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Preclinical and translational pharmacokinetics of a novel THIOMAB™ antibody-antibiotic conjugate against . | LitMetric

AI Article Synopsis

  • DSTA4637S is a new type of antibody-antibiotic conjugate being studied for treating complicated bloodstream infections, combining a monoclonal antibody with a rifamycin-class antibiotic.
  • In preclinical studies with rats and monkeys, DSTA4637A, a liquid formulation, showed a complex pharmacokinetic profile with a quick initial distribution and a slower elimination phase, revealing that the antibiotic component clears faster than the antibody.
  • A semi-mechanistic pharmacokinetic model was developed to effectively describe the behavior of DSTA4637A, aiding predictions for human pharmacokinetics and guiding future clinical development.

Article Abstract

DSTA4637S, a novel THIOMAB™ antibody-antibiotic conjugate (TAC) against (), is currently being investigated as a potential therapy for complicated bloodstream infections. DSTA4637S is composed of a monoclonal THIOMAB IgG1 recognizing linked to a rifamycin-class antibiotic (dmDNA31) via a protease-cleavable linker. The pharmacokinetics (PK) of DSTA4637A (a liquid formulation of DSTA4637S) and its unconjugated antibody MSTA3852A were characterized in rats and monkeys. Systemic concentrations of three analytes, total antibody (TAb), antibody-conjugated dmDNA31 (ac-dmDNA31), and unconjugated dmDNA31, were measured to describe complex TAC PK in nonclinical studies. In rats and monkeys, following intravenous administration of a single dose of DSTA4637A, systemic concentration-time profiles of both TAb and ac-dmDNA31 were bi-exponential, 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, and ac-dmDNA31 cleared 2-3 times faster than TAb. Unconjugated dmDNA31 plasma concentrations were low (<4 ng/mL) in every study regardless of dose. In this report, an integrated semi-mechanistic PK model for two analytes (TAb and ac-dmDNA31) was successfully developed and was able to well describe the complicated DSTA4637A PK in mice, rats and monkeys. DSTA4637S human PK was predicted reasonably well using this model with allometric scaling of PK parameters from monkey data. This work provides insights into PK behaviors of DSTA4637A in preclinical species and informs clinical translatability of these observed results and further clinical development. : ADC: Antibody-drug conjugate; AUC: time curve extrapolated to infinity; ac-dmDNA31: antibody-conjugated dmDNA31; C: maximum concentration observed; DAR: drug-to-antibody ratio; CL: clearance; CL: distribution clearance; CL: systemic clearance of all DAR species; k: deconjugation rate constant; PK: Pharmacokinetics; IV: Intravenous; IgG: Immunoglobulin G; mAb: monoclonal antibody; ; TAC: THIOMAB antibody-antibiotic conjugate; TDC: THIOMAB antibody-drug conjugate; TAb: total antibody; t: terminal half-life; vc linker: valine-citrulline linker; V: volume of distribution at steady state; V: volume of distribution for the central compartment; V: the volume of distribution for the peripheral compartment.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748576PMC
http://dx.doi.org/10.1080/19420862.2019.1627152DOI Listing

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