Buckley Peter T, Chan Rita, Fernandez Jeffrey, Luo Jinquan, Lacey Keenan A, DuMont Ashley L, O'Malley Aidan, Brezski Randall J, Zheng Songmao, Malia Thomas, Whitaker Brian, Zwolak Adam, Payne Angela, Clark Desmond, Sigg Martin, Lacy Eilyn R, Kornilova Anna, Kwok Debra, McCarthy Steve, Wu Bingyuan, Morrow Brian, Nemeth-Seay Jennifer, Petley Ted, Wu Sam, Strohl William R, Lynch Anthony Simon, Torres Victor J
Janssen Research & Development, 1400 McKean Road, Spring House, PA, USA.
Department of Microbiology, New York University Grossman School of Medicine, Alexandria Center for Life Science, 430 East 29th Street, New York, NY 10016, USA.
Cell Host Microbe. 2023 May 10;31(5):751-765.e11. doi: 10.1016/j.chom.2023.04.004. Epub 2023 Apr 24.
Treating and preventing infections by antimicrobial-resistant bacterial pathogens is a worldwide problem. Pathogens such as Staphylococcus aureus produce an array of virulence determinants, making it difficult to identify single targets for the development of vaccines or monoclonal therapies. We described a human-derived anti-S. aureus monoclonal antibody (mAb)-centyrin fusion protein ("mAbtyrin") that simultaneously targets multiple bacterial adhesins, resists proteolysis by bacterial protease GluV8, avoids Fc engagement by S. aureus IgG-binding proteins SpA and Sbi, and neutralizes pore-forming leukocidins via fusion with anti-toxin centyrins, while maintaining Fc- and complement-mediated functions. Compared with the parental mAb, mAbtyrin protected human phagocytes and boosted phagocyte-mediated killing. The mAbtyrin also reduced pathology, reduced bacterial burden, and protected from different types of infections in preclinical animal models. Finally, mAbtyrin synergized with vancomycin, enhancing pathogen clearance in an animal model of bacteremia. Altogether, these data establish the potential of multivalent mAbs for treating and preventing S. aureus diseases.
治疗和预防由耐抗菌细菌病原体引起的感染是一个全球性问题。金黄色葡萄球菌等病原体产生一系列毒力决定因素，这使得难以确定开发疫苗或单克隆疗法的单一靶点。我们描述了一种人源抗金黄色葡萄球菌单克隆抗体（mAb）-centyrin融合蛋白（“mAbtyrin”），它同时靶向多种细菌黏附素，抵抗细菌蛋白酶GluV8的蛋白水解作用，避免金黄色葡萄球菌IgG结合蛋白SpA和Sbi与Fc结合，并通过与抗毒素centyrin融合中和成孔白细胞毒素，同时保持Fc和补体介导的功能。与亲本单克隆抗体相比，mAbtyrin保护人类吞噬细胞并增强吞噬细胞介导的杀伤作用。mAbtyrin还减轻了病理变化，降低了细菌载量，并在临床前动物模型中预防了不同类型的感染。最后，mAbtyrin与万古霉素协同作用，增强了菌血症动物模型中的病原体清除率。总之，这些数据证实了多价单克隆抗体在治疗和预防金黄色葡萄球菌疾病方面的潜力。
