Ad11-5EP Recombinant Adenovirus Vector for Tumor Targeting
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Solution Overview
Problem
Current adenovirus vectors, particularly Ad5, face challenges in effectively targeting and infecting tumor cells due to low expression of CAR and CEACAM6, leading to reduced antitumoral efficacy and high neutralizing antibody levels, as well as hepatotoxicity, limiting their application in cancer therapy.
Innovation Solution
Development of a recombinant adenovirus vector Ad11-5EP with the E1A gene enhancer and promoter replaced by those of Ad5, and the creation of Ad11-5ETel-GFP, which uses the telomerase promoter to enhance tumor specificity and sensitivity for detecting circulating tumor cells by expressing GFP.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Ad5 is used as a gene conversion vector, then high neutralizing antibody levels are produced, but hepatotoxicity occurs and infection rate is reduced due to downregulation of virus acceptor
Solution Approach 1:
The patent segments the adenovirus system by separating the capsid protein genes (hexon, fiber) from the E1A regulatory genes. This allows independent optimization: using Ad11 capsid proteins for reduced hepatotoxicity and improved tumor cell infection, while using Ad5 E1A genes for high-level transgene expression and neutralizing antibody induction.
Solution Approach 2:
The patent uses Ad11 as an intermediary serotype to bridge the gap between Ad5's high immunogenicity and reduced hepatotoxicity. Ad11's capsid proteins serve as a mediator that enables infection of tumor cells with low CAR expression while avoiding liver-specific tropism, thus resolving the contradiction between immunogenicity and safety.
2Reliability
If Ad5 is used to infect tumor cells, then transduction occurs, but infection ability is significantly decreased due to low expression of CAR and CEACAM6
Solution Approach 1:
The patent changes the serotype parameter from Ad5 to Ad11, which alters the virus-receptor interaction properties. Ad11 has different tropism characteristics that allow it to infect tumor cells with low CAR and CEACAM6 expression, thus expanding the range of infectible tumor cell types while maintaining transduction efficiency.
3Measurement precision
If replication-selective oncolytic adenovirus is used to detect CTCs, then sensitivity is improved, but genetic variation of tumor cells and low CAR expression reduce infection ability
Solution Approach 1:
The patent creates a universal oncolytic adenovirus vector that can infect diverse tumor cell types regardless of genetic variation. By using Ad11 capsid proteins with broader tropism, the system achieves multi-functionality in detecting CTCs from different tumor origins, overcoming the limitation of Ad5's restricted infectivity.
4Adaptability or versatility
If chimeric oncolytic Ad5 is constructed by substituting cilium with B subgroup adenovirus, then ability to combine with membrane receptor CD46 is improved, but neutralizing ability of hexon antigen of Ad5 remains
Solution Approach 1:
The patent merges the advantages of Ad11 (receptor binding to CD46 and surface receptor X, reduced neutralizing antibodies) with Ad5 (high transgene expression, established safety profile) by constructing a recombinant vector with Ad11 capsid proteins and Ad5 E1A genes. This combination achieves both improved receptor binding and reduced immunogenicity.
Data Source
AI summary
A subgroup B recombinant human adenovirus vector Ad11-5EP (SEQ ID NO: 1), which is constructed by a method including: substituting a 365 bp fragment containing an enhancer and a promoter of an upstream coding sequence of Ad5 E1A (SEQ ID NO: 2) for a corresponding region of a serotype Ad11 (SEQ ID NO: 3) of a subgroup B human adenovirus vector by homologous recombination to construct the subgroup B recombinant human adenovirus vector Ad11-5EP (SEQ ID NO: 1).