Abstract

Invasive Staphylococcus aureus (S. aureus) infection is a leading cause of infectious disease-related deaths due to the survival of S. aureus within host phagocytic cells, by which the bacteria are not adequately eliminated using current antibiotic treatments. Anti-S. aureus THIOMAB^TM antibody-antibiotic conjugate (TAC), an anti-S. aureus antibody conjugated with antibiotic payload dmDNA31, was designed to deliver antibiotics into phagocytes, thereby killing intracellular S. aureus. Herein, we present the distribution, metabolism/catabolism, and elimination properties for this modality. The tissue distribution of TAC, as well as the release and elimination of its payload dmDNA31 were characterized in rats using multiple approaches. Intravenous injection of unconjugated [¹⁴C]-dmDNA31 to rats resulted in a rapid clearance in both systemic circulation and tissues, with biliary secretion as the major route of elimination. Six major metabolites were identified. When [¹⁴C]-dmDNA31 was conjugated to an antibody as TAC and administered to rat intravenously, a sustained exposure was observed in both systemic circulation and tissues. The dmDNA31 in blood and tissues mainly remained in conjugated form after administering TAC, although minimal deconjugation of dmDNA31 from TAC was also observed. Several TAC catabolites were identified, which were mainly eliminated through the biliary-fecal route with dmDNA31 and deacetylated dmDNA31 as the most abundant catabolites. In summary, these studies provide a comprehensive characterization of the distribution, metabolism/catabolism, and elimination properties of TAC. These data fully support further clinical development of TAC for the invasive and difficult-to-treat S. aureus infection.

Significance Statement The present studies provided a comprehensive investigation of the absorption, distribution, catabolism/metabolism, and elimination (ADME) of the first antibody-antibiotic conjugate developed for the treatment of infectious diseases. Though many antibody-drug conjugates (ADCs) are in development for various disease indications, limited amount of ADME information is available in the literatures. This study presented an example on how to use radiolabeling technology to delineate the ADME properties of a complex modality and help address the key questions related to clinical pharmacological studies.