IL-2 Variant Engineering for Selective Treg Activation
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Solution Overview
Problem
Existing IL-2 therapies face challenges with high toxicity at high doses and short half-life at low doses, necessitating improved IL-2 variants for immune disorder treatments, particularly autoimmune and inflammatory diseases, and graft-versus-host disease, while maintaining efficacy and reducing side effects.
Innovation Solution
Engineering resurfaced IL-2 variants with specific amino acid substitutions to preferentially stimulate T-regulatory cells or antagonize IL-2, enhancing Treg activation or blocking IL-2 overactivation, respectively, to modulate immune responses effectively.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high doses of IL-2 are administered to stimulate immune response against cancer, then immune activation is enhanced, but toxicity increases and efficacy is limited due to unwanted effects on Tregs
Solution Approach 1:
The patent applies local quality by creating IL-2 variants with modified binding affinities for different receptor subunits. Specifically, the variants have enhanced affinity for the beta-gamma chain (IL-2RB/IL-2RG) while maintaining or reducing affinity for the alpha chain (IL-2RA). This selective binding allows the IL-2 to preferentially activate effector T cells through the high-affinity receptor complex while avoiding unwanted activation of regulatory T cells, thus reducing toxicity while maintaining anti-cancer efficacy
Solution Approach 2:
The patent employs parameter changes by modifying the amino acid sequence of IL-2 at specific positions (e.g., positions 9, 12, 16, 19, 26, 31, 87, 91, 95) to alter its binding parameters. These sequence modifications change the affinity and selectivity of IL-2 for different receptor chains, enabling the cytokine to achieve selective activation of pro-inflammatory pathways while avoiding suppression of protective Treg functions
2Reliability
If low doses of IL-2 are administered to boost Tregs and dampen inflammation, then autoimmune diseases are treated, but repeated administration is needed due to short half-life
Solution Approach 1:
The patent applies dynamics by creating IL-2 variants with extended half-life characteristics. The modified IL-2 variants maintain their immunosuppressive activity over prolonged periods, reducing the frequency of administration. This is achieved through structural modifications that enhance stability and prolong circulation time while preserving the ability to selectively activate Tregs at low doses
3Object-affected harmful factors
If IL-2 is complexed with anti-IL-2 antibody to improve pharmacodynamics and redirect action, then toxicity is lowered, but device complexity increases
Solution Approach 1:
The patent applies the extraction principle by removing the need for anti-IL-2 antibody complexes. Instead of combining IL-2 with antibodies to achieve selective activity, the invention directly modifies the IL-2 molecule itself to possess inherent selective binding properties. The modified IL-2 variants naturally preferentially bind to the beta-gamma chain over the alpha chain, eliminating the complexity of antibody conjugation while maintaining toxicity reduction benefits
Data Source
AI summary
The invention relates to Interleukin-2 (IL-2) variants for the prevention or treatment of immune disorders, including with no limitations allergic, autoimmune, chronic or acute inflammatory and infectious diseases; graft-versus-host disease; graft rejection and cancer. The invention also relates to the use of said IL-2 variants for the screening of anti-IL-2 antibodies with pro-T-effector or pro-T-regulatory cell activity.