Modified IL-2 Cytokine Conjugates for Selective Treg Expansion

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Solution Overview

Problem

Existing treatments for autoimmune diseases, particularly those targeting regulatory T cells, face challenges in achieving optimal modulation of immune responses due to issues with cytokine receptor signaling potency and toxicity.

Innovation Solution

Development of interleukin 2 (IL-2) conjugates with unnatural amino acids that reduce IL-2Rβγ signaling potency and modify receptor interactions, enhancing IL-2Rαβγ activation, thereby expanding CD4+ T regulatory (Treg) cells while minimizing toxicity and improving therapeutic windows.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If wild-type IL-2 is used to expand Treg cells, then Treg cell expansion is achieved, but toxicity increases and therapeutic window narrows

Engineering Contradiction:

ImproveTreg cell expansion efficacyVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces unnatural amino acids at specific positions (K8, K9, Q11, L12, E15, H16, L19, D20, Q22, M23, N26) of the IL-2 polypeptide to create localized modifications that selectively alter receptor binding properties. These position-specific modifications enable the cytokine to differentiate between IL-2Rαβγ and IL-2Rβγ receptors, achieving selective Treg cell expansion with reduced toxicity to other cell types.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent systematically varies the position and type of unnatural amino acid substitutions to modulate receptor signaling potency. By changing parameters such as the identity of the unnatural amino acid (e.g., azido lysine, alkynyl phenylalanine) and its position in the polypeptide sequence, the invention optimizes the balance between Treg cell expansion efficacy and toxicity reduction, thereby widening the therapeutic window.

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If IL-2Rβγ signaling potency is reduced to minimize toxicity, then therapeutic window improves, but Treg cell expansion efficacy may be compromised

Engineering Contradiction:

Improvetoxicity reductionVSAvoidTreg cell expansion efficacy

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent inverts the conventional approach by designing IL-2 variants that preferentially activate IL-2Rαβγ (high-affinity receptor on Treg cells) while reducing activation of IL-2Rβγ (intermediate-affinity receptor on effector T cells). This inverse selectivity ensures that Treg cell expansion is maintained or enhanced while toxicity to effector T cells is minimized, thereby widening the therapeutic window.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The unnatural amino acids serve as intermediary elements that mediate selective interactions with different IL-2 receptor complexes. These modified residues act as molecular mediators that favor binding to IL-2Rαβγ while reducing affinity for IL-2Rβγ, enabling selective Treg cell activation without compromising expansion efficacy while reducing toxicity.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250325633A1Cytokine conjugates for the treatment of autoimmune diseases

Publication Date: 2025.10.23 SANOFI SA(FR)

AI summary

Disclosed herein are interleukin (IL) conjugates (e.g., IL-2 conjugates) and use in the treatment of one or more indications. Also described herein are pharmaceutical compositions and kits comprising one or more of the interleukin conjugates (e.g., IL-2 conjugates).