Antibody-antibiotic conjugate targeted therapy for orthopedic implant-associated intracellular S. aureus infections

作者：Leilei Qin, Ning Hu, Yanhao Zhang, Jianye Yang, Liqun Zhao, Xiaokai Zhang, Yun Yang, Jinyong Zhang, Yinshuang Zou, Keyu Wei, Chen Zhao, Yujian Li, Hao Zeng, Wei Huang, Quanming Zou · 发表于：Journal of Advanced Research · 年份：2023 · DOI：10.1016/j.jare.2023.12.001 · 被引用次数：22 · 研究领域：Orthopedic Infections and Treatments、Monoclonal and Polyclonal Antibodies Research、Polymer Surface Interaction Studies

INTRODUCTION: Treating orthopedic implant-associated infections, especially those caused by Staphylococcus aureus (S. aureus), remains a significant challenge. S. aureus has the ability to invade host cells, enabling it to evade both antibiotics and immune responses during infection, which may result in clinical treatment failures. Therefore, it is critical to identify the host cell type of implant-associated intracellular S. aureus infections and to develop a strategy for highly targeted delivery of antibiotics to the host cells. OBJECTIVES: Introduced an antibody-antibiotic conjugate (AAC) for the targeted elimination of intracellular S. aureus. METHODS: The AAC comprises of a human monoclonal antibody (M0662) directly recognizes the surface antigen of S. aureus, Staphylococcus protein A, which is conjugated with vancomycin through cathepsin-sensitive linkers that are cleavable in the proteolytic environment of the intracellular phagolysosome. AAC, vancomycin and vancomycin combined with AAC were used in vitro intracellular infection and mice implant infection models. We then tested the effect of AAC in vivo and in vivo by fluorescence imaging, in vivo imaging, bacterial quantitative analysis and bacterial biofilm imaging. RESULTS: In vitro, it was observed that AAC captured extracellular S. aureus and co-entered the cells, and subsequently released vancomycin to induce rapid elimination of intracellular S. aureus. In the implant infection model, AAC significantly improved ...