IL-21 Mutant Protein Engineering for Selective Immune Activation
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Solution Overview
Problem
Interleukin-21 (IL-21) has limitations due to its high affinity for the IL-21 receptor, leading to short half-life and challenges in purification and druggability, as well as non-selective activation of immune cells, which complicates its therapeutic application in immunotherapy and production processes.
Innovation Solution
A novel IL-21 mutant protein with specific mutations, such as amino acid substitutions and deletions, is developed to reduce binding affinity to the IL-21 receptor, enhance stability, and improve druggability, including glycosylation mutations and fusion with antibodies like PD-1, to achieve selective activation of antigen-positive cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Force
If wild-type IL-21 is used, then high binding affinity to IL-21R is achieved, but half-life becomes very short
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations (e.g., N82A, N82Q, N82P, N82D, N82E, N82K, N82R, N82M, N82F, N82W, N82Y, N82C, N82S, N82T, N82G, N82H, N82V, N82I, N82L, N82A) at position 82 of the IL-21 molecule. These mutations modify the binding characteristics of IL-21 to IL-21R, reducing affinity while extending half-life, thereby resolving the contradiction between high binding affinity and short duration of action.
2Power
If wild-type IL-21 is used, then potent immune activation is achieved, but molecular toxicity increases
Solution Approach 1:
The patent applies local quality by making targeted local modifications at position 82 of the IL-21 molecule. This specific local mutation reduces the non-selective activation of immune cells while preserving the desired immune activation potency, thereby reducing molecular toxicity without sacrificing therapeutic efficacy.
3Reliability
If wild-type IL-21 is used, then biological activity is maintained, but purification difficulty increases
Solution Approach 1:
The patent applies parameter changes through amino acid substitution at position 82, which modifies the physical and chemical properties of IL-21. These changes improve the purification characteristics of the molecule while maintaining its biological activity, thereby resolving the contradiction between reliability and ease of manufacture.
4Reliability
If wild-type IL-21 is used, then natural function is preserved, but druggability deteriorates
Solution Approach 1:
The patent applies parameter changes by introducing specific mutations at position 82 of IL-21. These mutations improve the druggability of the molecule, making it more suitable for therapeutic applications, while preserving its natural biological function and reducing non-selective immune activation.
Data Source
AI summary
The present invention relates to a novel interleukin-21 (IL-21) mutant protein and use thereof. In particular, the present invention relates to an IL-21 mutant protein that has improved properties, such as a reduced binding property to an IL-21 receptor and improved druggability, compared to wild-type IL-21. The present invention also provides a fusion comprising the IL-21 mutant protein, a nucleic acid encoding the IL-21 mutant protein or the fusion, and a vector and a host cell comprising the nucleic acid. The present invention further provides a method for preparing the IL-21 mutant protein or the fusion, a pharmaceutical composition comprising the same, and therapeutic use.