Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec;13(1):2294860.
doi: 10.1080/22221751.2023.2294860. Epub 2024 Feb 28.

In vivo delivery of engineered synthetic DNA-encoded SARS-CoV-2 monoclonal antibodies for pre-exposure prophylaxis in non-human primates

Ami Patel  1 , Kyle Rosenke  2 , Elizabeth M Parzych  1 , Friederike Feldmann  2 , Suman Bharti  1 , Amanda J Griffin  2 , Blake Schouest  3 , Matt Lewis  2 , Jihae Choi  1 , Neethu Chokkalingam  1 , Viviane Machado  3 , Brian J Smith  2 , Drew Frase  1 , Ali R Ali  1 , Jamie Lovaglio  2 , Brian Nguyen  3 , Patrick W Hanley  2 , Susanne N Walker  1 , Ebony N Gary  1 , Abhijeet Kulkarni  1 , Allison Generotti  3 , Joseph R Francica  4 , Kim Rosenthal  4 , Daniel W Kulp  1 , Mark T Esser  4 , Trevor R F Smith  3 , Carl Shaia  2 , David B Weiner  1 , Heinz Feldmann  2
Affiliations

In vivo delivery of engineered synthetic DNA-encoded SARS-CoV-2 monoclonal antibodies for pre-exposure prophylaxis in non-human primates

Ami Patel et al. Emerg Microbes Infect. 2024 Dec.

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.

Keywords: DMAb; DNA; DNA-encoded monoclonal antibody; SARS-CoV-2; gene-encoded antibody; macaque; monoclonal antibody; prevention.

PubMed Disclaimer

Conflict of interest 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.

Figures

Figure 1.
Figure 1.
Human IgG antibody pharmacokinetic expression levels in the serum of cynomolgus macaques following administration of the DMAb-2130-YTE and DMAb-2196-YTE cocktail in cynomolgus macaques. (a) Overview of study. (b) Expression levels in Group 1 (n = 4), receiving two DMAb administrations. (c) Expression levels in Group 1 NHP M16912. (d) Expression levels in Group 2 (n = 5), receiving a single DMAb administration. (e) Detection of 2196 Fab by RBD K444A ELISA. (f) Detection of 2130 Fab by RBD F486A ELISA. (g) Detection of 2196 and 2130 Fab by RBD K444A and in NHP M16912.
Figure 2.
Figure 2.
SARS-CoV-2 authentic virus and pseudovirus titers in the serum of cynomolgus macaques following administration of DMAb-2130-YTE and DMAb-2196-YTE. Neutralization assays were performed on sera samples collected on day 15 post-DMAb administration. (a) Neutralization ID50 titers against authentic SARS-CoV-2 USA-WA1/2020 (WT lineage) and hCoV-19/USA/PHC658/2021 (Delta lineage). Graphs display animals all together (i, ii) and by individual group (iii, iv). (b) SARS-CoV-2 pseudovirus neutralization titers against WT, Beta, and Delta lineage pseudoviruses. Graphs display animals all together (i-iii) and by group (iv-vi). IC50 neutralization titers for (c) Live virus and (d) Pseudovirus. Omicron BA.2 and BA2.12 pseudovirus (e) ID50 titersand (f) IC50 values. Individual animals are displayed on the graphs, along with the geometric mean titer and geometric standard deviation. (*) p < 0.05 and (**) p < 0.01.
Figure 3.
Figure 3.
Overview of serum expression and neutralizing activity of DMAbs in rhesus macaques. (a) Schematic overview of DMAb delivery in rhesus macaques. (b) Human IgG antibody expression levels in the serum with no DMAb, DMAb-YTE, or DMAb-WT cocktails. (c) Neutralization ID50 titers against authentic SARS-CoV-2 USA-WA1/2020 (WT lineage). (d) Pseudovirus neutralization ID50 titers against WT lineage. Group 1 (control) is depicted in grey circles, Group 2 (DMAb-YTE) is depicted in orange triangles, Group 3 (DMAb-WT) is depicted in purple squares. Lines represent the mean and error bars represent the standard deviation.
Figure 4.
Figure 4.
Clinical scores, viral loads, and histopathological analysis. (a) Clinical scores in control and DMAb-administered rhesus macaques following SARS-CoV-2 challenge. (b) Viral loads in nasal washes and bronchioalveolar lavage (BAL) following SARS-CoV-2 challenge detected by subgenomic qPCR. (b) (i) Nasal swab viral loads from individual animals are shown. (ii) Nasal swabs on day 5 post-challenge. (c) (i) BAL washes from individual animals are shown. (ii) BAL on day 3 post-challenge. Bars represent the mean and standard deviation. p < 0.05 is considered significant. LOD = assay limit of detection. (d) Photomicrographs of histological sections of the lung (top row HE, 100x) and anti-SARS-CoV-2 IHC (middle row 100x; bottom row 400x). Lesions are minimal to mild and demonstrate increased alveolar septal thickening and septal and alveolar inflammation. Immunoreactivity is scattered and sparse when present and appears specific to type I and type II pneumocytes.
See this image and copyright information in PMC

References

    1. Dong E, Du H, Gardner L.. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020;20(5):533–534. doi:10.1016/S1473-3099(20)30120-1 PubMed PMID: 32087114; PubMed Central PMCID: PMCPMC7159018. - DOI - PMC - PubMed
    1. Premkumar L, Segovia-Chumbez B, Jadi R, et al. . The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients. Sci Immunol. 2020;5(48):eabc8413. doi:10.1126/sciimmunol.abc8413 PubMed PMID: 32527802; PubMed Central PMCID: PMCPMC7292505. - DOI - PMC - PubMed
    1. CDC . COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. [accessed 2022 September]. Available from: https://www.covid19treatmentguidelines.nih.gov/. - PubMed
    1. Cao Y, Yisimayi A, Jian F, et al. . BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection. Nature. 2022;608(7923):593–602. doi:10.1038/s41586-022-04980-y. PubMed PMID: 35714668; PubMed Central PMCID: PMCPMC9385493. - DOI - PMC - PubMed
    1. Takashita E, Kinoshita N, Yamayoshi S, et al. . Efficacy of antibodies and antiviral drugs against Covid-19 Omicron variant. N Engl J Med. 2022;386(10):995–998. doi:10.1056/NEJMc2119407. PubMed PMID: 35081300; PubMed Central PMCID: PMCPMC8809508. - DOI - PMC - PubMed

Supplementary concepts