DMAb inoculation of synthetic cross reactive antibodies protects against lethal influenza A and B infections

Abstract

Influenza virus remains a significant public health threat despite innovative vaccines and antiviral drugs. A major limitation to current vaccinations and therapies against influenza virus is pathogenic diversity generated by shift and drift. A simple, cost-effective passive immunization strategy via in vivo production of cross-protective antibody molecules may augment existing vaccines and antiviral drugs in seasonal and pandemic outbreaks. We engineered synthetic plasmid DNA to encode two novel and broadly cross-protective monoclonal antibodies targeting influenza A and B. We utilized enhanced in vivo delivery of these plasmid DNA-encoded monoclonal antibody (DMAb) constructs and show that this strategy induces robust levels of functional antibodies directed against influenza A and B viruses in mouse sera. Mice receiving a single inoculation with anti-influenza A DMAb survive lethal Group 1 H1 and Group 2 H3 influenza A challenges, while inoculation with anti-influenza B DMAb yields protection against lethal Victoria and Yamagata lineage influenza B morbidity and mortality. Furthermore, these two DMAbs can be delivered coordinately resulting in exceptionally broad protection against both influenza A and B. We demonstrate this protection is similar to that achieved by conventional protein antibody delivery. DMAbs warrant further investigation as a novel immune therapy platform with distinct advantages for sustained immunoprophylaxis against influenza.

Establishment of a pig influenza challenge model for evaluation of monoclonal antibody delivery platforms

“…Conventional mAbs remain an expensive approach from a manufacturing perspective so that a simple, cost-effective passive immunization strategy inducing sustained in vivo production would be extremely valuable. dMAbs, a DNA plasmid encoding mAbs have the potential to circumvent cost constraints and provide durable immunity, perhaps for the duration of an influenza pandemic or season 24–27 . Here we tested 2-12C dMAb in the pig influenza model and although the serum concentration of in vivo expressed dMAb was 100 times lower (∼1 μg/ml) than in pigs given the recombinant protein at 15 mg/kg (∼100 μg/ml) we observed significant protection against disease pathology in the lungs.…”

In Vivo Production of Monoclonal Antibodies by Gene Transfer via Electroporation Protects against Lethal Influenza and Ebola Infections

“…We believe our in-depth studies have moved pDNA/EP beyond preliminary reports, placing this platform technology on a solid foundation for clinical development. For our efficacy experiments in mice, we used doses of pDNA (5–10 μg) that are scalable for humans, in contrast to previous studies (25–300 μg) 11, 12, 13, 14, 15, 16, 17. Despite lower inoculum of pDNA, we observed higher mAb expression with mean peak serum concentrations (3–5 μg/mL) (Figure 2) that are 3- to 10-fold higher than previous findings 13, 14, 15, 16, 17.…”

In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

“…Plasmid DNA-encoded mAbs (pDNA-mAbs) are engineered to carry synthetic antibody genes, similar to AAV-mAb platforms. The literature describes that pDNA-mAbs can exhibit peak serum concentrations after just 2 weeks and then can express at consistent levels for 2-3 months and decline thereafter as the plasmid is lost from cells and then cleared from the serum due to the natural half-life of immunoglobulin G (IgG) [36][37][38][39][40][41]. Long-term small animal studies show the total duration of pDNA-mAb expression to be at least 1 year [42,43].…”