A multifunctional bispecific antibody protects against Pseudomonas aeruginosa

作者：Antonio DiGiandomenico, Ashley Keller, Cuihua Gao, G. Jonah Rainey, Paul Warrener, Mareia M. Camara, Jessica Bonnell, Ryan Fleming, Binyam Bezabeh, Nazzareno Dimasi, Bret R. Sellman, Jamese J. Hilliard, Caitlin M. Guenther, Vivekananda Datta, Zhao Wei, Changshou Gao, Xiang‐Qing Yu, JoAnn Suzich, C. Kendall Stover · 发表于：Science Translational Medicine · 年份：2014 · DOI：10.1126/scitranslmed.3009655 · 被引用次数：284 · 研究领域：Bacteriophages and microbial interactions、Antibiotic Resistance in Bacteria、Bacterial Genetics and Biotechnology

Widespread drug resistance due to empiric use of broad-spectrum antibiotics has stimulated development of bacteria-specific strategies for prophylaxis and therapy based on modern monoclonal antibody (mAb) technologies. However, single-mechanism mAb approaches have not provided adequate protective activity in the clinic. We constructed multifunctional bispecific antibodies, each conferring three mechanisms of action against the bacterial pathogen Pseudomonas aeruginosa by targeting the serotype-independent type III secretion system (injectisome) virulence factor PcrV and persistence factor Psl exopolysaccharide. A new bispecific antibody platform, BiS4, exhibited superior synergistic protection against P. aeruginosa-induced murine pneumonia compared to parent mAb combinations or other available bispecific antibody structures. BiS4αPa was protective in several mouse infection models against disparate P. aeruginosa strains and unexpectedly further synergized with multiple antibiotic classes even against drug-resistant clinical isolates. In addition to resulting in a multimechanistic clinical candidate (MEDI3902) for the prevention or treatment of P. aeruginosa infections, these antibody studies suggest that multifunctional antibody approaches may be a promising platform for targeting other antibiotic-resistant bacterial pathogens.