Modified IL-2 Conjugates for Selective Immune Cell Expansion

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Solution Overview

Problem

Current treatments for cancer and pathogenic infections using interleukin 2 (IL-2) face challenges in modulating specific T cell populations effectively, as they often activate regulatory T cells, which can hinder therapeutic efficacy.

Innovation Solution

Development of IL-2 conjugates with modified amino acid residues and conjugating moieties that reduce binding to IL-2Rα, allowing for selective expansion of CD4+ helper cells, CD8+ effector cells, NK cells, and NKT cells while minimizing activation of regulatory T cells, using polymers like PEG and proteins for conjugation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If wild-type IL-2 is used for treatment, then immune response is activated, but regulatory T cells are also activated which hinders therapeutic efficacy

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidregulatory T cell activation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by modifying specific amino acid residues at particular positions (K35, T37, R38, T41, F42, K43, F44, Y45, E61, E62, E68, K64, P65, V69, L72, Y107) of the IL-2 polypeptide to create differential binding affinity. The conjugating moiety is attached at specific positions to selectively reduce binding to IL-2Rα while maintaining or enhancing binding to IL-2Rβγ, thereby achieving selective activation of desired T cell populations while minimizing regulatory T cell activation.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent changes the binding affinity parameter of IL-2 to different receptor subtypes by introducing a conjugating moiety. The conjugate exhibits decreased affinity to IL-2Rα (by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% decrease) relative to wild-type IL-2, while maintaining signaling potency through IL-2Rβγ. This parameter change enables selective modulation of immune response.

Inventive Principle:

Principle #35Parameter changes

2Measurement precision

If IL-2 conjugates with reduced IL-2Rα binding are developed, then specificity of immune response is improved, but molecular complexity increases

Engineering Contradiction:

Improveimmune response specificityVSAvoidmolecular structure complexity

Core Design Contradiction:

Measurement precisionVSDevice complexity

Solution Approach 1:

The patent uses a conjugating moiety as an intermediary between the IL-2 polypeptide and the desired therapeutic effect. The conjugating moiety (comprising water-soluble polymers like PEG, polysaccharides, glycan, polyamine, or proteins like albumin, transferrin, transthyretin, Fc portion) serves as a mediator that modulates receptor binding without directly interacting with the immune cells themselves. This intermediary approach achieves specificity while managing complexity through modular design.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250325632A1Cytokine conjugates for the treatment of proliferative and infectious 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).