Minimal physiologically-based pharmacokinetic modeling of DSTA4637A, A novel THIOMAB™ antibody antibiotic conjugate against Staphylococcus aureus, in a mouse model

Abstract

DSTA4637A, a THIOMAB™ antibody-antibiotic conjugate targeting Staphylococcus aureus, has shown promising bactericidal activity in a mouse model. DSTA4637A consists of a monoclonal anti-S. aureus antibody with an average of two rifalogue antibiotic molecules, dmDNA31, linked to its light chains. The goal of this study was to develop a minimal physiologically-based pharmacokinetic (mPBPK) model to characterize the pharmacokinetic (PK) properties of three analytes of DSTA4637A (i.e., total antibody, antibody-conjugated dmDNA31, and unconjugated dmDNA31) in mice, and to predict pharmacokinetics of DSTA4637A analytes in humans, as well as to provide an initial assessment for potential PK drug-drug interactions (DDI) in clinical trials via cross-species scaling of the mPBPK model. In the proposed model, selected organs, including heart, liver, and kidney, were connected anatomically with plasma and lymph flows. Mouse plasma and tissue concentrations of the three analytes of DSTA4637A were fitted simultaneously to estimate the PK parameters. Cross-species scaling of the model was performed by integrating allometric scaling and human physiological parameters. The final mPBPK model was able to successfully capture PK profiles of three DSTA4637A analytes in mouse plasma and in investigated organs. The model predicted a steady-state peak unbound dmDNA31 concentration lower than 5% of the IC of dmDNA31 towards cytochrome P450 following 100 mg/kg weekly intravenous dose, which suggests a low risk of PK DDI in humans for DSTA4637A with co-administered cytochrome P450 substrates. The proposed mPBPK modeling and cross-species scaling approaches provide valuable tools that facilitate the understanding and translation of DSTA4637A disposition from preclinical species to humans.

Bivalent engagement of endothelial surface antigens is critical to prolonged surface targeting and protein delivery in vivo

“…While plausible, this simplified analysis fails to incorporate the full range of properties of affinity ligand and target (eg, binding affinity, kinetics, expression, and internalization), or the multitude of physiologic processes (eg, blood flow rates, organ volumes) relevant to biodistribution. Indeed, relatively few efforts have been made to develop mechanistic understanding of the PK of endothelial surface targeting, despite significant work done on modeling intracellular delivery [53][54][55] and transcytosis. 56 To our knowledge, the only example of a mechanistic model of cell surface anchoring has been in the case of bispecific T-cell engagers, 57,58 making the PBPK approach described here relatively unique.…”

Monoclonal antibody-based therapies for bacterial infections

“…The mAb F598 [Alopexx, Concord MA] has met numerous hurdles in clinical development, as both Phase II clinical studies examining the efficacy of the anti-PNAG antibody have been halted. However, trials on the antibody-antibiotic conjugate DSTA4637S [Genentech, San Francisco CA] against a narrower teichoic acid motif shows promise as an anti-Staphylococcus therapy (46).…”

Cutting-edge multi-level analytical and structural characterization of antibody-drug conjugates: present and future

“…ADCs In addition, new applications for ADCs have been explored outside the field of oncology using non-cytotoxic drugs and will probably increase in the future [218,219].…”