IL-2 Mutant Protein Receptor Selectivity for Immunotherapy
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Solution Overview
Problem
Current IL-2 therapies face challenges such as toxicity due to high affinity for IL-2Rα receptors and limited effectiveness in stimulating CD25− cells, which are essential for immunotherapy.
Innovation Solution
Development of a novel IL-2 mutant protein with reduced binding affinity for IL-2Rα and enhanced binding affinity for IL-2Rβ, achieved through specific mutations at amino acid residue positions 35-72 and 79-92, thereby improving receptor selectivity and immune stimulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type IL-2 is used for immunotherapy, then it can stimulate T cell proliferation and activate immune cells, but it causes toxicity due to high affinity binding to IL-2Rα receptors on lung endothelial cells
Solution Approach 1:
The patent applies local quality by making specific amino acid substitutions at positions 35-72 and 79-92 of the IL-2 molecule. These localized changes modify the binding interface properties to reduce affinity for IL-2Rα while preserving or enhancing affinity for IL-2Rβ, thereby reducing toxicity to lung endothelial cells while maintaining therapeutic effectiveness on immune cells.
Solution Approach 2:
The patent changes the binding parameters of IL-2 by introducing multiple amino acid substitutions that alter the equilibrium dissociation constant (KD) values. The mutant IL-2 exhibits reduced KD for IL-2Rβ (enhanced binding) and increased KD for IL-2Rα (reduced binding), fundamentally changing the interaction parameters to achieve selective immunostimulation without vascular leak syndrome.
2Reliability
If wild-type IL-2 is used for immunotherapy, then it can activate immune cells, but it preferentially activates CD25+ Treg cells due to high affinity for IL-2Rα, limiting effectiveness on CD25− effector cells
Solution Approach 1:
The patent modifies specific local regions of the IL-2 molecule (amino acid positions 35-72 and 79-92) to change its receptor interaction profile. These localized mutations create a version of IL-2 that selectively targets IL-2Rβ-expressing cells (CD25− effector T cells and NK cells) while avoiding preferential binding to IL-2Rα-expressing Treg cells, thereby expanding the therapeutic versatility.
Solution Approach 2:
The patent inverts the natural binding preference of IL-2. Instead of preferring IL-2Rα (CD25+) as wild-type IL-2 does, the mutant IL-2 is designed to prefer IL-2Rβ (CD25−), effectively reversing the activation hierarchy to stimulate effector cells rather than suppressor cells.
3Object-affected harmful factors
If IL-2 binding affinity for IL-2Rα is reduced to decrease toxicity, then activation of CD25+ cells is reduced, but binding affinity for IL-2Rβ must be enhanced to maintain immune stimulation
Solution Approach 1:
The patent applies local quality modifications at two distinct regions of the IL-2 molecule: positions 35-72 (affecting IL-2Rα binding) and positions 79-92 (affecting IL-2Rβ binding). By independently optimizing these local regions through specific amino acid substitutions, the patent simultaneously reduces toxic binding to IL-2Rα while enhancing therapeutic binding to IL-2Rβ.
Solution Approach 2:
The patent changes multiple binding parameters simultaneously through combinatorial amino acid substitutions. The mutant IL-2 achieves increased KD for IL-2Rα (reduced binding affinity, lower toxicity) and decreased KD for IL-2Rβ (enhanced binding affinity, maintained stimulation), effectively decoupling the trade-off between toxicity and efficacy.
Data Source
AI summary
The present invention relates to a novel interleukin-2 (IL-2) mutant protein and use thereof. In particular, the present invention relates to an IL-2 mutant protein with reduced IL-2Rα receptor binding ability and/or increased IL-2Rβ receptor binding ability compared with the wild-type IL-2. The present invention further provides a fusion protein and an immunoconjugate comprising the IL-2 mutant protein, a nucleic acid encoding the IL-2 mutant protein, and a vector and a host cell comprising the nucleic acid. The present invention further provides a method for preparing the IL-2 mutant protein, a pharmaceutical composition comprising the IL-2 mutant protein, and therapeutic use of the mutant protein.