Fc-IL-2 Fusion Proteins for Extended Half-Life and Lower Toxicity

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Solution Overview

Problem

Interleukin-2 (IL-2) has a short half-life in humans, necessitating frequent dosing and can induce life-threatening toxicities, complicating its use in treatments that require sufficient immunostimulatory effects without immunosuppression.

Innovation Solution

A heterodimeric fusion protein comprising a human IgG4 Fc domain and an IL-2 variant (IL-2v) with reduced binding affinity to IL-2RA and enhanced binding to IL-2RB/IL-2RG, promoting CD8+ T cell proliferation and reduced Treg cell activation, and a serum half-life extension through Fc region linkage.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If IL-2 is administered to achieve immunostimulatory effects, then immune cell activation is improved, but serum half-life is short requiring frequent dosing

Engineering Contradiction:

Improveserum half-lifeVSAvoiddosing frequency

Core Design Contradiction:

Duration of action of moving objectVSProductivity

Solution Approach 1:

The patent combines IL-2 with an Fc domain to create a fusion protein that leverages the long half-life properties of Fc regions while maintaining IL-2's immunostimulatory function, thereby extending duration of action and reducing dosing frequency

Inventive Principle:

Principle #5Merging (Combining)

2Reliability

If IL-2 is administered at sufficient doses to achieve immunostimulatory effects, then immune activation is improved, but life-threatening toxicities increase

Engineering Contradiction:

ImprovesafetyVSAvoidtoxicities

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent introduces amino acid substitutions at specific positions (e.g., R38A, F42L, E62K) to locally modify IL-2's binding properties, reducing affinity for IL-2RA (which mediates toxicity) while preserving or enhancing affinity for IL-2RB/IL-2RG (which mediate therapeutic effects), thereby improving safety profile

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent converts the harmful high-dose requirement into a benefit by engineering IL-2 variants that achieve therapeutic effects at lower doses through selective receptor binding, transforming the toxicity problem into an opportunity for safer therapy

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Reliability

If IL-2 binding affinity to IL-2RA is high, then Treg cell activation is enhanced, but immunosuppression increases

Engineering Contradiction:

Improveimmunosuppression controlVSAvoidimmunosuppression

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent changes the binding affinity parameters of IL-2 by introducing specific amino acid substitutions that reduce binding to IL-2RA while maintaining or enhancing binding to IL-2RB/IL-2RG, thereby shifting the balance away from immunosuppression toward immunostimulation

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP4232463B1Interleukin-2-fc fusion proteins and methods of use

Publication Date: 2025.09.03 GILEAD SCIENCES INC

Figure 1A~1B
Figure 1C~1D
Figure 1E~1F

AI summary

Provided are serum half-life extended-IL-2 variant (IL-2v) heterodimers having reduced binding to the IL2Rα (CD25) subunit. In particular, Fc-IL-2v heterodimers are provided and methods for making and using, e.g. for enhancing an immune response, e.g. in the prevention and treatment of viral infections and cancer.