Parzych EM, Du J, Ali AR, Schultheis K, Frase D, Smith TRF, Cui J, Chokkalingam N, Tursi NJ, Andrade VM, Warner BM, Gary EN, Li Y, Choi J, Eisenhauer J, Maricic I, Kulkarni A, Chu JD, Villafana G, Rosenthal K, Ren K, Francica JR, Wootton SK, Tebas P, Kobasa D, Broderick KE, Boyer JD, Esser MT, Pallesen J, Kulp DW, Patel A, Weiner DB. DNA-delivered antibody cocktail exhibits improved pharmacokinetics and confers prophylactic protection against SARS-CoV-2. Nat Commun. 2022 Oct 6;13(1):5886. doi: 10.1038/s41467-022-33309-6. PMID: 36202799; PMCID: PMC9537531.
Abstract
Monoclonal antibody therapy has played an important role against SARS-CoV-2. Strategies to deliver functional, antibody-based therapeutics with improved in vivo durability are needed to supplement current efforts and reach underserved populations. Here, we compare recombinant mAbs COV2-2196 and COV2-2130, which compromise clinical cocktail Tixagevimab/Cilgavimab, with optimized nucleic acid-launched forms. Functional profiling of in vivo-expressed, DNA-encoded monoclonal antibodies (DMAbs) demonstrated similar specificity, broad antiviral potency and equivalent protective efficacy in multiple animal challenge models of SARS-CoV-2 prophylaxis compared to protein delivery. In PK studies, DNA-delivery drove significant serum antibody titers that were better maintained compared to protein administration. Furthermore, cryo-EM studies performed on serum-derived DMAbs provide the first high-resolution visualization of in vivo-launched antibodies, revealing new interactions that may promote cooperative binding to trimeric antigen and broad activity against VoC including Omicron lineages. These data support the further study of DMAb technology in the development and delivery of valuable biologics.