IL-2 Mutant Composition for Stable Treg-Selective Receptor Binding
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Solution Overview
Problem
Existing IL-2 drugs face challenges in stability and yield, and their binding abilities to specific receptor complexes are not optimally tailored for preferential stimulation of regulatory T cells, limiting their effectiveness in treating tumors and autoimmune diseases.
Innovation Solution
Development of IL-2 mutants with specific mutations at positions such as Q13, L18, G27, Y31, A73, H79, P82, N90, V91, V93, F117, or R120, which reduce binding to IL-2Rβγ and enhance preferential stimulation of regulatory T cells, along with fusion proteins and conjugates that include stabilizers like polyethylene glycol.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type IL-2 is used to activate immune cells, then immune cell proliferation and activation are achieved, but binding specificity to regulatory T cells is insufficient and stability is poor
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations at positions Q13, L18, G27, Y31, A73, H79, P82, N90, V91, V93, F117, or R120 of the IL-2 molecule. These parameter changes in the protein structure modify the binding characteristics to achieve preferential binding to IL-2Rαβγ on regulatory T cells while improving overall stability
Solution Approach 2:
The patent applies local quality by making specific localized mutations at particular amino acid positions within the IL-2 molecule. Each mutation position represents a local modification that enhances binding specificity to the αβγ receptor complex while maintaining or improving overall protein stability
2Reliability
If high doses of IL-2 are administered to treat tumors, then therapeutic effect is improved, but binding specificity to regulatory T cells remains insufficient
Solution Approach 1:
The patent uses parameter changes through site-directed mutagenesis at specific positions to fundamentally alter the binding profile of IL-2. This enables high therapeutic efficacy through preferential binding to regulatory T cells at lower doses, eliminating the need for high-dose administration
3Manufacturing precision
If IL-2 mutants with multiple mutations are created to improve binding specificity, then regulatory T cell stimulation is enhanced, but protein stability may be compromised
Solution Approach 1:
The patent systematically applies parameter changes through combinations of specific mutations that have been optimized to work together. The selected mutation positions and combinations are designed to enhance binding specificity while maintaining or improving protein stability through synergistic effects
Solution Approach 2:
The patent creates composite mutant IL-2 proteins by combining multiple amino acid mutations within a single protein molecule. This composite structure integrates the beneficial effects of individual mutations to achieve both high binding specificity and improved stability simultaneously
Data Source
AI summary
The present disclosure discloses IL-2 mutants and uses thereof. More specifically, the disclosure provides IL-2 mutants and corresponding fusion proteins, conjugates, nucleic acid fragments, vectors, host cells, methods for preparing the mutants or fusion proteins, IL-2 mutants or fusion proteins prepared according to the methods, pharmaceutical compositions, pharmaceutical uses, methods for treating diseases, and methods for preferentially stimulating regulatory T cells. Compared to wild-type IL-2, the IL-2 mutants of the present disclosure have higher Tm values and improved stability; alternatively, the IL-2 mutants of the present disclosure have an increased yield or changed binding activity to the IL-2Rβγ complexes compared to wild-type IL-2.