Researchers at The Wistar Institute and colleagues say they have successfully engineered novel DNA-encoded monoclonal antibodies (DMAbs) targeting Zaire Ebolavirus that were effective in preclinical models. Their study (“In Vivo Delivery of Synthetic Human DNA-Encoded Monoclonal Antibodies Protect against Ebolavirus Infection in a Mouse Model”), published online in Cell Reports, showed that DMAbs were expressed over a wide window of time and offered complete and long-term protection against lethal virus challenges. DMAbs may also provide a novel powerful platform for rapid screening of monoclonal antibodies enhancing preclinical development, according to the scientists.
“Synthetically engineered DNA-encoded monoclonal antibodies are an in vivo platform for evaluation and delivery of human mAb to control against infectious disease. Here, we engineer DMAbs encoding potent anti-Zaire ebolavirus (EBOV) glycoprotein (GP) mAbs isolated from Ebola virus disease survivors. We demonstrate the development of a human IgG1 DMAb platform for in vivo EBOV-GP mAb delivery and evaluation in a mouse model. Using this approach, we show that DMAb-11 and DMAb-34 exhibit functional and molecular profiles comparable to recombinant mAb, have a wide window of expression, and provide rapid protection against lethal mouse-adapted EBOV challenge,” write the article investigators.
“The DMAb platform represents a simple, rapid, and reproducible approach for evaluating the activity of mAb during clinical development. DMAbs have the potential to be a mAb delivery system, which may be advantageous for protection against highly pathogenic infectious diseases, like EBOV, in resource-limited and other challenging settings.”
“Our studies show deployment of a novel platform that rapidly combines aspects of monoclonal antibody discovery and development technology with the revolutionary properties of synthetic DNA technology,” 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.
The team designed and enhanced optimized DMAbs that, when injected locally, provide the genetic blueprint for the body to make functional and protective Ebola virus-specific antibodies, circumventing multiple steps in the antibody development and manufacturing process. Dozens of DMAbs were tested in mice and the best-performing ones were selected for further studies. These proved to be highly effective for providing complete protection from disease in challenge studies.
“Due to intrinsic biochemical properties, some monoclonal antibodies might be difficult and slow to develop or even impossible to manufacture, falling out of the development process and causing loss of potentially effective molecules,” added Dr. Weiner. “The DMAb platform allows us to collect protective antibodies from protected persons and engineer and compare them rapidly and then deliver them in vivo to protect against infectious challenge. Such an approach could be important during an outbreak, when we need to design, evaluate, and deliver life-saving therapeutics in a time-sensitive manner.”
“We started with antibodies isolated from survivors and compared the activity of anti-Ebola virus DMAbs and recombinant monoclonal antibodies over time,” added Ami Patel, Ph.D., first author on the study and associate staff scientist in the Wistar Vaccine and Immunotherapy Center. “We showed that in vivo expression of DMAbs supports extended protection over traditional antibody approaches.”
The researchers also looked at how DMAbs physically interact with their Ebola virus epitopes and confirmed that DMAbs bind to identical epitopes as the corresponding recombinant monoclonal antibodies made in traditional bioprocess facilities.
The Weiner Laboratory is also developing an anti-Ebola virus DNA vaccine. Preclinical results from this efforts were published recently in the Journal of Infectious Diseases.