TGFβ Trap Linker Sequences for Optimal Ligand Binding
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Solution Overview
Problem
Current fusion proteins, particularly TGFβ receptor fusion proteins, are inadequate in neutralizing the biological activity of human TGFβ for treating disorders mediated by TGFβ.
Innovation Solution
Incorporation of linker sequences into fusion proteins to enhance their function, including optimal ligand binding, temporal and spatial colocalization, improved expression, reduced immunogenicity, and provision of a cleavage site, thereby optimizing the structure and function of cytokine receptor fusion proteins like TGFβ traps.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional fusion proteins are used to trap TGFβ, then the structure is simpler and manufacturing is easier, but the ligand binding ability is insufficient and therapeutic efficacy is limited
Solution Approach 1:
The fusion protein is segmented into distinct functional domains: TGFβ receptor extracellular domain for ligand binding, linker region for flexibility and proper spacing, and Fc portion for stabilization and immune modulation. This segmentation allows each component to optimize its function while maintaining overall protein stability
Solution Approach 2:
The fusion protein combines different protein components (TGFβ receptor domain and Fc domain) with distinct functional properties into a single composite molecule. The TGFβ receptor portion provides specific ligand binding while the Fc portion provides structural stability and extended half-life, creating a composite therapeutic agent with enhanced overall performance
2Reliability
If fusion proteins are administered to treat TGFβ-mediated disorders, then therapeutic activity is enhanced, but inappropriate cellular localization increases the risk of toxicity
Solution Approach 1:
The Fc domain acts as an intermediary that directs the fusion protein to appropriate cellular locations and interacts with Fc receptors on immune cells. This intermediary component ensures proper trafficking and reduces off-target effects, thereby enhancing therapeutic activity while minimizing toxicity risk
3Reliability
If fusion proteins are used to neutralize TGFβ activity, then immune tolerance is reduced, but immunogenicity of the fusion protein may increase
Solution Approach 1:
The fusion protein uses human-derived sequences for both the TGFβ receptor domain and the Fc domain, matching human protein structures. This parameter change in sequence composition reduces recognition by the human immune system as foreign, thereby maintaining effective TGFβ neutralization while minimizing immunogenicity and antibody formation against the therapeutic protein
Data Source
AI summary
Provided is a fusion protein, e.g., a cytokine receptor fusion protein, e.g., a TGFβ trap, with a novel linker sequence to permit the fusion protein to functionally optimally, e.g., to permit a cytokine receptor portion of a cytokine receptor fusion protein to bind optimally to its target cytokine. The fusion proteins, or expression vectors encoding for the fusion proteins, e.g., oncolytic adenoviral expression vectors, can be used to treat cell proliferative diseases and disorders, including certain forms of cancer and inflammatory disorders.