Targeted Adenovirus AB-Loop Modification for CAR-Negative Cancer
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Solution Overview
Problem
Current adenovirus-based oncolytic agents face challenges in targeting cancer cells due to low expression of primary adenovirus receptors, such as Coxsackie adenovirus receptor (CAR), in many cancer cells, limiting their effectiveness.
Innovation Solution
Development of adenoviruses with an AB-loop comprising a targeting motif that selectively binds to specific cancer cells, including prostate, colorectal, pancreatic, and mesothelin-expressing cells, allowing for targeted delivery and replication within these cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adenovirus-based oncolytic agents are used for cancer treatment, then high in vivo transduction efficiency is achieved, but lack of primary Ad receptor (CAR) expression in majority of cancer cells limits effectiveness
Solution Approach 1:
The patent modifies the adenovirus fiber protein structure, specifically the AB-loop region, to change its binding parameters. By substituting amino acid sequences in the fiber knob domain, the virus gains ability to bind to alternative receptors (integrins, CD46, CD55) beyond the native CAR receptor, enabling infection of cancer cells that lack CAR expression while maintaining transduction efficiency
Solution Approach 2:
The modified fiber protein acts as an intermediary structure that bridges the adenovirus capsid to alternative cell surface receptors. The engineered AB-loop region serves as a mediator that can interact with multiple receptor types (integrins, CD46, CD55), allowing the virus to enter cells through alternative pathways when the primary CAR receptor is absent
2Measurement precision
If adenovirus library is screened in vitro to identify targeting motifs, then selective binding to target cells is achieved, but in vivo tumor targeting and reduced non-target organ sequestration remain challenging
Solution Approach 1:
The patent applies local quality modification by specifically altering the AB-loop region of the fiber protein while leaving the rest of the viral structure intact. This localized change in the fiber knob domain enables selective binding to tumor-associated receptors (mesothelin, EGFR, CD46) without affecting overall viral function, achieving both in vitro selectivity and in vivo tumor targeting
Solution Approach 2:
The patent creates a dynamic targeting system where the fiber protein can adapt to different receptor environments. By introducing multiple potential binding specificities through AB-loop modification, the virus can dynamically switch between binding to CAR, integrins, CD46, or CD55 depending on which receptors are available on the target cell surface, enhancing both selectivity and in vivo efficacy
Data Source
AI summary
Described herein is an adenovirus comprising an AB-loop comprising a targeting motif and methods of making and using the adenovirus. The targeting motif of the adenovirus can selectively bind to a tumor cell. The targeting motif of the adenovirus can selectively bind to cell markers and/or cell surface antigens including, for example, CD 133.