Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhou, Chenguang, Lehar, Sophie, Gutierrez, Johnny, Rosenberger, Carrie M., Ljumanovic, Nina, Dinoso, Jason, Koppada, Neelima, Hong, Kyu, Baruch, Amos, Carrasco-Triguero, Montserrat, Saad, Ola, Mariathasan, Sanjeev, Kamath, Amrita V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098440/
https://www.ncbi.nlm.nih.gov/pubmed/27653831
http://dx.doi.org/10.1080/19420862.2016.1229722
_version_ 1782465782183100416
author Zhou, Chenguang
Lehar, Sophie
Gutierrez, Johnny
Rosenberger, Carrie M.
Ljumanovic, Nina
Dinoso, Jason
Koppada, Neelima
Hong, Kyu
Baruch, Amos
Carrasco-Triguero, Montserrat
Saad, Ola
Mariathasan, Sanjeev
Kamath, Amrita V.
author_facet Zhou, Chenguang
Lehar, Sophie
Gutierrez, Johnny
Rosenberger, Carrie M.
Ljumanovic, Nina
Dinoso, Jason
Koppada, Neelima
Hong, Kyu
Baruch, Amos
Carrasco-Triguero, Montserrat
Saad, Ola
Mariathasan, Sanjeev
Kamath, Amrita V.
author_sort Zhou, Chenguang
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5098440
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Taylor & Francis
record_format MEDLINE/PubMed
spelling pubmed-50984402016-11-23 Pharmacokinetics and pharmacodynamics of DSTA4637A: A novel THIOMAB™ antibody antibiotic conjugate against Staphylococcus aureus in mice Zhou, Chenguang Lehar, Sophie Gutierrez, Johnny Rosenberger, Carrie M. Ljumanovic, Nina Dinoso, Jason Koppada, Neelima Hong, Kyu Baruch, Amos Carrasco-Triguero, Montserrat Saad, Ola Mariathasan, Sanjeev Kamath, Amrita V. MAbs Report 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. Taylor & Francis 2016-09-21 /pmc/articles/PMC5098440/ /pubmed/27653831 http://dx.doi.org/10.1080/19420862.2016.1229722 Text en © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.
spellingShingle Report
Zhou, Chenguang
Lehar, Sophie
Gutierrez, Johnny
Rosenberger, Carrie M.
Ljumanovic, Nina
Dinoso, Jason
Koppada, Neelima
Hong, Kyu
Baruch, Amos
Carrasco-Triguero, Montserrat
Saad, Ola
Mariathasan, Sanjeev
Kamath, Amrita V.
Pharmacokinetics and pharmacodynamics of DSTA4637A: A novel THIOMAB™ antibody antibiotic conjugate against Staphylococcus aureus in mice
title Pharmacokinetics and pharmacodynamics of DSTA4637A: A novel THIOMAB™ antibody antibiotic conjugate against Staphylococcus aureus in mice
title_full Pharmacokinetics and pharmacodynamics of DSTA4637A: A novel THIOMAB™ antibody antibiotic conjugate against Staphylococcus aureus in mice
title_fullStr Pharmacokinetics and pharmacodynamics of DSTA4637A: A novel THIOMAB™ antibody antibiotic conjugate against Staphylococcus aureus in mice
title_full_unstemmed Pharmacokinetics and pharmacodynamics of DSTA4637A: A novel THIOMAB™ antibody antibiotic conjugate against Staphylococcus aureus in mice
title_short Pharmacokinetics and pharmacodynamics of DSTA4637A: A novel THIOMAB™ antibody antibiotic conjugate against Staphylococcus aureus in mice
title_sort pharmacokinetics and pharmacodynamics of dsta4637a: a novel thiomab™ antibody antibiotic conjugate against staphylococcus aureus in mice
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098440/
https://www.ncbi.nlm.nih.gov/pubmed/27653831
http://dx.doi.org/10.1080/19420862.2016.1229722
work_keys_str_mv AT zhouchenguang pharmacokineticsandpharmacodynamicsofdsta4637aanovelthiomabantibodyantibioticconjugateagainststaphylococcusaureusinmice
AT leharsophie pharmacokineticsandpharmacodynamicsofdsta4637aanovelthiomabantibodyantibioticconjugateagainststaphylococcusaureusinmice
AT gutierrezjohnny pharmacokineticsandpharmacodynamicsofdsta4637aanovelthiomabantibodyantibioticconjugateagainststaphylococcusaureusinmice
AT rosenbergercarriem pharmacokineticsandpharmacodynamicsofdsta4637aanovelthiomabantibodyantibioticconjugateagainststaphylococcusaureusinmice
AT ljumanovicnina pharmacokineticsandpharmacodynamicsofdsta4637aanovelthiomabantibodyantibioticconjugateagainststaphylococcusaureusinmice
AT dinosojason pharmacokineticsandpharmacodynamicsofdsta4637aanovelthiomabantibodyantibioticconjugateagainststaphylococcusaureusinmice
AT koppadaneelima pharmacokineticsandpharmacodynamicsofdsta4637aanovelthiomabantibodyantibioticconjugateagainststaphylococcusaureusinmice
AT hongkyu pharmacokineticsandpharmacodynamicsofdsta4637aanovelthiomabantibodyantibioticconjugateagainststaphylococcusaureusinmice
AT baruchamos pharmacokineticsandpharmacodynamicsofdsta4637aanovelthiomabantibodyantibioticconjugateagainststaphylococcusaureusinmice
AT carrascotrigueromontserrat pharmacokineticsandpharmacodynamicsofdsta4637aanovelthiomabantibodyantibioticconjugateagainststaphylococcusaureusinmice
AT saadola pharmacokineticsandpharmacodynamicsofdsta4637aanovelthiomabantibodyantibioticconjugateagainststaphylococcusaureusinmice
AT mariathasansanjeev pharmacokineticsandpharmacodynamicsofdsta4637aanovelthiomabantibodyantibioticconjugateagainststaphylococcusaureusinmice
AT kamathamritav pharmacokineticsandpharmacodynamicsofdsta4637aanovelthiomabantibodyantibioticconjugateagainststaphylococcusaureusinmice