https://orcid.org/0000-0001-8907-8821
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ABSTRACT
COVID-19 remains a major public health concern. Monoclonal antibodies have received emergency use authorization (EUA) for pre-exposure prophylaxis against COVID-19 among high-risk groups for treatment of mild to moderate COVID-19. In addition to recombinant biologics, engineered synthetic DNA-encoded antibodies (DMAb) are an important strategy for direct in vivo delivery of protective mAb. A DMAb cocktail was synthetically engineered to encode the immunoglobulin heavy and light chains of two different two different Fc-engineered anti-SARS-CoV-2 antibodies. The DMAbs were designed to enhance in vivo expression and delivered intramuscularly to cynomolgus and rhesus macaques with a modified in vivo delivery regimen. Serum levels were detected in macaques, along with specific binding to SARS-CoV-2 spike receptor binding domain protein and neutralization of multiple SARS-CoV-2 variants of concern in pseudovirus and authentic live virus assays. Prophylactic administration was protective in rhesus macaques against signs of SARS-CoV-2 (USA-WA1/2020) associated disease in the lungs. Overall, the data support further study of DNA-encoded antibodies as an additional delivery mode for prevention of COVID-19 severe disease. These data have implications for human translation of gene-encoded mAbs for emerging infectious diseases and low dose mAb delivery against COVID-19.
Acknowledgements
The authors would like to thank The Wistar Institute Core facilities for assistance with SPR. The authors are grateful to staff of the Rocky Mountain Veterinary Branch for animal care, veterinary service and pathology investigation. This work was approved for public release, distribution unlimited. Additional funding includes Award T32 CA09171 (to E.N.G.), the WW Smith Charitable Trust (to D.B.W.), The Jill and Mark Fishman Foundation (to D.B.W.). The views, opinions and/or findings expressed are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the US Government. Funding sources were not involved in the design of this study, collection and analyses of data, decision to submit or preparation of the manuscript.
Disclosure statement
D.B.W. has received grant funding, participates in industry collaborations, has received speaking honoraria, and has received fees for consulting, including serving on scientific review committees and board series. Remuneration received by D.B.W. includes direct payments and stock or stock options. D.B.W. also discloses the following paid associations with commercial partners: GeneOne (consultant), Geneos (advisory board), AstraZeneca (advisory board, speaker), Inovio (BOD, SRA, Stock), Sanofi (advisory board) and BBI (advisory board). A.J.G, B.S., V.M., B.J.S., B.N., A.G., and T.R.F.S. are employees of Inovio Pharmaceuticals and as such receives salary and benefits, including ownership of stock and stock options. J.R.F, K.R, and M.T.E are employees of and hold or may hold stock in AstraZeneca. All other authors declare no completing interests.
Author contributions
D.B.W. and A.P. conceived the project and secured funding. A, P. K.R., E.M.P., D.B.W., T.R.F.S, C.S, H.F. designed and supervised studies. A.P., K.R., E.M.P., F.F, S.B, A.J.G, B.S., M.L., J.C., N.C., V.M., B.J.S., D.F., A.R.A., J.L., B.N., P.W.H., S.N.W., E.N.G., A.K., A.G., generated reagents, performed laboratory experiments, and analysis. J.R.F., K.R., D.W.K., M.T.E., T.R.F.S. provided valuable materials and programmatic support/guidance. A.P., K.R., D.B.W. prepared the original manuscript. All authors edited, reviewed, and approved the manuscript.