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

• Published in: mBio 2021-03, Vol.12 (2)
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Bacterial - administration & dosage; Antibodies, Bacterial - genetics; Antibodies, Bacterial - immunology; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - immunology; Antigens, Bacterial - immunology; Bacterial Vaccines - administration & dosage; Bacterial Vaccines - immunology; Complement Activation; Epitopes - immunology; Female; Gonorrhea - immunology; Gonorrhea - prevention & control; Immunization, Passive; Immunoglobulin G - administration & dosage; Immunoglobulin G - genetics; Immunoglobulin G - immunology; Mice; Mice, Inbred BALB C; Neisseria gonorrhoeae - immunology; Research Article
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mBio.00242-21

Monoclonal antibody (MAb) 2C7 recognizes a lipooligosaccharide epitope expressed by most clinical 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) Because natural infection with often does not elicit protective immunity and reinfections are common, approaches that prolong bacterial control 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 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 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 -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 production of antibodies engineered to promote and optimize downstream innate effector mechanisms such as complement-mediated killing, leading to hastened bacterial elimination. 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 Here, we utilized a DNA-encoded MAb (DMAb) construct designed to launch production and assembly of "complement-enhanced"