Phase 1, dose-escalation trial of the safety and pharmacokinetics of SARS-CoV-2 DNA-encoded monoclonal antibodies (DMAb) in healthy adults

Local intramuscular administration of synthetic plasmid DNA (pDNA) encoding monoclonal antibodies (mAb) represents an alternative approach to recombinant protein technology. In this Phase 1, dose escalation study (NCT05293249), we administered a pDNA cocktail encoding AZD5396 and AZD8076, modified versions of the SARS-CoV-2 neutralizing mAb cocktail Evusheld™, by CELLECTRA™ in vivo electroporation technology to healthy adults. Primary endpoints of this study were safety and pharmacokinetics of the in vivo expressed DNA-encoded mAbs (DMAbs). Muscle-expressed DMAbs were detected in the serum of all dosed subjects (N=39), with concentrations reaching 1.39 µg/ml. Remarkably consistent levels of serum DMAbs were measured for at least 72 weeks post-administration in 24/24 subjects who have reached this time point. DMAbs isolated from serum demonstrated SARS-CoV-2 RBD binding and neutralization activity in a standard pseudovirus assay. While the study is ongoing, we have not detected anti-drug antibodies in any of the trial participants thus far. These data represent the first clinical proof-of-concept that synthetic pDNA DMAb technology permits the durable in vivo production of a functional mAb cocktail. This study further underscores the collective importance of synthetic design, formulation, and delivery to achieve biologically relevant expression of gene-encoded biologics. DMAb delivery may represent a valuable strategy against a wide range of diseases which can be targeted with mAbs and their derivatives.