Multi-Chain Chimeric Polypeptides With Soluble Tissue Factor Scaffolds
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Solution Overview
Problem
The mechanism of 'decryption' of cell-surface tissue factor for coagulation is unclear, and existing methods do not effectively utilize soluble tissue factor as a scaffold for chimeric polypeptides to stimulate immune cells or treat conditions.
Innovation Solution
Development of multi-chain chimeric polypeptides comprising a soluble tissue factor domain and antigen-binding domains, which associate through affinity domains to stimulate immune cells and treat various diseases and conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If soluble tissue factor is used as a scaffold for chimeric polypeptides, then immune cell activation and proliferation are enhanced, but the mechanism of tissue factor decryption for coagulation remains unclear and unutilized
Solution Approach 1:
The patent uses soluble tissue factor as an intermediary scaffold to bridge immune cell targets and affinity domains. The soluble TF domain (residues 1-220) serves as a mediating structure that can be engineered to bind specific immune cell surface antigens while maintaining the ability to associate with affinity domains through defined interfaces, thereby enabling controlled immune cell activation without requiring understanding of the natural decryption mechanism.
Solution Approach 2:
The chimeric polypeptide is segmented into distinct functional modules: a target-binding domain (antigen-specific), a soluble tissue factor domain (residues 1-220 serving as scaffold), and affinity domains (for association). This segmentation allows independent optimization of each domain's function while maintaining overall stability and activity of the chimeric construct.
2Adaptability or versatility
If multi-chain chimeric polypeptides are developed with multiple domains, then versatility in treating diseases is improved, but structural complexity increases
Solution Approach 1:
The soluble tissue factor domain serves multiple functions simultaneously: it acts as a structural scaffold, provides a platform for target antigen binding, enables association with affinity domains through defined interfaces, and maintains stability in solution. This multi-functionality reduces the need for separate structural elements, thereby managing complexity while enhancing versatility.
Solution Approach 2:
The chimeric polypeptide combines different functional domains (target-binding, soluble TF scaffold, affinity domains) into a single composite molecular structure. This composite approach allows integration of diverse functions (antigen recognition, cell activation, stability) within a unified polypeptide architecture, enhancing versatility without proportionally increasing complexity.
Data Source
AI summary
Provided herein are multi-chain chimeric polypeptides that include:(a) a first chimeric polypeptide including a first target-binding domain, a soluble tissue factor domain, and a first domain of a pair of affinity domains; and (b) a second chimeric polypeptide including a second domain of a pair of affinity domains and a second target-binding domain, where the first chimeric polypeptide and the second chimeric polypeptide associate through the binding of the first domain and the second domain of the pair of affinity domains. Also provided here are methods of using these multi-chain chimeric polypeptides and nucleic acids encoding these multi-chain chimeric polypeptides.