Il-2 mutant protein proliferating immune cells
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Solution Overview
Problem
Existing IL-2 immunotherapy is limited by severe side effects such as vascular leak syndrome and reduced efficacy at low doses, and existing IL-2 mutants fail to effectively balance receptor affinity and biological activity.
Innovation Solution
A novel IL-2 mutant with specific amino acid mutations reduces affinity to the high-affinity IL-2 receptor while retaining affinity to the medium-affinity receptor, enhancing proliferation of tumor immune cells like T effector cells and NK cells, and is produced through site-directed mutagenesis and glycosylation modification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high-dosage IL-2 treatment is used to expand effector cells and enhance anti-tumor effects, then therapeutic efficacy is improved, but severe side effects including vascular leak syndrome occur
Solution Approach 1:
The patent applies local quality by modifying specific amino acid residues at the IL-2 receptor binding interface (positions 38, 42, and 72) to selectively alter affinity for different receptor forms. The mutant IL-2 protein maintains high affinity for medium-affinity IL-2R (βγ chain) while having reduced affinity for high-affinity IL-2R (αβγ chain), thereby locally optimizing binding properties to achieve therapeutic efficacy with reduced side effects
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid substitutions at key binding positions to tune the affinity parameters of IL-2 for different receptor forms. Through multiple mutant variants (e.g., F42A, F42L, Y45A, Y45L, L72G), the patent optimizes the binding affinity parameters to selectively stimulate medium-affinity receptors while minimizing activation of high-affinity receptors that cause vascular leak syndrome
2Object-affected harmful factors
If low-dosage IL-2 regimens are used to avoid vascular leak syndrome, then side effects are reduced, but treatment outcomes are compromised
Solution Approach 1:
The mutant IL-2 protein exhibits locally optimized binding properties with selective high affinity for medium-affinity IL-2R (βγ chain) and reduced affinity for high-affinity IL-2R (αβγ chain). This local optimization at the binding interface allows the protein to effectively stimulate effector cell expansion through medium-affinity receptors while avoiding the pathological activation of high-affinity receptors, thereby maintaining treatment efficacy at lower doses
Solution Approach 2:
The patent introduces mutant IL-2 variants as an intermediary that mediates selective stimulation of medium-affinity IL-2R (βγ chain) without strongly activating high-affinity IL-2R (αβγ chain). This intermediary approach allows therapeutic effect to be achieved through alternative receptor pathways, bypassing the toxic high-affinity receptor activation while maintaining immunotherapeutic benefit
3Productivity
If wild-type IL-2 is used to expand immune cells, then proliferation of T cells and NK cells is achieved, but non-selective expansion of non-tumor-killing immune cells occurs
Solution Approach 1:
The patent applies local quality by introducing specific amino acid mutations at the receptor binding interface (positions 38, 42, 72) to create differential binding properties. The mutant IL-2 protein exhibits selective high affinity for medium-affinity IL-2R (βγ chain) which is preferentially expressed on tumor-killing effector cells, while having reduced affinity for high-affinity IL-2R (αβγ chain). This local optimization enables selective expansion of desired immune cell populations
Solution Approach 2:
The patent inverts the conventional approach by designing IL-2 mutants that primarily activate medium-affinity receptors rather than high-affinity receptors. Instead of relying on high-affinity binding to achieve potency, the invention achieves selective cell expansion through preferential activation of medium-affinity IL-2R (βγ chain), thereby inverting the traditional affinity paradigm to achieve both selectivity and efficacy
Data Source
AI summary
Provided in the present invention are an IL-2 mutant protein, a fusion protein or conjugate containing the IL-2 mutant protein, and a pharmaceutical composition containing the IL-2 mutant protein, fusion protein or conjugate. Compared with wild-type IL-2 protein, the IL-2 mutant protein of the present invention eliminates or reduces the affinity for a high-affinity IL-2 receptor and substantially retains the affinity for a medium-affinity IL-2 receptor.