Journal Article

Fc-modification of anti-PcrV gene-encoded antibodies modulates complement-mediated killing of Pseudomonas aeruginosa

Chu, Jacqueline D., Custodio-Zegarra, David, Bai, Shuangyi, Flowers, Kaitlyn, Miller, Sarah J., Parzych, Elizabeth M., Bhardwaj, Bhavya, Gutierrez, Maria de la Paz, Weiner, David B., Smith, Trevor R. F., Choi, Jihae, Trachtman, Abigail R., Witt, William T., Eisenhauer, Jillian, Patel, Ami, Bharti, Suman, Barbier, Mariette, Dublin, Spencer, Gunn, Bronwyn M.

2025

Overview

Pseudomonas aeruginosa is a high priority multi-drug-resistant (MDR) bacterial pathogen with increasing resistance against broad-spectrum antibiotics. Multiple efforts are ongoing to develop anti-pseudomonal vaccines however achieving meaningful outcomes has been challenging in human clinical trials. Monoclonal antibodies (MAbs) are emerging as promising biologics for targeting P. aeruginosa infections and engineering strategies that bridge engagement with innate immune mechanisms like complement-mediated antibody dependent phagocytosis may be beneficial to improve bacterial clearance. We previously described both protection and long-term expression of synthetic DNA-encoded MAb (DMAb) expressing the anti-PcrV MAb V2L2-MD. Here, we show that modification of DMAb-V2L2-MD with an Fc-point mutation designed to enhance complement engagement demonstrates improved binding to C1q, C3 deposition, and improved opsonophagocytic killing. This Fc-modified DMAb reduced P. aeruginosa bacteria burden in lungs and nasal washes in a lethal acute murine intranasal infection model. These data highlight the importance of tailoring downstream antibody innate effector functions to improve clearance of difficult-to-treat bacteria like MDR P. aeruginosa.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animals / Antibiotics / Antibodies / Antibodies, Bacterial - genetics / Antibodies, Bacterial - immunology / Antibodies, Monoclonal - genetics / Antibodies, Monoclonal - immunology / Antigens, Bacterial - genetics / Antigens, Bacterial - immunology / Bacterial Toxins / Clinical trials / Complement C1q - immunology / Complement system / Complement System Proteins - immunology / Disease Models, Animal / DNA-encoded monoclonal antibody / Drug resistance / Female / Humans / Immune clearance / Immunoglobulin Fc Fragments - genetics / Immunoglobulin Fc Fragments - immunology / Immunology / Laboratory animals / Mice / Monoclonal antibodies / Multidrug resistance / Nosocomial infections / Pathogens / PcrV / Phagocytosis / Phagocytosis - immunology / Plasmids / Pneumonia / Point mutation / Pore Forming Cytotoxic Proteins / Proteins / Pseudomonas aeruginosa / Pseudomonas aeruginosa - immunology / Pseudomonas Infections - immunology / Pseudomonas Infections - microbiology / type III secretion system / Vaccines