Inovio Pharmaceuticals said that it has completed animal testing of DNA-encoded monoclonal antibodies targeting the immune checkpoint molecule CTLA-4.
The breakthrough preclinical study demonstrated that highly optimized dMAbs targeting mouse CTLA-4 protein can be robustly expressed in vivo, and shrank tumors in mice.
More importantly, Inovio’s dMAb constructs for anti-human CTLA-4 antibodies ipilimumab (YERVOY) and tremelimumab, achieved high expression levels in mice (approximately 85µg/ml and 58µg/ml, respectively). These dMAbs exhibited long-term expression with maintenance of serum levels >15µg/ml for over a year.
This research publication is significant because it is the first to report on the use of Inovio dMAb technology to develop novel monoclonal antibody-based therapies targeting checkpoint inhibitors. Inovio is developing additional dMAbs targeting other checkpoint molecules including PD-1.
When delivered directly into the body, the genetic instructions provided from the dMAb construct enable the patient’s own cells to become the factory which manufactures the therapeutic monoclonal antibody products. Inovio has previously published several papers demonstrating its dMAb product candidate’s ability to treat multiple virus targets such as flu, dengue, chikungunya, and HIV.
Inovio research & development senior vice president Laurent Humeau said: “Even though conventional monoclonal antibodies represent one of the most successful segments of the biotechnology market, accounting for over $50 billion in sales today, manufacturing complexity and repeated dosing may limit a broader use of this technology.
“Inovio’s dMAb products may improve upon this class using our synthetic design and in vivo production. This newly published study further support that Inovio’s potent dMAb platform can be expanded to target cancer.
“We plan on advancing the first clinical dMAb candidate into the first-in-human study in 2019. Moreover, we expect to form partnerships to advance several dMAb products targeting cancers and infectious diseases.”
David Weiner, the paper’s senior author said: “Our work provides the first demonstration that we can use synthetic DNA technology to produce checkpoint inhibitor molecules in vivo to impact tumor growth in a preclinical setting.
“We showed that dMAbs may represent a valuable addition to the cancer immunotherapy toolbox: In our preclinical studies, dMAbs achieved antitumor activity comparable to that of traditional monoclonal antibodies, while being delivered through a simpler formulation that may provide a bridge to expand target populations for checkpoint inhibitors.”
The study highlights that delivery of a synthetic, sequence-optimized DNA plasmid designed to encode anti-mouse CTLA-4 monoclonal antibodies, with the aid of an electroporation device to enhance uptake, resulted in significant and prolonged antibody expression with even a single dose.
Importantly, this approach stimulated robust CD8+ T cell infiltration, achieving tumor clearance across multiple mouse tumor models. The researchers then went on to develop human checkpoint inhibitor molecules and demonstrated their production in mice and their ability to stimulate human T cell responses associated with antitumor activity.
The study clearly demonstrates how optimized dMAbs encoding the human CPI’s ipilimumab and tremelimumab are potently expressed in vivo and enhance the activation of human effector T cells with the potential to destroy tumors.
This strategy provides a novel approach to immune checkpoint therapy, with the potential to expand patient access to this breakthrough immunotherapy to treat cancer.
Funded with over $60 million in R&D support from top agencies like DARPA, NIH, and the Gates Foundation, Inovio dMAb products could extend the medical benefits that marketed monoclonal antibodies have already achieved, and even potentially address diseases that conventional monoclonal antibodies cannot.
Source: Company Press Release.