title: 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.
authors.affiliation: a Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Zhou
authors.affiliation: a Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lehar
authors.affiliation: a Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Johnny
authors.initials: J
authors.lastname: Gutierrez
authors.affiliation: a Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Rosenberger
authors.affiliation: a Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Ljumanovic
authors.affiliation: a Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Dinoso
authors.affiliation: a Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Neelima
authors.initials: N
authors.lastname: Koppada
authors.affiliation: a Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Kyu
authors.initials: K
authors.lastname: Hong
authors.affiliation: a Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Amos
authors.initials: A
authors.lastname: Baruch
authors.affiliation: a Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Carrasco-Triguero
authors.affiliation: a Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Ola
authors.initials: O
authors.lastname: Saad
authors.affiliation: a Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Mariathasan
authors.affiliation: a Genentech Inc. , South San Francisco , CA , USA.
authors.forename: Amrita V
authors.initials: AV
authors.lastname: Kamath
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D000907:Antibodies, Bacterial / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D018796:Immunoconjugates / Q000493:pharmacokinetics*; D051379:Mice; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus
chemical_list: D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D018796:Immunoconjugates
keywords: Antibody-drug conjugate; Staphylococcus aureus infections; THIOMAB™ antibody antibiotic conjugate; antibody-antibiotic conjugate; pharmacodynamics; pharmacokinetics