IL-2 Mutein Selective Receptor Binding for Cancer Therapy
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Solution Overview
Problem
Current IL-2 therapies face challenges due to their dual role in activating and attenuating immune responses, leading to inefficacies in treating conditions like cancer, as they activate Treg cells that suppress CD8+ T cells, and existing solutions like anti-CD25 antibodies have limitations.
Innovation Solution
An IL-2 mutein with specific amino acid substitutions at positions 35, 38, 42, and 45, which reduces binding to the IL-2 receptor α while maintaining binding to IL-2 receptors β and γ, enhancing the therapeutic efficacy by suppressing Treg proliferation while activating CD8+ T cells and NK1.1+ cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If IL-2 is used to stimulate immune cells, then activation of adaptive immune response is improved, but activation of Treg cells occurs which suppresses CD8+ T cells
Solution Approach 1:
The patent applies local quality by creating an IL-2 mutein with specific amino acid substitutions (positions 35, 38, 42, and 45) that selectively modifies binding properties to different IL-2 receptor subtypes. The mutein maintains high affinity for IL-2Rβγ (activating CD8+ T cells and NK cells) while having reduced affinity for IL-2Rα (avoiding Treg activation), thereby achieving localized functional differentiation of IL-2 activity across different cell types
Solution Approach 2:
The patent employs parameter changes by altering the amino acid sequence parameters of IL-2 at specific positions (35, 38, 42, and 45) to modify its binding characteristics. These sequence parameter changes result in differential binding affinity parameters for various IL-2 receptor complexes, enabling selective stimulation of desired immune cells while avoiding suppression by Tregs
2Productivity
If IL-2 binds to IL-2 receptor α, then Treg cell activation occurs, but this suppresses the anti-tumor immune response
Solution Approach 1:
The patent applies the taking out principle by extracting the harmful binding interaction between IL-2 and IL-2Rα while preserving the beneficial binding to IL-2Rβγ. The mutein design selectively removes the affinity for α-containing receptors (which mediate Treg activation and suppression) while maintaining binding to βγ receptors (which mediate activation of anti-tumor effector cells), thereby separating the harmful from the useful effects
3Adaptability or versatility
If anti-CD25 antibodies are used to block Treg activation, then IL-2 mediated signaling in activated T cells is inhibited, but this shows immunosuppressive effects that limit therapeutic efficacy
Solution Approach 1:
Instead of blocking CD25 to prevent Treg activation (which inadvertently blocks all high-affinity IL-2 signaling), the patent inverts the approach by designing an IL-2 mutein that naturally cannot bind to α-containing receptors. This inverted strategy achieves selective Treg avoidance through receptor affinity design rather than blocking, allowing full activation of βγ-expressing cells without suppressing effector function
Data Source
AI summary
Provided is an IL-2 mutein having an amino acid sequence set forth in SEQ ID NO: 3 or an amino acid sequence which has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 3 and in which amino acids at position 35, position 38, position 42 or position 43, and position 45 are all A's.