On January 15, 2019 Inovio Pharmaceuticals, Inc. (NASDAQ: INO) reported the successful development of optimized DNA-encoded monoclonal antibodies (dMAbs) targeting the immune checkpoint molecule PD-1 (Press release, Inovio, JAN 15, 2019, View Source [SID1234532653]). The breakthrough preclinical data demonstrated that a single injection of synthetic designer dMAb versions of pembrolizumab (KEYTRUDA) or nivolumab (OPDIVO) sequences targeting PD-1 protein can be robustly redeveloped to be expressed directly in vivo in mice for up to several months. Furthermore, Inovio’s proprietary sequence optimization of the molecular design of these therapeutics resulted in significantly improved expression compared to the original KEYTRUDA and OPDIVO native sequences while maintaining identical binding capabilities.
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These published dMAb results demonstrate the potential of advancing of a new generation of checkpoint inhibitors with multiple benefits including: 1) simplifying the patient regimen for checkpoint blockade therapy – converting 90-minute intravenous infusions administered every three weeks with currently marketed protein-based mAbs into a single local injection of dMAbs, 2) possibly resulting in more consistency of expression in vivo providing improved benefits for the patient, and 3) through simple additional modifications and simplified dMAb combination formulations, engender further improved functions rapidly providing additional clinical benefit. The PD-1 dMAb results were published in the recent edition of Oncotarget in an article entitled, "Simplifying checkpoint inhibitor delivery through in vivo generation of synthetic DNA-encoded monoclonal antibodies (dMAbs)," by Inovio’s collaborators at The Wistar Institute.
Dr. J. Joseph Kim, Inovio’s President and CEO, said, "We are rapidly pioneering a potentially breakthrough class of medicines – dMAbs – produced directly in the human body. PD-1/PD-L1 targeting checkpoint inhibitor mAb products represent some of the most important advancements in immuno-oncology today. We look forward to advancing our PD-1 targeting dMAb products as potentially better versions of blockbusters KEYTRUDA and OPDIVO – with whole new sets of IP behind them – through corporate partnerships, external funding and collaborations."
Inovio recently initiated the first human study of its dMAb technology. In addition to demonstrating safety and tolerability, the Phase 1 dose-escalation study of INO-A002 (for preventing or treating Zika virus infection) will assess initially the level of the body’s production of the Zika dMAb over several doses. Using direct delivery into the body, the genetic instructions provided by the designed synthetic dMAbs delivered locally by the CELLECTRA platform, instruct the body’s cells to become a customized patient specific factory which manufactures their own therapeutic antibody products, enabling a major leap in antibody technology.
Traditional monoclonal antibodies represent the largest segment of pharmaceutical markets today, accounting for more than $100 billion in pharmaceutical sales each year, with treatments spanning cancer, infectious diseases, inflammation and cardiovascular diseases. With its synthetic design and in-patient production, dMAb products represent a disruptive entrant to this important class of pharmaceuticals. Inovio and its collaborators have already received over $60 million in non-dilutive grant funding to advance its dMAb platform in the last few years. There is a significant interest in dMAb’s as a disruptive entrant to a highly profitable overall mAb market as well as its unique applicability for rapid responses against emerging global infectious disease threats and for addressing critical vaccine limitations.
In the past few years Inovio and collaborators have published multiple impactful papers consistently demonstrating potent preclinical data from the dMAb platform, with therapeutic displays spanning protection against deadly infections to eliminating cancers and lowering life-threatening levels of cholesterol. In this regard dMAbs offer unique features for rapid production, deployment and advancement of new mAb-like biologics, with much increased efficiency. In addition, the dMAb’s constructed in vivo likely have additional advantages such as expression profiles, as well as patient specific glycosylation, and unlike traditional mAb approaches, there is no reliance on in vivo tissue culture and costly or time consuming production systems. Inovio has previously published successful animal testing of dMAbs targeting the immune checkpoint molecule CTLA-4 (Duperret et al. Cancer Res. 2018). The preclinical study demonstrated that highly optimized dMAbs targeting mouse CTLA-4 protein can be robustly expressed in vivo, and can drive therapeutic anti-tumor immune responses in established disease models. Importantly, Inovio’s dMAb constructs for anti-human CTLA-4 antibodies ipilimumab and tremelimumab, achieved high levels and prolonged expression for months from a single delivery. Inovio has multiple patents awarded in this space including the first two patents from the U.S. patent office covering this specific dMAb technology granted last quarter.
KEYTRUDA is a registered trademark of Merck & Co. (MRK); OPDIVO is a registered trademark of Bristol-Myers Squibb Company (BMY).
About Inovio’s DNA-based Monoclonal Antibody Platform
Traditional monoclonal antibodies are manufactured outside the body in bioreactors, typically requiring costly large-scale manufacturing facility development and laborious production. Inovio’s disruptive dMAb technology has the potential to overcome these limitations by virtue of their simplified design using novel plasmid vectors and unique formulations allowing for rapidity of development, product stability, ease of manufacturing and deployability, ultimately all resulting in increases in cost effectiveness, providing potential new avenues for treating a range of diseases. These dMAbs are delivered directly into cells of the body using CELLECTRA and the encoded monoclonal antibody is then produced by the locally transfected cells. Previously published studies show that a single administration of a highly optimized DNA-encoded monoclonal antibody targeting Ebola virus produced a high level of expression of the antibody in the bloodstream of mice that was protective against lethal animal challenge; Additional studies similarly reported data showing that dMAb products against flu, chikungunya and dengue protected animals against lethal challenge. In addition the team has reported delivery of dMAbs that impact prostate as well as breast and ovarian cancers in animals.