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dc.contributor.authorParzych, Elizabeth M.
dc.contributor.authorGulati, Sunita
dc.contributor.authorZheng, Bo
dc.contributor.authorBah, Mamadou A.
dc.contributor.authorElliott, Sarah T. C.
dc.contributor.authorChu, Jacqueline D.
dc.contributor.authorNowak, Nancy
dc.contributor.authorReed, George W.
dc.contributor.authorBeurskens, Frank J.
dc.contributor.authorSchuurman, Janine
dc.contributor.authorRice, Peter A.
dc.contributor.authorWeiner, David B.
dc.contributor.authorRam, Sanjay
dc.date2022-08-11T08:09:59.000
dc.date.accessioned2022-08-23T16:51:22Z
dc.date.available2022-08-23T16:51:22Z
dc.date.issued2021-03-16
dc.date.submitted2021-06-14
dc.identifier.citation<p>Parzych EM, Gulati S, Zheng B, Bah MA, Elliott STC, Chu JD, Nowak N, Reed GW, Beurskens FJ, Schuurman J, Rice PA, Weiner DB, Ram S. Synthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection. mBio. 2021 Mar 16;12(2):e00242-21. doi: 10.1128/mBio.00242-21. PMID: 33727348; PMCID: PMC8092225. <a href="https://doi.org/10.1128/mBio.00242-21">Link to article on publisher's site</a></p>
dc.identifier.issn2150-7511 (Electronic)
dc.identifier.doi10.1128/mBio.00242-21
dc.identifier.pmid33727348
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41843
dc.description.abstractMonoclonal 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. IMPORTANCE Neisseria gonorrhoeae has become resistant to most antibiotics in clinical use. Currently, there is no safe and effective vaccine against gonorrhea. Measures to prevent the spread of gonorrhea are a global health priority. A monoclonal antibody (MAb) called 2C7, directed against a lipooligosaccharide glycan epitope expressed by most clinical isolates, displays complement-dependent bactericidal activity and hastens clearance of gonococcal vaginal colonization in mice. Fc mutations in a human IgG1 chimeric version of MAb 2C7 further enhance complement activation, and the resulting MAb displays greater activity than wild-type MAb 2C7 in vivo Here, we utilized a DNA-encoded MAb (DMAb) construct designed to launch production and assembly of "complement-enhanced" chimeric MAb 2C7 in vivo The ensuing rapid and sustained MAb 2C7 expression attenuated gonococcal colonization in mice at 8 days as well as 65 days postadministration. The DMAb system may provide an effective, economical platform to deliver MAbs for durable protection against gonorrhea.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=33727348&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright © 2021 Parzych et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectDNA-delivered monoclonal antibody
dc.subjectNeisseria gonorrhoeae
dc.subjectcomplement
dc.subjectgonorrhea
dc.subjectmonoclonal antibodies
dc.subjectBacterial Infections and Mycoses
dc.subjectImmunology of Infectious Disease
dc.subjectImmunoprophylaxis and Therapy
dc.subjectMicrobiology
dc.titleSynthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection
dc.typeJournal Article
dc.source.journaltitlemBio
dc.source.volume12
dc.source.issue2
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5677&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4646
dc.identifier.contextkey23344517
refterms.dateFOA2022-08-23T16:51:22Z
html.description.abstract<p>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.</p> <p>IMPORTANCE Neisseria gonorrhoeae has become resistant to most antibiotics in clinical use. Currently, there is no safe and effective vaccine against gonorrhea. Measures to prevent the spread of gonorrhea are a global health priority. A monoclonal antibody (MAb) called 2C7, directed against a lipooligosaccharide glycan epitope expressed by most clinical isolates, displays complement-dependent bactericidal activity and hastens clearance of gonococcal vaginal colonization in mice. Fc mutations in a human IgG1 chimeric version of MAb 2C7 further enhance complement activation, and the resulting MAb displays greater activity than wild-type MAb 2C7 in vivo Here, we utilized a DNA-encoded MAb (DMAb) construct designed to launch production and assembly of "complement-enhanced" chimeric MAb 2C7 in vivo The ensuing rapid and sustained MAb 2C7 expression attenuated gonococcal colonization in mice at 8 days as well as 65 days postadministration. The DMAb system may provide an effective, economical platform to deliver MAbs for durable protection against gonorrhea.</p>
dc.identifier.submissionpathoapubs/4646
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.source.pagese00242-21


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Copyright © 2021 Parzych et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Except where otherwise noted, this item's license is described as Copyright © 2021 Parzych et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.