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Wistar Scientists Develop Innovative Synthetic DNA-based Cancer Immunotherapy Approach

Wistar scientists have developed a novel innovative synthetic DNA approach for patient-specific production of cancer-targeting molecules called bispecific T cell engagers (BiTEs).

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.

BiTEs are a type of artificial monoclonal antibody that connects tumor targets, while at the same time binding to and activating killer T cells. These T cells help to kill the tumors with high accuracy and they will have the capability to see them also.

BiTEs were developed as biologically produced molecules. The first BiTE was recently approved for treatment of a form of B-cell cancer.

For the currently approved BiTE, patients are required to be continuously infused for up to seven days for the treatment to be effective.

Scientists have developed the dBiTE approach that could make these molecules available for treating more patients.

In preclinical studies, dBiTEs demonstrated a unique profile compared to conventional BiTEs, overcoming some of the technical challenges associated with production.

Delivery of BiTEs and permitting combinations of dBiTEs to be administered at one time as a multi-pronged approach to treat resistant cancer.

They have focused on advancing new synthetic DNA designs for BiTE-like molecules by engineering and encoding them in optimised 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.

ER2 dBiTEs were highly expressed after just a single injection, after 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.

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