Complement alone drives efficacy of a chimeric antigonococcal monoclonal antibody
Authors
Gulati, SunitaBeurskens, Frank J.
Zheng, Bo
DeOliveira, Rosane B.
Shaughnessy, Jutamas
Nowak, Nancy
Rice, Peter A.
Ram, Sanjay
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2019-06-19Keywords
Neisseria gonorrhoeaeComplement system
Complement activation
Gonorrhea
Antibodies
Analysis of variance
Mouse models
Monoclonal antibodies
Bacteria
Bacterial Infections and Mycoses
Immunology of Infectious Disease
Immunoprophylaxis and Therapy
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Multidrug-resistant Neisseria gonorrhoeae is a global health problem. Monoclonal antibody (mAb) 2C7 recognizes a gonococcal lipooligosaccharide epitope that is expressed by > 95% of clinical isolates and hastens gonococcal vaginal clearance in mice. Chimeric mAb 2C7 (human immunoglobulin G1 [IgG1]) with an E430G Fc modification that enhances Fc:Fc interactions and hexamerization following surface-target binding and increases complement activation (HexaBody technology) showed significantly greater C1q engagement and C4 and C3 deposition compared to mAb 2C7 with wild-type Fc. Greater complement activation by 2C7-E430G Fc translated to increased bactericidal activity in vitro and, consequently, enhanced efficacy in mice, compared with "Fc-unmodified" chimeric 2C7. Gonococci bind the complement inhibitors factor H (FH) and C4b-binding protein (C4BP) in a human-specific manner, which dampens antibody (Ab)-mediated complement-dependent killing. The variant 2C7-E430G Fc overcame the barrier posed by these inhibitors in human FH/C4BP transgenic mice, for which a single 1 mug intravenous dose cleared established infection. Chlamydia frequently coexists with and exacerbates gonorrhea; 2C7-E430G Fc also proved effective against gonorrhea in gonorrhea/chlamydia-coinfected mice. Complement activation alone was necessary and sufficient for 2C7 function, evidenced by the fact that (1) "complement-inactive" Fc modifications that engaged Fc gamma receptor (FcgammaR) rendered 2C7 ineffective, nonetheless; (2) 2C7 was nonfunctional in C1q-/- mice, when C5 function was blocked, or in C9-/- mice; and (3) 2C7 remained effective in neutrophil-depleted mice and in mice treated with PMX205, a C5a receptor (C5aR1) inhibitor. We highlight the importance of complement activation for antigonococcal Ab function in the genital tract. Elucidating the correlates of protection against gonorrhea will inform the development of Ab-based gonococcal vaccines and immunotherapeutics.Source
PLoS Biol. 2019 Jun 19;17(6):e3000323. doi: 10.1371/journal.pbio.3000323. eCollection 2019 Jun. Link to article on publisher's site
DOI
10.1371/journal.pbio.3000323Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41107PubMed ID
31216278Notes
Full author list omitted for brevity. For the full list of authors, see article.
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Copyright: © 2019 Gulati et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1371/journal.pbio.3000323
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Except where otherwise noted, this item's license is described as Copyright: © 2019 Gulati et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.