Noninvasive optical and nuclear imaging of Staphylococcus-specific infection with a human monoclonal antibody-based probe

Abstract

Staphylococcus aureus infections are a major threat in healthcare, requiring adequate early-stage diagnosis and treatment. This calls for novel diagnostic tools that allow noninvasive in vivo detection of staphylococci. Here we performed a preclinical study to investigate a novel fully-human monoclonal antibody 1D9 that specifically targets the immunodominant staphylococcal antigen A (IsaA). We show that 1D9 binds invariantly to S. aureus cells and may further target other staphylococcal species. Importantly, using a human post-mortem implant model and an in vivo murine skin infection model, preclinical feasibility was demonstrated for 1D9 labeled with the near-infrared fluorophore IRDye800CW to be applied for direct optical imaging of in vivo S. aureus infections. Additionally, 89Zirconium-labeled 1D9 could be used for positron emission tomography imaging of an in vivo S. aureus thigh infection model. Our findings pave the way towards clinical implementation of targeted imaging of staphylococcal infections using the human monoclonal antibody 1D9.

Towards clinical application of non-invasive imaging to detect bacterial infections

“…In order to test the antibody-800CW conjugate for specificity, the authors compared binding to wildtype bacteria with mutants lacking IsaA or the IgG-binding S. aureus proteins Spa, and Sbi, respectively. In all models, the detected signal was specific for IsaA, supporting the idea of using antibodies for in vivo imaging diagnosis of bacterial infections [8]. Furthermore, fluorescence imaging results correlated roughly with bioluminescence signals of luciferase (lux)-expressing bacteria.…”

“…However, with this approach it is not possible to discriminate between different bacterial species as vancomycin binds to the cell wall of almost all Gram-positive bacteria. To detect specifically infections due to S. aureus, Pastrana and colleagues published in a recent issue of Virulence the use of a highly specific antibody for detection of S. aureus infectious foci by two different modalities, optical fluorescent imaging and PET imaging [8]. The authors selected an antibody that recognizes the broadly expressed surface antigen IsaA of S. aureus [9] in order to ensure detection of all clinical strains of the pathogen and coupled it to the near infrared dye 800CW.…”

Multimodal imaging guides surgical management in a preclinical spinal implant infection model

“…The 1D9-Alexa Fluor 555 probe readily detected S. aureus Xen36 and SH1000 in the in vitro biofilms. In comparison there was minimal background labeling in the ΔisaA mutant, which was likely due to nonspecific binding of the antibody by the Fc-binding factors Spa and Sbi (26). These data revealed highly effective binding of the 1D9 antibody to in vitro S. aureus biofilms.…”

“…To increase the specificity of pathogen diagnosis, the fully human monoclonal antibody 1D9 that targets the immunodominant staphylococcal antigen A (IsaA) of S. aureus (25, 26) labeled with a radionuclide (89-zirconium [ 89 Zr]) or a near-infrared fluorophore (NIR680) was previously effective in noninvasively diagnosing a S. aureus soft tissue infection in mice using PET-CT or in vivo fluorescence imaging (FLI), respectively (26). However, it is unclear so far whether the 1D9 probe could facilitate diagnosis as well as guide treatment of a more complex biofilm-associated S. aureus implant infection.…”

Preclinical Optical Imaging to Study Pathogenesis, Novel Therapeutics and Diagnostics Against Orthopaedic Infection

“…Objective determination of infected versus healthy tissue may optimize surgical management by guiding the appropriate amount of tissue removal and/or a number of operations as well as adjunctive therapies. Romero Pastrana et al combined in vivo BLI and FLI imaging to demonstrate that a fluorescently labeled mAb (800CW‐labeled 1D9) directed against the immunodominant staphylococcal antigen A (IsaA) of S. aureus accumulated at the site of an MSSA (ALC2906) and MRSA (SAP231) skin and soft tissue infection. Interestingly, in a spine model of S. aureus (Xen36) OIAI, in vivo BLI and FLI imaging was combined to demonstrate that the 800CW‐labeled 1D9 mAb accumulated at the site of infection and also decreased the bacterial burden .…”