title: Novel antibody-antibiotic conjugate eliminates intracellular S. aureus.
abstract: Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S. aureus within host cells may provide a reservoir relatively protected from antibiotics, thus enabling long-term colonization of the host and explaining clinical failures and relapses after antibiotic therapy. Here we confirm that intracellular reservoirs of S. aureus in mice comprise a virulent subset of bacteria that can establish infection even in the presence of vancomycin, and we introduce a novel therapeutic that effectively kills intracellular S. aureus. This antibody-antibiotic conjugate consists of an anti-S. aureus antibody conjugated to a highly efficacious antibiotic that is activated only after it is released in the proteolytic environment of the phagolysosome. The antibody-antibiotic conjugate is superior to vancomycin for treatment of bacteraemia and provides direct evidence that intracellular S. aureus represents an important component of invasive infections.
authors.affiliation: Infectious Diseases Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Lehar
authors.affiliation: Medicinal Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pillow
authors.affiliation: Translational Immunology Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Medicinal Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Leanna
authors.initials: L
authors.lastname: Staben
authors.affiliation: Infectious Diseases Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Kajihara
authors.affiliation: Protein Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Vandlen
authors.affiliation: Protein Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: DePalatis
authors.affiliation: Protein Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Helga
authors.initials: H
authors.lastname: Raab
authors.affiliation: Infectious Diseases Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Wouter L
authors.initials: WL
authors.lastname: Hazenbos
authors.affiliation: Infectious Diseases Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: J Hiroshi
authors.initials: JH
authors.lastname: Morisaki
authors.affiliation: Translational Immunology Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Kim
authors.affiliation: Translational Immunology Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Summer
authors.initials: S
authors.lastname: Park
authors.affiliation: Protein Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Martine
authors.initials: M
authors.lastname: Darwish
authors.affiliation: Protein Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Byoung-Chul
authors.initials: BC
authors.lastname: Lee
authors.affiliation: Biochemical and Cellular Pharmacology Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Hilda
authors.initials: H
authors.lastname: Hernandez
authors.affiliation: Biochemical and Cellular Pharmacology Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Loyet
authors.affiliation: Structural Biology Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lupardus
authors.affiliation: Structural Biology Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Rina
authors.initials: R
authors.lastname: Fong
authors.affiliation: Translational Immunology Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Donghong
authors.initials: D
authors.lastname: Yan
authors.affiliation: Pathology Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Cecile
authors.initials: C
authors.lastname: Chalouni
authors.affiliation: Protein Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Luis
authors.affiliation: Biochemical and Cellular Pharmacology Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Yana
authors.initials: Y
authors.lastname: Khalfin
authors.affiliation: Drug metabolism and Pharmacokinetics Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Emile
authors.initials: E
authors.lastname: Plise
authors.affiliation: Drug metabolism and Pharmacokinetics Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cheong
authors.affiliation: Medicinal Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
authors.affiliation: Symphogen A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark.
authors.forename: Magnus
authors.initials: M
authors.lastname: Strandh
authors.affiliation: Symphogen A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark.
authors.forename: Klaus
authors.initials: K
authors.lastname: Koefoed
authors.affiliation: Symphogen A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Andersen
authors.affiliation: Medicinal Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Flygare
authors.affiliation: Infectious Diseases Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Man
authors.initials: M
authors.lastname: Wah Tan
authors.affiliation: Infectious Diseases Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brown
authors.affiliation: Infectious Diseases Department, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Mariathasan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016470:Bacteremia / Q000188:drug therapy / Q000382:microbiology; D002353:Carrier State / Q000188:drug therapy / Q000382:microbiology; D015195:Drug Design; D005260:Female; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D042541:Intracellular Space / Q000187:drug effects / Q000382:microbiology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity; D051379:Mice; D008826:Microbial Sensitivity Tests; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology* / Q000473:pathology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity; D014640:Vancomycin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D018796:Immunoconjugates; D014640:Vancomycin