Engineered Thioredoxin-Like Fold Proteins for Targeted Binding
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Solution Overview
Problem
Current therapeutic proteins, such as antibodies, face challenges due to their complex and costly biophysical properties, requiring eukaryotic manufacturing processes, and lack of evolvability for directed evolution of enzymatic activities, limiting their application in targeted therapies and diagnostics.
Innovation Solution
Engineered thioredoxin-like fold proteins with modified domains through loop-diversification and chemical modifications, such as PEGylation, to enhance affinity, stability, and pharmacokinetic properties, allowing for targeted binding and conjugation with small molecule drugs or toxins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibodies are used as therapeutic agents, then high specificity and bivalency are achieved, but complex biophysical properties and multi-domain assemblage require eukaryotic manufacturing processes that are more complex and expensive
Solution Approach 1:
The patent extracts the binding function from complex antibody structures and implements it using minimal protein scaffolds (affibodies, nanobodies, thioredoxin-like fold proteins) that require only prokaryotic expression systems, eliminating the need for complex eukaryotic manufacturing while maintaining therapeutic specificity
Solution Approach 2:
The invention employs small, simple protein scaffolds that can be produced in prokaryotic systems (cheaper, simpler manufacturing) rather than using complex, expensive antibody molecules that require eukaryotic cell cultures, thereby reducing manufacturing complexity and cost
2Reliability
If traditional protein scaffolds are used, then binding function is achieved, but lack of evolvability limits directed evolution of enzymatic activities
Solution Approach 1:
The patent introduces dynamic mutability to protein scaffolds through directed evolution techniques, creating families of proteins with variable enzymatic activities while maintaining the core binding function, thereby achieving both reliability and adaptability
Solution Approach 2:
The invention creates universal protein scaffolds that can serve multiple functions - binding to targets and performing enzymatic activities - by incorporating catalytic residues into the scaffold structure, enabling a single protein family to address diverse therapeutic needs
3Ease of operation
If small scaffolds are used instead of antibodies, then tissue penetration is improved for solid tumor targets, but binding affinity and stability may be compromised
Solution Approach 1:
The patent optimizes scaffold size, charge distribution, and surface properties to enhance both tissue penetration and binding affinity simultaneously, demonstrating that small proteins can achieve therapeutic efficacy comparable to antibodies
Solution Approach 2:
The invention combines small protein scaffolds with conjugated molecules (drugs, toxins, radioligands) to create composite therapeutic agents that leverage the penetrating ability of small proteins while the conjugated components provide the necessary binding affinity and therapeutic effect
Data Source
AI summary
The invention features compositions based on thioredoxin-like fold protein domains described as engineered thioredoxin-like fold proteins (ETRXs). These proteins include one or more artificially diversified thioredoxin-like fold protein domains; each domain may be originated from the same or different thioredoxin-like fold protein domains. Features of the invention also include methods for identifying and preparing an enriched composition of target binding, loop-diversified ETRXs with additional sequence variations to improve affinity, stability, selectivity, or solubility. The invention also features compositions of ETRXs substituted with prosthetic groups, polymers, proteins, nucleic acids, carbohydrates, metals, natural or synthetic small molecules and toxins.