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Updated: May 23, 2025
Utilizing the Antigen Capsid-Incorporation Strategy for the Development of Adenovirus Serotype 5-Vectored Vaccine Approaches
Published on: May 6, 2015
Chimeric Ad5/35 oncolytic adenovirus overcome preexisting neutralizing antibodies and enhance tumor targeting
Zhoutong Dai1,2, Yao Si1,2, Shengfeng Xiong1,2
1Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
KD01, a third-generation conditionally replicating adenovirus serotype 5 developed by our team, has approved by the China Center for Drug Evaluation (CDE) for Phase I clinical trials (NCT06552598). However, 60% seroprevalence of anti-Ad5 neutralizing antibodies is a major hurdle for Ad5-based oncolytic viruses. To address this issue, we developed oAd5/35-HF, a fourth-generation oncolytic adenovirus vector designed to enhance infection efficiency and evade pre-existing neutralizing antibodies (NABs). To achieve this, we introduced targeted capsid modifications, replacing hexon hypervariable regions (HVRs) 1 and 5 with those from adenovirus serotype 35 (Ad35), along with alterations to the fiber region. These combined modifications significantly improved infection efficiency, maintained high viral titers, and enabled the virus to resist NABs. This is the first report of replacing both the Ad5 hexon HVRs and fiber regions with those from Ad35 in an oncolytic adenovirus, resulting in potent antitumor activity across multiple cancer types, even in the presence of high NAB levels. The oAd5/35-HF backbone provides a versatile platform for developing new chimera oncolytic adenovirus and adenovirus vector-based vaccine.
Insights
A novel oncolytic adenovirus, oAd5/35-HF, overcomes pre-existing neutralizing antibodies by modifying capsid proteins. This enhances oncolytic virus therapy efficacy against various cancers.
Area of Science:
- Oncolytic virotherapy
- Adenovirus vector engineering
- Cancer immunology
Background:
- Adenovirus serotype 5 (Ad5) based oncolytic viruses face challenges due to high pre-existing neutralizing antibody (NAB) prevalence.
- A significant portion of the population has antibodies against Ad5, limiting the effectiveness of Ad5-based therapies.
Purpose of the Study:
- To develop a fourth-generation oncolytic adenovirus vector, oAd5/35-HF, capable of evading pre-existing neutralizing antibodies and enhancing infection efficiency.
- To create a versatile platform for oncolytic adenovirus and adenovirus vector-based vaccines.
Main Methods:
- Engineered oAd5/35-HF by replacing adenovirus serotype 5 (Ad5) hexon hypervariable regions (HVRs) 1 and 5 with those from adenovirus serotype 35 (Ad35).
- Modified the fiber region of the adenovirus vector.
- Evaluated infection efficiency, viral titers, and resistance to neutralizing antibodies (NABs).
Main Results:
- The oAd5/35-HF vector demonstrated significantly improved infection efficiency.
- High viral titers were maintained post-modification.
- The engineered virus effectively resisted pre-existing neutralizing antibodies (NABs).
- Demonstrated potent antitumor activity across multiple cancer types, even with high NAB levels.
Conclusions:
- The oAd5/35-HF represents a novel chimera oncolytic adenovirus with enhanced efficacy against cancer.
- This vector platform shows promise for overcoming Ad5 immunity and advancing oncolytic virotherapy and vaccine development.
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