Pharmacokinetics and pharmacodynamics of DSTA4637A: A novel THIOMAB™ antibody antibiotic conjugate against Staphylococcus aureus in mice
| Autor: | Ola Saad, Jason B Dinoso, Carrie M. Rosenberger, Sanjeev Mariathasan, Chenguang Zhou, Johnny Gutierrez, Kyu Hong, Montserrat Carrasco-Triguero, Neelima Koppada, Amos Baruch, Nina Ljumanovic, Amrita V. Kamath, Sophie M. Lehar |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Staphylococcus aureus Antibody-drug conjugate Immunoconjugates medicine.drug_class 030106 microbiology Immunology Antibiotics Pharmacology medicine.disease_cause Staphylococcal infections antibody-antibiotic conjugate Microbiology Mice 03 medical and health sciences Pharmacokinetics Report pharmacodynamics medicine Animals Immunology and Allergy Distribution (pharmacology) biology business.industry Antibodies Monoclonal Staphylococcal Infections medicine.disease Antibodies Bacterial Anti-Bacterial Agents 030104 developmental biology Pharmacodynamics biology.protein Staphylococcus aureus infections Antibody business pharmacokinetics THIOMAB™ antibody antibiotic conjugate |
| Zdroj: | mAbs |
| ISSN: | 1942-0870 1942-0862 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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