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Novel DNA-based Immunotherapy for Neutralizing Hepatitis B Virus infection 

PHILADELPHIA — (May. 28, 2020) — Scientists at The Wistar Institute developed a synthetic DNA approach that instructs in vivo production of a human monoclonal antibody able to neutralize hepatitis B virus (HBV) and prevent infection of liver cells in vitro. The new strategy, described in a paper in Human Vaccines & Immunotherapeutics, may be useful one day in preventing and treating HBV infection and a wide range of cancers associated with this virus. Synthetic DNA human monoclonal antibodies also have broader potential as a virus-neutralizing therapy for infectious diseases.

HBV is a viral liver infection that can cause both acute and chronic disease and is the most common risk factor for liver cancer. Three hundred fifty million people worldwide live with chronic HBV infection, and nearly 1 million die each year due to complications including liver cirrhosis and hepatocellular carcinoma.

The lab of Kar Muthumani, Ph.D., associate professor in the Vaccine & Immunotherapy Center at Wistar, specializes in synthetic DNA technologies for vaccines and immunotherapies in infectious diseases and cancer. The lab decided to apply their novel platform to develop a new strategy for passive immunization using DNA-encoded anti-HBV antibodies to neutralize hepatitis B infection. This system has the potential to be explored in the future to inhibit the progression of HBV-associated cancer.

Current therapies include interferon-alpha and antiviral therapies that control HBV replication but fail to eliminate infection. A safe and effective vaccine is available and recommended for all children and at-risk adults, but an estimated 5-15% of people do not respond to immunization and remain susceptible to infection. Passive immunization utilizing hepatitis B immune globulin is required to protect non-responders in case of possible acute exposure.

"Immunoglobulins (IgG) used for passive immunization are derived from the blood of donors with high antibody levels, but one limitation of this approach is that antibody titers and neutralization efficiency are variable from donor to donor," said Muthumani. "In our platform, we encode a monoclonal antibody with well-characterized specificity, which offers advantages in terms of consistency and reproducibility, whereas precise antigen specificity of most HBV immunoglobulin preparations is not known and represents a source of variability. Also, our approach is easy to produce and deliver and is more cost-effective compared to protein therapies."

Muthumani and team designed and developed synthetic DNA encoding a human anti-HBV monoclonal antibody as a novel approach to immunotherapy of HBV infection. Pioneered by Wistar scientists, DNA-encoded monoclonal antibodies (DMAbs) are based on the ability of engineered DNA sequences to instruct the cells to produce therapeutic monoclonal antibodies against infectious diseases and cancer.

In the study, the Muthumani lab demonstrated that a single administration of an anti-HBV-DMAb generates functional neutralizing activity against HBV for several weeks. Furthermore, immunoglobulins generated in vivo had the proper folding and were able to prevent HBV infection of HepaRG liver cells.

Based on these results, the DMAb technology might be developed as a stand-alone additional therapy or be used in combination with current HBV immunotherapies to prevent and/or treat HBV infection and its associated diseases including hepatocellular carcinoma. 

Co-authors: Urvi S. Zankharia, Sagar Kudchodkar, Makan Khoshnejad, Alfredo Perales Puchalt, Hyeree Choi, Michelle Ho, Faraz Zaidi, Kenneth E. Ugen, and David B. Weiner from Wistar; Kenneth E. Ugen from University of South Florida; and Joseph J. Kim from Inovio Pharmaceuticals, Inc.
 
Work supported by: Inovio Pharmaceuticals. 

Publication information: Neutralization of hepatitis B virus by a novel DNA-encoded monoclonal 1 antibody, Human Vaccines & Immunotherapeutics (2020). Advanced online publication. 

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

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