Inovio Pharmaceuticals’ synthetic plasmid DNA-based dMAb® monoclonal antibody (mAb) technology provided mice with complete protection from lethal challenge with multiple influenza A and B virus strains. The dMAb platform utilizes synthetic plasmids that directly encode sequences for protective cross-reactive anti-influenza monoclonal antibodies. The plasmids are delivered directly to the body’s cells by electroporation, and the plasmid DNA is then expressed by the cells to generate fully functional anti-influenza mAbs. In effect, “the patient becomes a factory for the production of their monoclonal of interest,” the company explained to GEN.
Conventional active immunization against influenza may not be completely effective in the elderly, infants, or immunocompromised people who can’t mount effective immune responses after immunization. It is also hugely costly to reformulate vaccines every year to counteract antigenic drift, and then reimmunize populations prior to each flu season.
A number of approaches to developing a universal influenza vaccine have focused on designing recombinant antigens that trigger the immune system to develop cross-protective, anti-influenza antibodies. It may also be possible to administer broadly neutralizing anti-influenza mAbs as a complementary form of passive immunization.
As an alternative concept, the Inovio platform effectively prompts cells to create desired antibodies from their genetic code, administered as a plasmid. In contrast with conventional monoclonal antibody approaches, dMAbs are more simple to design and develop, easier to manufacture, and could allow rapid responses to unexpected changes in seasonal flu strains or in the event of a pandemic.
The latest studies testing the dMAb platform were carried out by Inovio in collaboration with David B Weiner, Ph.D., and a team at the Wistar Institute of Anatomy & Biology in Philadelphia, together with scientists from AstraZeneca’s MedImmune biologics operation. Dr. Weiner, who is an Inovio board member and scientific advisor, is evp and director of the Vaccine and Immune Therapy Center at the Wistar Institute. Mice were given plasmid DNA encoding either one or both of two broadly cross-protective mAbs, FluA and FluB, targeting influenza A and B. Mice receiving a single inoculation with anti-influenza A dMAb survived lethal challenges from Group 1 H1 and Group 2 H3 influenza A strains. Animals inoculated with anti-influenza B dMAb were protected against lethal challenge using Victoria and Yamagata influenza B strains. Mice receiving both dMAbs demonstrated what the researchers state was “exceptionally broad” protection against both influenza A and B.
The studies were published in npj Vaccines, in a paper titled, “DMAb Inoculation of Synthetic Cross Reactive Antibodies Protects against Lethal Influenza A and B Infections.” The work was supported by grants from the Defense Advanced Projects Research Agency (DARPA) and the NIH, and follows on from similar studies using dMAb products for HIV, dengue, and Chikungunya.
The authors envisage that the dMAb technology could provide an alternative to existing mAb technologies that are in development for treating chronic diseases, such as cancer and autoimmune disorders. To date, they note, MedImmune’s antirespiratory syncytial virus mAb palivizumab is the only protein mAb that has been approved and is routinely used for prophylaxis against an infectious disease.
The Innovio platform could also offer important treatment options for immunocompromised individuals who can’t mount functional active immune responses to current vaccines and allow for the fast development of new dMAbs that counteract viral escape. “Conceivably, inoculation with influenza-specific dMAbs may have utility to augment a vaccine campaign, generating almost immediate prophylaxis against severe influenza infection while allowing for an adequate vaccine-induced immune response to mature,” the authors write.
Manufacturing processes for dMAb products should in addition be more simple and cost-effective than for traditional mAbs. “DNA plasmid-based delivery of monoclonal antibodies provides conceptual advantages at each step of the supply chain,” the authors write. “In production, dMAb are inexpensive relative to protein monoclonal antibody (and viral vectors) because DNA replication does not require mammalian cell culture. DNA is simple to scale up and stable for storage, a particularly important consideration in resource-limited settings.”
“We could predict many possible applications for the technology which would be wide-ranging…all under consideration,” the company commented to GEN. “However, currently, we are in the late preclinical development stage looking to push forward into the clinic early 2018.”
“With respect to influenza, our dMAb product offers a new game-changing model to address seasonal and pandemic influenza with a single dose,” stated J. Joseph Kim, Ph.D., Inovio's president and CEO. “Inovio’s dMAb products represent a new class of products we are developing to treat cancers and infectious diseases using our potent platform. Funded by over $60 million in grants from DARPA, NIH, and the Gates Foundation, these dMAb products can extend the medical benefits that marketed monoclonal antibodies have already achieved and potentially address diseases that conventional monoclonal antibodies cannot… . We look forward to advancing the first dMAb product—our therapeutic Ebola product funded by DARPA—into human testing in 2018.”
Last month, Inovio started a Phase III trial evaluating VGX-3100, a DNA-based immunotherapy for treating cervical dysplasia caused by human papillomavirus (HPV). The trial had been placed on clinical hold by FDA in October 2016, but the regulator's concerns were not related to the product itself or electroporation delivery, the company told GEN. “The issue regarding the hold was related to packaging… . The FDA has been very supportive of our technology.”
Earlier this year, Chinese biomed ApolloBio negotiated exclusive rights to develop VGX-3100 within China, Hong Kong, Macao, and Taiwan.