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Aptamer-facilitated Protection of Oncolytic Virus from Neutralizing Antibodies
Darija Muharemagic1, Anna Zamay2, Shahrokh M Ghobadloo1
1Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada.
Abstract:
Oncolytic viruses promise to significantly improve current cancer treatments through their tumor-selective replication and multimodal attack against cancer cells. However, one of the biggest setbacks for oncolytic virus therapy is the intravenous delivery of the virus, as it can be cleared from the bloodstream by neutralizing antibodies before it reaches the tumor cells. We have selected DNA aptamers against an oncolytic virus, vesicular stomatitis virus, using a competitive binding approach, as well as against the antigen binding fragment (Fab) of antivesicular stomatitis virus polyclonal antibodies, in order to shield the virus from nAbs and enhance its in vivo survival. We used flow cytometry to identify these aptamers and evaluated their efficiency to shield vesicular stomatitis virus in a cell-based plaque forming assay. These oligonucleotides were then modified to obtain multivalent binders, which led to a decrease of viral aggregation, an increase in its infectivity and an increase in its stability in serum. The aptamers were also incubated in nondiluted serum, showing their effectiveness under conditions mimicking those in vivo. With this approach, we were able to increase viral infectivity by more than 70% in the presence of neutralizing antibodies. Thus, this method has the potential to enhance the delivery of vesicular stomatitis virus through the bloodstream without compromising the patient's immune system.
Insights
DNA aptamers shield oncolytic viruses from neutralizing antibodies, enhancing their delivery and effectiveness in cancer treatment. This method improves in vivo survival and infectivity, offering a promising solution for intravenous virus therapy.
Area of Science:
- Biotechnology
- Virology
- Cancer Therapy
Background:
- Oncolytic virus therapy offers a promising approach to cancer treatment due to tumor-selective replication and multimodal attack.
- Intravenous delivery of oncolytic viruses is hindered by clearance from the bloodstream by neutralizing antibodies, limiting therapeutic efficacy.
Purpose of the Study:
- To develop DNA aptamers that can shield oncolytic viruses from neutralizing antibodies.
- To enhance the in vivo survival and delivery of vesicular stomatitis virus (VSV) for cancer therapy.
Main Methods:
- Selection of DNA aptamers against VSV and anti-VSV antibodies using competitive binding.
- Identification of aptamers via flow cytometry and evaluation of VSV shielding in plaque-forming assays.
- Modification of aptamers into multivalent binders to improve viral infectivity and serum stability.
Main Results:
- Selected aptamers effectively shielded VSV from neutralizing antibodies.
- Multivalent aptamer binders decreased viral aggregation and increased VSV infectivity and serum stability.
- Viral infectivity was enhanced by over 70% in the presence of neutralizing antibodies.
Conclusions:
- DNA aptamers can be engineered to protect oncolytic viruses from immune clearance.
- This aptamer-based shielding strategy significantly enhances VSV infectivity and stability in vivo.
- The approach holds potential for improving intravenous delivery of oncolytic viruses without compromising the patient's immune system.
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