Gene-Delivery Method Generates Immune Checkpoint Antibodies In Vivo
A new drug-delivery method could allow for less-frequent administration and formulations that are easier to manufacture.
In a proof-of-principle study in mice, researchers showed that DNA-encoded plasmids can be used to generate antibodies to immune checkpoint molecules, known as DNA-encoded monoclonal antibodies (DMAbs), to shrink tumors. The DMAb platform, used to deliver anti-CTLA-4 monoclonal antibodies (mAbs), can be retooled to encode for other monoclonal antibodies in vivo, such as those targeting PD-1, and may offer advantages over traditional mAbs, such as reduced manufacturing complexity and lower costs. The study was recently published in Cancer Research.1
“It's really a demonstration of a new and upcoming technology,” senior author David Weiner, PhD, executive vice president and director of the Vaccine & Immunotherapy Center at The Wistar Institute, Philadelphia, Pennsylvania, told Cancer Therapy Advisor. “A very short time ago, most people did not think this kind of technology could produce a protein of value inside a living animal like this.”
DNA-encoded plasmids have historically been perceived as lacking the ability to generate sufficient protein expression within an organism and therefore, were never widely pursued as a technology for gene therapies. “It was a second-class citizen to viral vectors. It just never could produce enough to generate a protein level that might be of use,” Dr Weiner said. “If you can demonstrate a protein level that might be of use, now there's a lot of possibility.”
To demonstrate the utility of the DMAb platform, researchers from The Wistar Institute and Inovio Pharmaceuticals engineered DNA-encoded plasmids to generate antibodies against immune checkpoint inhibitor CTLA-4. The DMAbs were injected into the muscle of mice and in vivo electroporation was used to facilitate delivery of the plasmid to the target muscle cells.
In mouse models, a single intramuscular injection of DMAbs resulted in high serum levels of antibodies to CTLA-4 and also, tumor regression. DMAbs were engineered to express checkpoint inhibitors ipilimumab (ipi-DMab) and tremelimumab (treme-DMab), and both antibodies were expressed at high levels in mouse models. Ipilimumab reached a peak level of approximately 85 mg/mL and tremelimumab reached a peak level of approximately 58 mg/mL. Both antibodies had prolonged expression that lasted for more than 1 year at 15 mg/mL. In addition, an in vitro functional T-cell activation assay showed that the DMAbs for ipilimumab and tremelimumab each produced functional antibodies that could induce T-cell activation.