INOVIO has announced promising interim results from its ongoing Phase 1 proof-of-concept clinical trial evaluating DNA-encoded monoclonal antibodies (DMAbs) for COVID-19, demonstrating unprecedented durability of antibody expression without immune rejection.
The trial, led by The Wistar Institute in collaboration with INOVIO, AstraZeneca, and clinical investigators at the University of Pennsylvania's Perelman School of Medicine, has shown that 100% of participants (24/24) who reached the 72-week mark maintained biologically relevant levels of DMAbs, confirming long-term in vivo antibody production.
Breakthrough in Antibody Delivery Technology
One of the most significant findings from the trial is the complete absence of anti-drug antibodies (ADA) across approximately 1,000 blood samples analyzed. This represents a major advantage over other gene-based delivery platforms, such as adeno-associated virus (AAV) mediated antibody expression, where immune rejection has been a persistent challenge limiting therapeutic effectiveness.
"This study provides the first clinical proof-of-concept that DNA-encoded monoclonal antibodies can be durably and tolerably expressed in humans," said David B. Weiner, Ph.D., Executive Vice President of The Wistar Institute and lead investigator for the study. "These findings could represent a breakthrough as they demonstrate the potential of DMAb technology to overcome traditional monoclonal antibody production challenges, such as short half-life and anti-drug immune responses."
The expressed DMAbs successfully bound to the SARS-CoV-2 Spike protein receptor-binding domain (RBD), confirming functional activity through week 72, demonstrating not only persistence but also maintained biological activity.
Safety Profile and Trial Design
The DMAbs were well-tolerated across the study population, with the most common side effects being mild, temporary injection site reactions such as pain and redness. No serious adverse events (SAEs) related to the study drug were reported.
The Phase 1 trial is the first clinical study to use synthetic DNA technology for in vivo production of monoclonal antibodies directly from muscle cells. Participants received an intramuscular injection of synthetic DNA plasmids encoding AZD5396 and AZD8076 (derived from AstraZeneca's cilgavimab and tixagevimab) delivered via INOVIO's proprietary CELLECTRA 2000 electroporation device.
Dr. Pablo Tebas, a professor of Infectious Diseases at Penn and investigator on the trial, highlighted the significance of these findings: "One of the biggest hurdles for gene-based antibody delivery has been the immune system's response to the vector or the antibody itself, leading to anti-drug antibodies that can limit how long a treatment will be effective. Our DNA-based approach has demonstrated sustained antibody expression without generating ADA."
The open-label, single-center, dose-escalation trial began enrollment in May 2022 and completed recruitment in March 2024. It is funded by the Coronavirus Aid, Relief, and Economic Security Act (CARES Act) and the Defense Advanced Research Projects Agency (DARPA).
INOVIO's DNA Medicines Platform
INOVIO's approach utilizes precisely designed DNA plasmids delivered by the company's proprietary CELLECTRA® device. These plasmids function as molecular instructions that cells can use to produce specific proteins to target and fight disease.
Unlike traditional antibody therapies that require regular infusions or injections, or viral vector-based gene therapies that often trigger immune responses against the delivery vehicle, INOVIO's technology aims to enable sustained production of therapeutic proteins without chemical adjuvants, lipid nanoparticles, or the risk of anti-vector responses.
"We believe these data highlight the potential to apply our DNA Medicines technology to deliver a broad spectrum of therapeutic proteins that could be used to treat diseases with missing or defective proteins," said Laurent Humeau, Ph.D., INOVIO's Chief Scientific Officer.
Broader Implications for Therapeutic Development
The successful demonstration of durable antibody expression without immune rejection opens possibilities for treating conditions requiring continuous therapeutic protein delivery. This approach could potentially address limitations in current treatment paradigms for various diseases, including infectious diseases, cancer, and metabolic disorders.
The consortium plans to present additional interim results at upcoming scientific conferences in 2025, and a manuscript describing the interim results has been uploaded to Research Square for early dissemination while undergoing peer review by a leading scientific journal.
As the trial enters its third year, these promising results suggest that DNA-encoded antibody technology could represent a significant advancement in the field of protein therapeutics, potentially offering patients longer-lasting treatments with fewer administrations and reduced risk of immune rejection.
