HVR1-Modified Adenovirus Hexon for MSC and Tumor Transduction
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Solution Overview
Problem
Efficient delivery of adenoviruses to tumors after systemic administration is challenging due to cellular and non-cellular interactions and sequestration mechanisms, and mesenchymal stromal cells (MSCs) are poorly infected by adenoviruses despite their potential as carriers to tumor tissue.
Innovation Solution
A human adenovirus species C with a modified hexon protein having a specific sequence in the HVR1 region (DEAATALEINLKKKKQAEQQ) enhances transduction efficiency by reducing negative surface charge, avoiding Factor X binding, neutralization by IgM antibodies, and scavenger receptor uptake, thereby facilitating systemic delivery and improved transduction of MSCs and tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wildtype adenovirus is used for systemic administration, then the virus can infect CAR-expressing cells, but it fails to efficiently transduce MSCs and is subject to non-target interactions and sequestration
Solution Approach 1:
The patent modifies the surface charge parameter of the adenovirus capsid by introducing basic amino acid residues (arginine or lysine) at specific positions in the hexon protein. This parameter change alters the viral surface properties to reduce negative charge, thereby avoiding recognition by Factor X and scavenger receptors, while maintaining or enhancing transduction efficiency of target cells including MSCs.
Solution Approach 2:
The invention applies local modification to specific regions of the hexon protein (positions 445-451 and/or 477-483) rather than global changes. By introducing basic amino acids at these specific locations, the virus achieves localized charge modification that selectively interacts with Factor X and scavenger receptors without compromising overall viral structure or function.
2Productivity
If adenovirus is administered systemically, then it can reach tumor tissue, but it is neutralized by IgM antibodies and taken up by scavenger receptors
Solution Approach 1:
The patent changes the electrostatic parameter of the viral surface by introducing basic amino acid residues that reduce the negative surface charge. This parameter modification specifically interferes with the binding interface between the virus and IgM antibodies and scavenger receptors, thereby reducing neutralization and uptake while preserving delivery efficiency to tumor tissue.
Solution Approach 2:
The invention converts the harmful effect of negative surface charge (which triggers neutralization and scavenger receptor uptake) into a beneficial property by introducing basic amino acids. This creates a new surface charge characteristic that specifically blocks harmful interactions while maintaining or enhancing viral transduction capability.
3Object-affected harmful factors
If the hexon protein is modified to reduce negative surface charge, then Factor X binding and scavenger receptor uptake are avoided, but the virus must maintain transduction efficiency
Solution Approach 1:
The patent applies localized modification to specific regions of the hexon protein (positions 445-451 and/or 477-483) rather than global changes. By introducing basic amino acids at these specific locations, the virus achieves localized charge modification that selectively interacts with Factor X and scavenger receivers without compromising overall viral structure or function.
Solution Approach 2:
The invention modifies the surface charge parameter of the adenovirus capsid by introducing basic amino acid residues (arginine or lysine) at specific positions in the hexon protein. This parameter change alters the viral surface properties to reduce negative charge, thereby avoiding recognition by Factor X and scavenger receptors, while maintaining or enhancing transduction efficiency of target cells.
Data Source
AI summary
The invention discloses a human adenovirus species C having a capsid which comprises a modified adenovirus hexon protein, wherein the modified adenovirus hexon protein has a modified HVR1 region, wherein the modified HVR1 region has the sequence DEAATALEINLKKKKQAEQQ (SEQ ID NO.: 1). The invention further discloses the adenovirus of the disclosure for use in treating or preventing a human disease. The invention further discloses a nucleic acid encoding the modified adenovirus hexon protein. The invention further discloses the use of an adenovirus according to the disclosure for transducing mesenchymal stromal cells (MSCs) or tumor cells. The invention further discloses an in vitro method for transducing MSCs and a transduced MSC obtainable by the method. The invention further discloses the transduced MSC of the disclosure for use in treating a disease.