DSG2-Binding Adenoviral Fiber Proteins for Epithelial Cell Targeting
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Solution Overview
Problem
Existing adenoviruses, particularly species B serotypes Ad3, Ad7, Ad14, and Ad14a (AdB-⅔), face challenges in infecting epithelial cancer cells due to the trapping of their primary receptors, CAR and CD46, in tight junctions, and lack efficient methods for targeted delivery to these cells.
Innovation Solution
Development of recombinant AdB-⅔ fiber polypeptides with enhanced affinity for desmoglein 2 (DSG2) by modifying the fiber knob domain and incorporating non-AdB-⅔-derived dimerization domains, allowing for improved binding and delivery to epithelial tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If AdB-2/3 adenoviruses use CAR or CD46 as primary attachment receptors, then they can infect epithelial cells, but the receptors are trapped in tight junctions and not accessible to the viruses
Solution Approach 1:
The patent introduces a recombinant fiber polypeptide with a modified knob domain that binds to DSG2 as an intermediary mechanism. This new binding interface acts as a mediator that bypasses the blocked CAR/CD46 receptors, allowing the virus to attach to epithelial cells through an alternative pathway via DSG2 on the cell surface
Solution Approach 2:
The patent modifies the fiber knob domain structure and composition to change the binding parameters. By altering the amino acid sequence of the knob domain to enhance affinity for DSG2, the virus changes its attachment characteristics from receptor-dependent (CAR/CD46) to DSG2-dependent, overcoming the accessibility problem
2Reliability
If adenoviruses target epithelial cancer cells, then therapeutic efficacy is improved, but delivery efficiency remains low due to receptor trapping
Solution Approach 1:
The recombinant fiber polypeptide with enhanced DSG2 binding affinity serves as an intermediary delivery mechanism. This modified fiber structure mediates efficient attachment to epithelial cancer cells by binding to DSG2, which is accessible on the cell surface, thereby improving delivery efficiency while maintaining therapeutic efficacy
Solution Approach 2:
The patent performs preliminary modification of the fiber knob domain before viral delivery. By pre-engineering the fiber polypeptide to have enhanced DSG2 binding capability, the system is prepared in advance to efficiently recognize and attach to target cells, ensuring both high delivery efficiency and therapeutic efficacy
3Reliability
If the fiber knob domain is modified to enhance DSG2 binding affinity, then targeted delivery to epithelial tissues is improved, but the complexity of protein engineering increases
Solution Approach 1:
The patent applies local quality modification by focusing engineering changes specifically on the fiber knob domain rather than the entire viral structure. By concentrating the protein engineering efforts on this localized region to enhance DSG2 binding, the complexity is managed while achieving improved binding affinity and targeted delivery
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified AdB-⅔ fiber polypeptides demonstrate enhanced binding to DSG2, facilitating targeted delivery to epithelial tissues and improved therapeutic efficacy in cancer models, including enhanced chemotherapy responses.
Implementation Method 1
The modified AdB-2/3 fiber polypeptides demonstrate enhanced binding to DSG2
Data Source
AI summary
Disclosed are recombinant adenoviral compositions and methods for their use in treating disorders associated with epithelial tissues.