Sustained activity of novel THIOMAB antibody-antibiotic conjugate against Staphylococcus aureus in a mouse model: Longitudinal pharmacodynamic assessment by bioluminescence imaging

Abstract

Staphylococcus aureus (S. aureus) infections are a leading cause of death by an infectious agent. Survival within host phagocytic cells is one mechanism by which S. aureus evades antibiotic treatment. A novel THIOMAB™ antibody-antibiotic conjugate (TAC) strategy was developed to kill S. aureus intracellularly and mitigate the spread of infection. In this report, we used a longitudinal whole-body bioluminescence imaging method to study the antibacterial dynamics of TAC alone or in combination with vancomycin in a mouse infection model. Injections of stably luminescent S. aureus bacteria into mice resulted in exponential increases in whole body bioluminescence with a reduction in body weight and survival rate. Vancomycin, a standard-of-care antibiotic, suppressed bacterial growth in mice. However, bacterial growth rebounded in these animals once treatment was discontinued. In contrast, single dose of TAC showed rapid reduction of bioluminescence intensity, which persisted for up to 19 days. The combination of TAC and vancomycin achieved a more sustained and significantly greater reduction of bioluminescence compared with vancomycin alone. In summary, the present study showed an imaging method to longitudinally assess antibacterial drug dynamics in mice and demonstrated that TAC monotherapy or in combination with vancomycin had superior and sustained activity compared to vancomycin alone.

Characterization of Tissue Distribution, Catabolism, and Elimination of an Anti–Staphylococcus aureusTHIOMAB Antibody-Antibiotic Conjugate in Rats

“…Single administration of TAC significantly reduced the bacterial load in kidney and heart from SCID mice infected with S. aureus bacteria (Zhou et al, 2016). A dose-dependent and sustained suppression of bacterial growth was also observed via whole body imaging using a bioluminescent mouse model (Zhou et al, 2019).…”

A homogeneous high-DAR antibody-drug conjugate platform combining THIOMABTM antibodies and XTEN polypeptides

“…Its mechanism of action includes binding to the S. aureus surface, followed by phagocytosis by phagocytic cells, linker cleavage and antibiotic release, and intracellular killing of the bacteria. This TDC enabled intracellular killing of S. aureus in phagocytes in vitro and antibacterial efficacy in in vivo models of S. aureus infection when given at high doses of 25-50 mg/kg was superior to standard-of-care antibiotics 9,10,46 . The anti-S. aureus TDC molecule has recently been tested in a phase I human clinical trial to assess its safety and pharmacokinetics 47 .…”

Staphylococcus aureus Vaccine Research and Development: The Past, Present and Future, Including Novel Therapeutic Strategies

“…In early clinical and preclinical studies, novel antibiotics and delivery systems improving the efficacy of established antibiotics are being investigated along with the usage of novel drug combinations. An example of such effects at work can be seen by the recent development of DSTA4637S, an antibody-antibiotic conjugate consisting of a monoclonal antibody targeting S. aureus wall teichoic acid, fused to a novel rifamycin-class antibiotic ( 163 ). Mechanistically, DSTA4637S works to promote opsonophagocytosis which, upon entry into the intracellular phagolysosome of human phagocytes, initiates the cleavage of the fused antibiotic, and subsequent bacterial inhibition ( 164 ).…”