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Innovative Synthetic DNA-based Cancer Immunotherapy Approach Shows Tumor-clearing Ability in Preclinical Models

PHILADELPHIA — (April 18, 2019) — Wistar scientists have developed a novel synthetic DNA approach for patient-specific production of cancer-targeting molecules called bispecific T cell engagers. DNA-encoded bispecific T cell engagers (dBiTEs) designed against the HER2 protein were tested in preclinical models of ovarian cancer and induced tumor regression, demonstrating the potential of this novel approach for immunotherapy. Study results were published online in JCI Insights

BiTEs are a type of artificial monoclonal antibody that directly bind to tumor targets, while at the same time binding to and activating killer T cells, providing these T cells with the ability to see and specifically kill the tumors with high accuracy. BiTEs were developed as biologically produced molecules. The first BiTE was recently approved for treatment of a form of B-cell cancer. 

While there is a great deal of interest in this type of approach, BiTEs development has been slow, in part due to difficulty of production and their short bloodstream half-life of just a few hours, according to 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. Accordingly, for the currently approved BiTE, patients are required to be continuously infused for up to seven days for the treatment to be effective. A simpler, more cost-effective way to provide patients with such important molecules through a technology that would also allow for rapid design modification would be an advantage. 

“Leveraging our expertise in designing synthetic DNA molecules that can be produced in vivo and building on the DNA-encoded monoclonal antibody technology that Wistar’s Vaccine & Immunotherapy Center has been advancing, we developed the dBiTE approach that could make these molecules available for treating more patients,” said Weiner. “In our preclinical studies, dBiTEs demonstrated a unique profile compared to conventional BiTEs, overcoming some of the technical challenges associated with production and delivery of BiTEs and permitting combinations of dBiTEs to be administered at one time as a multi-pronged approach to treat resistant cancer.”

Wistar and colleagues at Inovio Pharmaceuticals, Inc., focused on advancing new synthetic DNA designs for BiTE-like molecules by engineering and encoding them in optimized synthetic plasmid DNA cassettes. dBiTEs are then injected locally into the muscle and muscle cells convert the genetic instructions into protein to allow for direct in vivo launching of the novel molecule directly into the bloodstream to the seek and destroy tumors.  

Through reengineering a DNA-encoded monoclonal antibody (DMab) that the lab had previously designed to target HER2, an important cancer antigen found on breast and ovarian cancer cells, the team designed HER2-specific dBiTEs. Tested in mouse models of ovarian cancer, HER2 dBiTEs were highly expressed after just a single injection and were able to bind to their molecular target on the tumor and attract T cells that were activated to kill the tumor cells. Importantly, the tumor killing activity persisted for more than a month.   

“These results showed that dBiTEs are much more potent than traditional monoclonal antibodies. Not only did treatment extend survival of tumor-bearing mice, but also 80% of the animals treated with dBiTE were cured – a high bar to reach in this animal model,” said co-lead researcher Kar Muthumani, Ph.D., assistant professor in the Vaccine & Immunotherapy Center at Wistar. “Our results show that further exploration of the dBiTE approach for therapeutic development is warranted.”

Co-authors: First author Alfredo Perales Puchalt, Elizabeth K. Duperret, Xue Yang, Patricia Hernandez, Krzysztof Wojtak, Xizhou Zhu, Seang-Hwan Jung, Edgar Tello-Ruiz, and Luis J. Montaner from Wistar; Megan C. Wise from Inovio. 
  
Work supported by: National Institutes of Health (NIH) Special Program of Research Excellence grant P50 CA174523 to Wistar and the University of Pennsylvania, and NIH grants T32-AI055400 and F32 CA213795. Additional funding was provided by the W.W. Smith Charitable Trust, the Basser Foundation and Inovio. Core support for Wistar was provided by Cancer Center Support Grant P30CA010815.
  
Publication information: DNA-encoded bispecific T cell engagers and antibodies present long-term
antitumor activity, JCI Insight (2019). 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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