IL-2 Variants With Reduced IL-2Rα Binding for Cancer Immunotherapy
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Solution Overview
Problem
Wild-type IL-2 exhibits dual functions in immune response, mediating both effector cell expansion and immune tolerance, compromising anti-tumor immunity due to high affinity to the α-subunit of IL-2R, which is expressed on regulatory T cells, leading to immunosuppression.
Innovation Solution
Development of IL-2 variants with reduced affinity to the α-subunit of IL-2R while maintaining affinity to the β- and γc-subunits, achieved through specific amino acid substitutions at positions 42, 45, 50, 72, or 125, enhancing anti-tumor activity by minimizing immunosuppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type IL-2 is used to expand effector cells and enhance anti-tumor immunity, then anti-tumor activity is improved, but immunosuppression occurs due to binding to the α-subunit of IL-2R on regulatory T cells
Solution Approach 1:
The patent applies local quality by making specific amino acid substitutions at positions 42, 45, 50, 72, or 125 of the IL-2 molecule. These localized changes selectively reduce affinity for the α-subunit of IL-2R (thereby reducing immunosuppression) while preserving affinity for the β- and γc-subunits (maintaining effector cell expansion capability).
Solution Approach 2:
The patent changes the biochemical parameters of IL-2 by introducing amino acid substitutions that alter its binding characteristics. Specifically, the substitutions modify the dissociation constant (Kd) for different IL-2R subunit combinations, creating variants with differential affinity profiles that favor effector cell activation over regulatory T cell suppression.
2Object-generated harmful factors
If IL-2 variants with reduced affinity to α-subunit are developed, then immunosuppression is reduced, but affinity to β- and γc-subunits must be maintained to preserve effector cell expansion
Solution Approach 1:
The patent applies local quality by making specific amino acid substitutions at positions 42, 45, 50, 72, or 125 of the IL-2 molecule. These localized changes selectively reduce affinity for the α-subunit of IL-2R (thereby reducing immunosuppression) while preserving affinity for the β- and γc-subunits (maintaining effector cell expansion capability).
Solution Approach 2:
The patent employs feedback through screening and characterization of multiple IL-2 variants to identify those with optimal affinity profiles. By measuring binding affinities to different IL-2R subunit combinations and evaluating biological activities, the patent selects variants that achieve the desired balance between reduced immunosuppression and maintained effector cell expansion.
Data Source
AI summary
Disclosed herein is generally related to an isolated interleukin-2 (IL-2) variant that exhibits reduced affinity to the α-subunit of IL-2 receptor (IL-2R), for use as immunotherapeutic agents. In addition, the present disclosure relates to a pharmaceutical composition comprising the isolated IL-2 variant, and uses thereof in treating a cancer in a subject.