Complement alone drives efficacy of a chimeric antigonococcal monoclonal antibody

Area of Science:

• Immunology
• Microbiology
• Infectious Diseases

Background:

• Multidrug-resistant Neisseria gonorrhoeae poses a significant global health threat.
• Monoclonal antibody (mAb) 2C7 targets a gonococcal lipooligosaccharide epitope present in most clinical isolates.
• Previous studies showed mAb 2C7 hastens gonococcal clearance in mice.

Purpose of the Study:

• To evaluate the efficacy of a modified mAb 2C7 (2C7-E430G Fc) utilizing HexaBody technology for enhanced complement activation against Neisseria gonorrhoeae.
• To assess the antibody's effectiveness in overcoming complement inhibitors and its performance in coinfection models.

Main Methods:

• Engineered chimeric mAb 2C7 (human IgG1) with an E430G Fc modification for enhanced hexamerization and complement activation.
• In vitro bactericidal assays and in vivo efficacy studies in mouse models, including human FH/C4BP transgenic and gonorrhea/chlamydia-coinfected mice.
• Experiments utilizing complement component-deficient mice (C1q-/-, C9-/-) and complement inhibitor treatments to dissect the mechanism of action.

Main Results:

• The 2C7-E430G Fc variant exhibited significantly greater complement activation (C1q, C4, C3 deposition) compared to wild-type mAb 2C7.
• Enhanced complement activation translated to increased in vitro bactericidal activity and superior in vivo efficacy in mouse models.
• The modified mAb 2C7 overcame complement inhibition by human factor H and C4b-binding protein, clearing established infections with a single low dose.
• The antibody was effective against gonorrhea in coinfection models and its function was dependent on complement activation, not Fc gamma receptor engagement.

Conclusions:

• The HexaBody-engineered mAb 2C7 (2C7-E430G Fc) demonstrates potent antigonococcal activity mediated by complement activation.
• This approach effectively overcomes key gonococcal immune evasion mechanisms in a human-specific manner.
• Findings highlight the critical role of complement activation in antibody efficacy against genital tract infections and inform the development of novel immunotherapeutics and vaccines.