Up in (Antibody) Arms: Synthetic DNA Immunotherapy Platform Combats Brain Cancer

Researchers in the Weiner Lab developed DNA-launched bispecific T cell engagers that controlled tumor growth and improved survival in glioblastoma.

Glioblastoma is one of the most severe and aggressive forms of brain cancer with limited treatment options and low survival rates. Wistar’s Weiner Lab is focused on creating new treatments to improve the patient’s quality of life and increase the opportunity to beat this difficult-to-treat cancer.

What approach is Dr. Weiner and his research team taking to tackle glioblastoma?

Dr. Weiner and his team are focused on dBTE’s – a synthetic DNA antibody platform for developing new T cell-redirecting immunotherapies. These immunotherapies deliver a lethal hit against diverse and difficult to-treat solid tumors.

The Weiner lab used genetic engineering combined with direct in vivo expression to create a novel dBTE which targets an important receptor on the surface of cells that initiate glioblastoma tumors. Approximately 75% of individuals with glioblastoma have a very specific receptor referred to as IL-13Ralpha2. The proof-of-concept study of IL-13Ralpha2 dBTEs on controlling glioblastoma was recently published in Molecular Therapy-Oncolytics.

“Glioblastoma is a severe disease with limited therapeutic options so the creation of novel and potentially more impactful therapeutic options for cancer patients such as the anti-glioblastoma dBTE is a major focus of Wistar’s Vaccine and Immunotherapy Center,” says David Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research.

Bispecific T cell engagers are synthetic antibodies with two chains or “arms” that can simultaneously bind an antigen expressed on a tumor and an antigen on a T cell and bring them closer together, triggering immune activation to protect the body from disease. “This redirects the activity of the T cell towards the tumor cell, attacking and killing the tumor.” explains Pratik Bhojnagarwala, graduate student in the Weiner lab and first author on the paper.

Challenges with conventional BTE treatments for cancer patients include the need for continuous IV injection over several weeks, costly treatment, and unwanted off-target issues. In this work, the team used synthetic DNA technologies to design, test and identify multiple synthetic DNA BTE forms having the most specific and potent killing activity against different glioblastoma human cancer cell lines.

It is this specific design combined with the dBTE approach that creates a kind of dBTE factory for the patient, enabling the consistent force and effectiveness of the therapy. Using this new anti-glioblastoma dBTE and direct nucleic acid encoded delivery, the researchers were able to more than double half-life of the bispecific antibodies in animal models – resulting in the clearing of tumors in vivo.

Dr. Weiner is also a leader in the development of another antibody based technology called DNA encoded monoclonal antibodies (dMAB) for treating infectious diseases including COVID-19, Zika, Ebola, and cancer. The biggest difference between dMABs and dBTEs is that dMABs encode for monoclonal antibodies that bind to a single target. DBTEs are designed to bind to two different targets at the same time and are more commonly used to engage the immune system to fight cancers. By innovating multiple types of platforms, the Weiner lab is on the forefront of translational studies harnessing basic science to fight difficult human diseases.

Bhojnagarwala plans to continue developing combination novel immunotherapies for cancer and infectious disease, specifically exploring additional designs for dBTE that can improve specificity and potency of the new approach and applying his studies towards targeting more tumor antigens for glioblastoma. He shares, “It is important for me to work in a lab where there is a high possibility that the work can rapidly be translated into clinical trials. The Weiner lab provides that platform.”