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Synthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection

Monoclonal antibody (MAb) 2C7 recognizes a lipooligosaccharide epitope expressed by most clinical Neisseria gonorrhoeae isolates and mediates complement-dependent bactericidal activity. We recently showed that a recombinant human IgG1 chimeric variant of MAb 2C7 containing an E430G Fc modification (...

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Autores principales: Parzych, Elizabeth M., Gulati, Sunita, Zheng, Bo, Bah, Mamadou A., Elliott, Sarah T. C., Chu, Jacqueline D., Nowak, Nancy, Reed, George W., Beurskens, Frank J., Schuurman, Janine, Rice, Peter A., Weiner, David B., Ram, Sanjay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092225/
https://www.ncbi.nlm.nih.gov/pubmed/33727348
http://dx.doi.org/10.1128/mBio.00242-21
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author Parzych, Elizabeth M.
Gulati, Sunita
Zheng, Bo
Bah, Mamadou A.
Elliott, Sarah T. C.
Chu, Jacqueline D.
Nowak, Nancy
Reed, George W.
Beurskens, Frank J.
Schuurman, Janine
Rice, Peter A.
Weiner, David B.
Ram, Sanjay
author_facet Parzych, Elizabeth M.
Gulati, Sunita
Zheng, Bo
Bah, Mamadou A.
Elliott, Sarah T. C.
Chu, Jacqueline D.
Nowak, Nancy
Reed, George W.
Beurskens, Frank J.
Schuurman, Janine
Rice, Peter A.
Weiner, David B.
Ram, Sanjay
author_sort Parzych, Elizabeth M.
collection PubMed
description Monoclonal antibody (MAb) 2C7 recognizes a lipooligosaccharide epitope expressed by most clinical Neisseria gonorrhoeae isolates and mediates complement-dependent bactericidal activity. We recently showed that a recombinant human IgG1 chimeric variant of MAb 2C7 containing an E430G Fc modification (2C7_E430G), which enhances complement activation, outperformed the parental MAb 2C7 (2C7_WT) in vivo. Because natural infection with N. gonorrhoeae often does not elicit protective immunity and reinfections are common, approaches that prolong bacterial control in vivo are of great interest. Advances in DNA-based approaches have demonstrated the combined benefit of genetic engineering, formulation optimizations, and facilitated delivery via CELLECTRA-EP technology, which can induce robust in vivo expression of protective DNA-encoded monoclonal antibodies (DMAbs) with durable serum activity relative to traditional recombinant MAb therapies. Here, we created optimized 2C7-derived DMAbs encoding the parental Fc (2C7_WT) or complement-enhancing Fc variants (2C7_E430G and 2C7_E345K). 2C7 DMAbs were rapidly generated and detected throughout the 4-month study. While all complement-engaging 2C7 variants facilitated rapid clearance following primary N. gonorrhoeae challenge (day 8 after DMAb administration), the complement-enhancing 2C7_E430G variant demonstrated significantly higher potency against mice rechallenged 65 days after DMAb administration. Passive intravenous transfer of in vivo-produced, purified 2C7 DMAbs confirmed the increased potency of the complement-enhancing variants. This study highlights the ability of the DMAb platform to launch the in vivo production of antibodies engineered to promote and optimize downstream innate effector mechanisms such as complement-mediated killing, leading to hastened bacterial elimination.
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spelling pubmed-80922252021-05-04 Synthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection Parzych, Elizabeth M. Gulati, Sunita Zheng, Bo Bah, Mamadou A. Elliott, Sarah T. C. Chu, Jacqueline D. Nowak, Nancy Reed, George W. Beurskens, Frank J. Schuurman, Janine Rice, Peter A. Weiner, David B. Ram, Sanjay mBio Research Article Monoclonal antibody (MAb) 2C7 recognizes a lipooligosaccharide epitope expressed by most clinical Neisseria gonorrhoeae isolates and mediates complement-dependent bactericidal activity. We recently showed that a recombinant human IgG1 chimeric variant of MAb 2C7 containing an E430G Fc modification (2C7_E430G), which enhances complement activation, outperformed the parental MAb 2C7 (2C7_WT) in vivo. Because natural infection with N. gonorrhoeae often does not elicit protective immunity and reinfections are common, approaches that prolong bacterial control in vivo are of great interest. Advances in DNA-based approaches have demonstrated the combined benefit of genetic engineering, formulation optimizations, and facilitated delivery via CELLECTRA-EP technology, which can induce robust in vivo expression of protective DNA-encoded monoclonal antibodies (DMAbs) with durable serum activity relative to traditional recombinant MAb therapies. Here, we created optimized 2C7-derived DMAbs encoding the parental Fc (2C7_WT) or complement-enhancing Fc variants (2C7_E430G and 2C7_E345K). 2C7 DMAbs were rapidly generated and detected throughout the 4-month study. While all complement-engaging 2C7 variants facilitated rapid clearance following primary N. gonorrhoeae challenge (day 8 after DMAb administration), the complement-enhancing 2C7_E430G variant demonstrated significantly higher potency against mice rechallenged 65 days after DMAb administration. Passive intravenous transfer of in vivo-produced, purified 2C7 DMAbs confirmed the increased potency of the complement-enhancing variants. This study highlights the ability of the DMAb platform to launch the in vivo production of antibodies engineered to promote and optimize downstream innate effector mechanisms such as complement-mediated killing, leading to hastened bacterial elimination. American Society for Microbiology 2021-03-16 /pmc/articles/PMC8092225/ /pubmed/33727348 http://dx.doi.org/10.1128/mBio.00242-21 Text en Copyright © 2021 Parzych et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Parzych, Elizabeth M.
Gulati, Sunita
Zheng, Bo
Bah, Mamadou A.
Elliott, Sarah T. C.
Chu, Jacqueline D.
Nowak, Nancy
Reed, George W.
Beurskens, Frank J.
Schuurman, Janine
Rice, Peter A.
Weiner, David B.
Ram, Sanjay
Synthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection
title Synthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection
title_full Synthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection
title_fullStr Synthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection
title_full_unstemmed Synthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection
title_short Synthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection
title_sort synthetic dna delivery of an optimized and engineered monoclonal antibody provides rapid and prolonged protection against experimental gonococcal infection
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092225/
https://www.ncbi.nlm.nih.gov/pubmed/33727348
http://dx.doi.org/10.1128/mBio.00242-21
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