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Author Notes:

Correspondence: dweiner@wistar.org

A.P., T.R.F.S., M.C.W., S.T.C.E., R.E., J.Y., J.C., K.M., K.E.B., L.H., N.Y.S., and D.B.W. designed and/or interpreted the reported experiments or results.

D.H.P., A.L., K.T., A.B., E.D., T.R., C.R., and M.E.G. participated in the acquisition and/or analysis of data.

A.P., D.H.P., A.L., K.T., E.D., T.R., B.J.D., M.C.W., S.T.C.E., R.E., D.K., and D.B.W. participated in drafting and/or revising the manuscript.

The following were primarily responsible for a particular specialized role in the research: C.W.D. and R.A. (isolation of mAb 5.6.1A2 and providing recombinant 5.6.1A2 reagents for experiments), J.E.C. (mAb isolation and sequence of mAb clones), X.Y. and E.O.S. (neutralization assay), and S.H. (maintenance and preparation of viral stocks and control antibodies).

B.J.D., G.P.K., X.Q., D.K., L.H., N.Y.S., and D.B.W. provided administrative, technical, or supervisory support.

The authors would like to thank Jonathan Audet (PHAC) for analysis of the EBOV-GFP neutralization assay, Dr. Alfredo Perales-Puchalt (Wistar) for statis-tical analysis, and the Wistar Histotechnology Core Facility for tissue sectioning and staining.

T.R.F.S., C.R., M.C.W., J.Y., J.C., K.E.B., L.H., and N.Y.S. are employees of Inovio Pharmaceuticals and as such receive salary and benefits, including ownership of stock and stock options, from the company.

A.B., E.D., and B.J.D. are employees of Integral Molecular and as such receive salary and benefits, including ownership of stock and stock options, from the company.

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 services.

Remuneration received by D.B.W. includes direct payments or stock or stock options, and in the interest of disclosure he notes potential conflicts associated with this work with Inovio and possibly others. In addition, he has a patent DNA vaccine delivery pending to Inovio.

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Research Funding:

This research was funded by DARPA Grant W31P4Q-15-1-0003 awarded to Inovio Pharmaceuticals and NIH Contract HHSN272201400058C to B.J.D.

K.M. reports receiving grants from DARPA and Inovio, receiving consulting fees from Inovio related to DNA vaccine development, and a pending patent application (to Inovio) for delivery of DNA-encoded monoclonal antibodies.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • EXPRESSION
  • DISEASE
  • MICE
  • IMMUNOGLOBULINS
  • DEVELOPABILITY
  • IMMUNOGENICITY
  • OPTIMIZATION
  • PROPHYLAXIS
  • VACCINATION
  • RECEPTORS

In Vivo Delivery of Synthetic Human DNA-Encoded Monoclonal Antibodies Protect against Ebolavirus Infection in a Mouse Model

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Journal Title:

Cell Reports

Volume:

Volume 25, Number 7

Publisher:

, Pages 1982-+

Type of Work:

Article | Final Publisher PDF

Abstract:

Synthetically engineered DNA-encoded monoclonal antibodies (DMAbs) are an in vivo platform for evaluation and delivery of human mAb to control against infectious disease. Here, we engineer DMAbs encoding potent anti-Zaire ebolavirus (EBOV) glycoprotein (GP) mAbs isolated from Ebola virus disease survivors. We demonstrate the development of a human IgG1 DMAb platform for in vivo EBOV-GP mAb delivery and evaluation in a mouse model. Using this approach, we show that DMAb-11 and DMAb-34 exhibit functional and molecular profiles comparable to recombinant mAb, have a wide window of expression, and provide rapid protection against lethal mouse-adapted EBOV challenge. The DMAb platform represents a simple, rapid, and reproducible approach for evaluating the activity of mAb during clinical development. DMAbs have the potential to be a mAb delivery system, which may be advantageous for protection against highly pathogenic infectious diseases, like EBOV, in resource-limited and other challenging settings. Monoclonal antibodies are an important approach for emerging infectious disease prevention. Patel et al. demonstrate engineering and in vivo delivery of DNA-encoded monoclonal antibodies (DMAbs) targeting the Zaire ebolavirus (EBOV) glycoprotein. DMAbs protect against lethal mouse-adapted EBOV and are useful for rapid evaluation of fully human mAbs in live animal models.

Copyright information:

© 2018 The Authors

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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