IL2-C4BPβ Chimeric Construct for Treg Selectivity
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Solution Overview
Problem
Interleukin-2 (IL2) therapies face limitations due to its short half-life in vivo, which affects its pharmacokinetics and pharmacodynamics, necessitating the development of new IL2 biologics with improved properties for enhanced therapeutic efficacy, particularly in autoimmune and inflammatory diseases.
Innovation Solution
A chimeric construct comprising an IL2 moiety fused with a beta chain of C4b-binding protein (C4BPβ) or its fragments, capable of forming dimeric proteins, which improves the half-life and selectivity of Treg expansion, achieved through covalent bonding between cysteines of C4BPβ, forming homodimers or heterodimers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If conventional IL2 is used for therapy, then immune response can be boosted, but the half-life is short leading to frequent administration requirements
Solution Approach 1:
The patent combines IL2 with C4b-binding protein (C4BP) to create a fusion protein. This merging of two different proteins allows the IL2 component to maintain its immune-stimulating function while the C4BP component extends the half-life by reducing renal clearance and increasing plasma residence time, thereby resolving the contradiction between duration of action and therapeutic efficacy
Solution Approach 2:
The invention creates a composite protein structure consisting of IL2 and C4BP domains. This composite material approach allows the fusion protein to exhibit properties of both components: the biological activity of IL2 and the pharmacokinetic benefits of C4BP, including extended circulation half-life and improved stability
2Reliability
If IL2 therapy is administered to boost immune response, then T cell expansion occurs, but selectivity between different T cell types is insufficient
Solution Approach 1:
The patent introduces amino acid substitutions at specific positions (such as N88R) within the IL2 sequence to locally modify the protein's binding properties. These localized changes alter the affinity and specificity of IL2 for different T cell receptor types, enhancing selectivity for regulatory T cells while reducing activation of conventional T cells, thereby improving reliability and reducing toxicity
Data Source
AI summary
The present invention relates to a chimeric construct, comprising i) an interleukin 2 (IL2) moiety and ii) a beta chain of the C4b-binding protein (C4BPβ) or at least one fragment or functional variant thereof that is capable of forming a dimeric protein.