Pharmacokinetics and pharmacodynamics of DSTA4637A: A novel THIOMAB™ antibody antibiotic conjugate against Staphylococcus aureus in mice

Abstract

DSTA4637A, a novel THIOMAB™ antibody antibiotic conjugate (TAC) against Staphylococcus aureus (S. aureus), is currently being investigated as a potential therapy against S. aureus infections. Structurally, TAC is composed of an anti-S. aureus antibody linked to a potent antibiotic, dmDNA31. The goal of the current study was to characterize the pharmacokinetics (PK) of TAC in mice, assess the effect of S. aureus infection on its PK, and evaluate its pharmacodynamics (PD) by measuring the bacterial load in various organs at different timepoints following TAC treatment. Plasma concentrations of 3 analytes, total antibody (TAb), antibody-conjugated dmDNA31 (ac-dmDNA31), and unconjugated dmDNA31, were measured in these studies. In non-infected mice (target antigen absent), following intravenous (IV) administration of a single dose of TAC, systemic concentration-time profiles of both TAb and ac-dmDNA31 were bi-exponential and characterized by a short distribution phase and a long elimination phase as expected for a monoclonal antibody-based therapeutic. Systemic exposures of both TAb and ac-dmDNA31 were dose proportional over the dose range tested (5 to 50 mg/kg). In a mouse model of systemic S. aureus infection (target antigen present), a single IV dose of TAC demonstrated PK behavior similar to that in the non-infected mice, and substantially reduced bacterial load in the heart, kidney, and bones on 7 and 14 d post dosing. These findings have increased our understanding of the PK and PK/PD of this novel molecule, and have shown that at efficacious dose levels the presence of S. aureus infection had minimal effect on TAC PK.

Drug delivery systems designed to overcome antimicrobial resistance

“…The conjugate ( 100 ), also known as DSTA4637S, was composed of an anti‐ S. aureus THIOMAB TM antibody ( 101 ) (a human IgG1 mAb generated by Genentech Inc, South San Francisco, CA), a protease cleavable valine‐citrulline linker (maleimido‐caproyl‐valine‐citrulline‐para‐aminobenzyl) and a potent antibiotic, dmDNA31 ( 102 ) (rifalog, 4‐dimethylamino piperidino‐hydroxybenzoxazino rifamycin) (Figure A). ( 102 ) was covalently linked to anti‐ S. aureus antibody through cysteine residues to yield an average antibiotic to unconjugated antibody ratio of ~2 . The in vitro evaluation showed that ( 100 ) was capable of eradicating intracellular S. aureus infections observed in every infected cell type tested, including human macrophages, endothelial and epithelial cell lines.…”

“…This ACC conjugate ( 100 ) was recently assessed for its pharmacokinetic (PK) and pharmacodynamics (PD) profiles in S. aureus ‐infected and noninfected mice models over a dosage range of 25 to 50 and 5 to 50 mg/kg, respectively . The results showed that a single intravenous dose of DSTA4637A (a preclinical formulation of ( 100 )) exhibited a PK behavior similar to that in the noninfected mice, and could significantly reduce bacterial load in the heart, kidney, and bones after both 7 and 14 days of treatment . Conjugation of dmDNA31 with a THIOMAB antibody improved the half‐life ( t 1/2 ) of the antibiotic in vivo, extending the t 1/2 from 3 to 4 hours to 4 days.…”

“…Conjugation of dmDNA31 with a THIOMAB antibody improved the half‐life ( t 1/2 ) of the antibiotic in vivo, extending the t 1/2 from 3 to 4 hours to 4 days. In addition, at an effective dose, infection of S. aureus had very little impact on the PK of the conjugate . DSTA4637S ( 100 ) has been submitted for an ongoing phase I clinical trial to investigate the safety, tolerability, and pharmacokinetics in participants with S. aureus bacterium who are receiving at least 4 weeks of anti‐staphylococcal standard‐of‐care antibiotics .…”

“…(102) was covalently linked to anti-S. aureus antibody through cysteine residues to yield an average antibiotic to unconjugated antibody ratio of~2. 34,224 The in vitro evaluation showed that (100) was capable of eradicating intracellular S. aureus infections observed in every infected cell type tested, including human macrophages, endothelial and epithelial cell lines. Furthermore, DSTA4637S exerted stronger ATB activity, when compared to that of vancomycin (34) and unconjugated rifalog (102), in an intravenous infection in vivo model.…”

A single dose of antibody-drug conjugate cures a stage 1 model of African trypanosomiasis

“…The binding of a host macromolecule to a receptor, followed by the internalisation of the complex, provides a potential route to specifically deliver therapeutics into trypanosome cells. Entry of TLF1 via the HpHbR and the release of a cytotoxin after internalisation is analogous to the mode of action of ADCs (20), a growing class of therapeutics, particularly used in applications in oncology(21–23) and also with demonstrated potential as anti-bacterials(24, 25). An early attempt to develop ADCs against the intracellular American trypanosome, Trypanosoma cruzi , used chlorambucil conjugated to polyclonal IgGs purified from chronically infected rabbits (26) and, while results were promising, this was only partially successful.…”