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

Abstract

Invasive Staphylococcus aureus (S. aureus) infection is a leading cause of infectious diseaserelated 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 [ 14 C]-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 [ 14 C]-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.

The Future of (Radio)‐Labeled Compounds in Research and Development within the Life Science Industry

“…The drug‐linker combination is then coupled to the antibody. For example, [ 14 C]‐dmDNA31 is an antibiotic that was conjugated to an anti‐staphylococcus aureus antibody via a valine‐citrulline linker [136] . This afforded the antibody with an average of 1.6 molecules of [ 14 C]dmDNA31 per antibody and this material was used to characterize the ADME properties of the molecule (Figure 17).…”

Antibody-Drug Conjugates: Functional Principles and Applications in Oncology and Beyond

“…Once dmDNA31 is liberated, it kills AAC-opsonized and pre-existing bacteria within the phagocytes. DSTA4637S remains stable in circulation after intravenous administration, with minimal antibiotic deconjugation reported [130]. In mouse models, the pharmacokinetic profile was similar between S. aureus infected and non-infected subjects [131].…”

Unusual Biotransformation Reactions of Drugs and Drug Candidates

“…Recent publications have described various approaches for studying the biotransformation of protein therapeutics, (Schadt et al, 2019) antisense oligonucleotides, N-acetylgalactosamine conjugated small interfering RNA (McDougall et al, 2022) (Robin McDougal) and ADCs. (Bolleddula et al, 2020;Cai et al, 2020) Admittedly, the resulting products from the degradation of these large molecule modalities are rather predictable, however, such biotransformation studies require different in vitro systems, analytical approaches and a knowledge of enzymes and biotransformation pathways rather different than the "traditional" small molecules and hence may be considered as unusual in the context of this review. For example, all of the 10 ASOs approved by FDA to date have been reported to be degraded primarily by endonucleases and exonucleases in the bloodstream and the target cells.…”