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Complement alone drives efficacy of a chimeric antigonococcal monoclonal antibody

Gulati, Sunita ; Beurskens, Frank J ; de Kreuk, Bart-Jan ; Roza, Marcel ; Zheng, Bo ; DeOliveira, Rosane B ; Shaughnessy, Jutamas ; Nowak, Nancy A ; Taylor, Ronald P ; Botto, Marina ; He, Xianbao ; Ingalls, Robin R ; Woodruff, Trent M ; Song, Wen-Chao ; Schuurman, Janine ; Rice, Peter A ; Ram, Sanjay Waldor, Matthew K.

PLoS Biology, 2019-06, Vol.17 (6), p.e3000323-e3000323 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Complement alone drives efficacy of a chimeric antigonococcal monoclonal antibody
Autor: Gulati, Sunita ; Beurskens, Frank J ; de Kreuk, Bart-Jan ; Roza, Marcel ; Zheng, Bo ; DeOliveira, Rosane B ; Shaughnessy, Jutamas ; Nowak, Nancy A ; Taylor, Ronald P ; Botto, Marina ; He, Xianbao ; Ingalls, Robin R ; Woodruff, Trent M ; Song, Wen-Chao ; Schuurman, Janine ; Rice, Peter A ; Ram, Sanjay
Waldor, Matthew K.
Assuntos: Animals ; Antibodies ; Antibodies, Bacterial - immunology ; Antibodies, Monoclonal - metabolism ; Antigenic determinants ; Antigens, Bacterial ; Bactericidal activity ; Biology and Life Sciences ; C4b-binding protein ; Chlamydia ; Clinical isolates ; Comorbidity ; Complement ; Complement activation ; Complement Activation - immunology ; Complement C4b-Binding Protein - immunology ; Complement component C1q ; Complement component C3 ; Complement component C4 ; Complement component C5a ; Complement factor H ; Complement Factor H - immunology ; Complement inhibitors ; Complement System Proteins - immunology ; Complement System Proteins - metabolism ; Epitopes ; Epitopes - immunology ; Fc receptors ; Female ; Genetic engineering ; Genital tract ; Global health ; Gonorrhea ; Gonorrhea - immunology ; Granulocytes ; Health ; Health aspects ; Healthy Volunteers ; Humans ; Immunoglobulin G ; Immunoglobulin G - immunology ; Immunoglobulins ; Immunology ; Infections ; Infectious diseases ; Inflammation ; Inhibitors ; Intravenous administration ; Lipooligosaccharides ; Listeria ; Medical schools ; Medicine ; Medicine and Health Sciences ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Transgenic ; Microbial drug resistance ; Monoclonal antibodies ; Multidrug resistance ; Neisseria gonorrhoeae - immunology ; Neisseria gonorrhoeae - pathogenicity ; Peptides ; Physical Sciences ; Protein binding ; Research and Analysis Methods ; Sexually transmitted diseases ; STD ; Surface science ; Technology ; Transgenic mice ; Vaccines ; Vagina ; World health
É parte de: PLoS Biology, 2019-06, Vol.17 (6), p.e3000323-e3000323
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I have read the journal's policy and the authors of this manuscript have the following competing interests. The following authors have a financial interest in Genmab: FJB, BJdK, MR, and JS have stock and/or warrants.
Descrição: 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 μg 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 (FcγR) 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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Complement alone drives efficacy of a chimeric antigonococcal monoclonal antibody

United States: Public Library of Science

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