβ, decreased binding to IL2Rα, or both.