Newswise — PHILADELPHIA — (Apr. 5, 2019) — A new approach for delivery of DNA-encoded monoclonal antibodies (DMAbs) has been reported by Wistar scientists and their collaborators. This new technology allows direct production of monoclonal antibody-like molecules in living animals.
In this study, published in Molecular Therapy, the researchers focused on developing novel DMAbs for protection against Zika virus (ZIKV) infection. DMAbs achieved persisting antibody expression that provided long-term protection against lethal virus challenge in both small animal and, for the first time, non-human primate preclinical models. This study provides a direct bridge to the clinic, supporting further development of the new DMAb technology towards wider application.
“We showed that the DMAb platform produces fast and transient but sustained antibody expression in the blood of small and large animal models,” said lead researcher David B. Weiner, Ph.D., executive vice president and director of Wistar’s Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research. “These properties, coupled with the ease of production and storage, support further development of DMAbs as a possibly ideal approach during infectious disease outbreaks to provide rapid protection to at-risk individuals and, in the case of Zika, to their offspring as well.”
Monoclonal antibodies (MAb) are a major category of therapeutic agents with potential for prevention and treatment of a host of infectious diseases. However, development and delivery of MAbs is expensive and limits its applications. The current study advances the novel DMAb technology by showing expression and protection from an infectious challenge.
ZIKV is a mosquito-borne infection endemic to several areas of the world and has become an important global public health concern, with more than two billion people at risk. No approved vaccine or treatment is currently available for ZIKV infection, which is associated with severe birth defects and neurological complications in adults. Survivors develop ZIKV-specific protective antibodies that are being studied as candidates for development of recombinant monoclonal antibodies for preventive use. However, this approach poses challenges related to development, delivery, manufacturing and storage.
The Weiner Lab engineered a synthetic plasmid DNA encoding an identified and developed potent anti-ZIKV monoclonal antibody ZK190 that binds to the virus envelope. When injected as DMAb intramuscularly in mice and non-human primates, DMAb-ZK190 resulted in antibody presence in circulating blood for several weeks to months.
Importantly, when the animals were challenged with a lethal dose of ZIKV, DMAb-ZK190 provided protection from both infection and disease.
“Our study represents the first evidence of protection with a nucleic acid-encoded antibody in a non-human primate model of infection with any infectious agent,” said Ami Patel, Ph.D., first author on the study and a research assistant professor in the Wistar Vaccine and Immunotherapy Center. “This takes us one step closer to clinical development of the DMAb platform for its deployment in the areas where it is most needed.”
Co-authors: co-first author Rianne N. Esquivel, Sagar B. Kudchodkar, Daniel H. Park, Hyeree Choi, Piyush Borole, Kanika Asija, Mamadou Bah, Shareef Shaheen, and Kar Muthumani from Wistar; Karin Stettler and Davide Corti from Humabs BioMed, SA; Jeff Allen, Janess Mendoza, Stephanie Ramos, Jing Chen, Jian Yan, Trevor R.F. Smith, Kate Broderick, Ghiabe Guibinga, and Laurent Humeau from Inovio Pharmaceuticals; Amy C. Durham from the University of Pennsylvania School of Veterinary Medicine.
Work supported by: National Institutes of Health grant T32-AI055400 and a grant from the Bill & Melinda Gates Foundation.
Publication information: In vivo delivery of a DNA-encoded monoclonal antibody (DMAb) protects non-human primates against Zika virus, Molecular Therapy (2019). Advanced online publication.
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.