Engineered IL-2 Conjugate for Selective IL-2Rβγ Binding

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Solution Overview

Problem

Existing IL-2 therapies for cancer treatment are limited by severe side effects such as vascular leak syndrome due to interactions with IL-2Rαβγ, and manufacturing IL-2 proteins with cysteine modifications for preferential binding to IL-2Rβγ is challenging due to aggregation issues.

Innovation Solution

An IL-2 protein sequence with an N-terminal alanine residue (Ala) and a cysteine residue (Cys*) is engineered to enhance expression yields and preferential binding to IL-2Rβγ, reducing IL-2Rα interaction, thereby minimizing side effects and improving therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If IL-2 protein is modified with cysteine (Cys*) to preferentially bind IL-2Rβγ, then binding selectivity is improved, but manufacturing becomes challenging due to aggregation issues

Engineering Contradiction:

Improvebinding selectivityVSAvoidmanufacturing feasibility

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent modifies the IL-2 protein structure by introducing a cysteine residue at a specific position (Cys*) to alter binding properties. This structural parameter change enables preferential binding to IL-2Rβγ while the N-terminal alanine addition addresses manufacturing challenges by preventing aggregation, thus resolving the contradiction between improved selectivity and manufacturing feasibility

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite modified IL-2 protein structure combining the wild-type IL-2 sequence with an additional N-terminal alanine residue and a cysteine modification. This composite structure integrates both the binding selectivity enhancement (through Cys*) and the manufacturing improvement (through N-terminal Ala) into a single functional protein molecule

Inventive Principle:

Principle #40Composite materials

2Reliability

If high-dose IL-2 is administered to stimulate antitumor efficacy, then immune response is enhanced, but severe side effects occur due to interaction with IL-2Rαβγ-expressing cells

Engineering Contradiction:

Improveantitumor efficacyVSAvoidsystemic side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The modified IL-2 protein exhibits local quality differentiation in its binding properties, showing preferential affinity for IL-2Rβγ over IL-2Rαβγ. This selective binding characteristic allows the drug to act locally on target cells (expressing IL-2Rβγ) while sparing non-target cells (expressing IL-2Rαβγ), thereby enhancing antitumor efficacy while reducing systemic side effects

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The cysteine modification (Cys*) acts as an intermediary element that mediates selective interaction with IL-2Rβγ. This molecular intermediary enables the IL-2 protein to distinguish between different receptor subtypes, directing its immunomodulatory effects specifically toward cells expressing IL-2Rβγ and reducing off-target effects on cells expressing only IL-2Rαβγ

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20260109747A1Conjugate Comprising an IL-2 Moiety

Publication Date: 2026.04.23 ASCENDIS PHARMA ONCOLOGY DIV AS

AI summary

The present invention relates to an IL-2 protein sequence of the formula Ala-SEQ A-Cys*-SEQ B (I), wherein SEQ A has at least 94% sequence identity to SEQ ID NO:1; SEQ B has at least 94% sequence identity to SEQ ID NO:2; Ala is an alanine residue; and Cys* is a cysteine residue; to conjugates thereof and their uses in the treatment of cancer.