Safety and pharmacokinetics of SARS-CoV-2 DNA-encoded monoclonal antibodies in healthy adults: a phase 1 trial.

Abstract

Local intramuscular administration of synthetic plasmid DNA (pDNA) encoding monoclonal antibodies (mAb) offers an alternative to recombinant protein-based mAb delivery. In this phase 1 dose-escalation study, we evaluated the safety, tolerability and pharmacokinetics of a pDNA cocktail encoding AZD5396 and AZD8076, modified versions of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing mAb cocktail tixagevimab/cilgavimab in healthy adults. Participants received up to four intramuscular doses of pDNA encoding both DNA-based mAbs (DMAbs), administered using CELLECTRA electroporation. The primary endpoints were safety and pharmacokinetics. All 44 participants received at least one dose; DMAbs were detected in 100% of evaluable participants (n = 39), with serum concentrations reaching a peak of 1.61 µg ml^-1. Sustained expression was observed in all participants during the 72 weeks of follow-up. The study product was well tolerated, with no product-related serious adverse events reported. Exploratory analyses demonstrated binding to multiple SARS-CoV-2 Spike protein variants and neutralizing activity in a standard pseudovirus assay. No antidrug antibodies were detected across approximately 1,000 serum samples using validated tiered assays. To our knowledge, these data represent the first-in-human 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 long-acting, scalable, cold-chain-independent platform against a wide range of diseases that can be targeted with mAbs and their derivatives. ClinicalTrials.gov registration: NCT05293249.