title: Heavy chain-only antibodies and tetravalent bispecific antibody neutralizing Staphylococcus aureus leukotoxins.
abstract: Panton-Valentine leukocidin (PVL) is a pore-forming toxin associated with current outbreaks of community-associated methicillin-resistant strains and implicated directly in the pathophysiology of Staphylococcus aureus-related diseases. Humanized heavy chain-only antibodies (HCAb) were generated against S. aureus PVL from immunized transgenic mice to neutralize toxin activity. The active form of PVL consists of the two components, LukS-PV and LukF-PV, which induce osmotic lysis following pore formation in host defense cells. One anti-LukS-PV HCAb, three anti-LukF-PV HCAbs with affinities in the nanomolar range, and one engineered tetravalent bispecific HCAb were tested in vitro and in vivo, and all prevented toxin binding and pore formation. Anti-LukS-PV HCAb also binds to γ-hemolysin C (HlgC) and inhibits HlgC/HlgB pore formation. Experiments in vivo in a toxin-induced rabbit endophthalmitis model showed that these HCAbs inhibit inflammatory reactions and tissue destruction, with the tetravalent bispecific HCAb performing best. Our findings show the therapeutic potential of HCAbs, and in particular, bispecific antibodies.
authors.affiliation: Faculté de Médecine, Physiopathologie et Médecine Translationnelle, Institut de Bactériologie, Centre Hospitalier Régional Universitaire,  Université de Strasbourg, 67000 Strasbourg,  France.
authors.forename: Benoît-Joseph
authors.initials: BJ
authors.lastname: Laventie
authors.forename: Hendrik Jan
authors.initials: HJ
authors.lastname: Rademaker
authors.forename: Maher
authors.initials: M
authors.lastname: Saleh
authors.forename: Ernie
authors.initials: E
authors.lastname: de Boer
authors.forename: Rick
authors.initials: R
authors.lastname: Janssens
authors.forename: Tristan
authors.initials: T
authors.lastname: Bourcier
authors.forename: Audrey
authors.initials: A
authors.lastname: Subilia
authors.forename: Luc
authors.initials: L
authors.lastname: Marcellin
authors.forename: Rien
authors.initials: R
authors.lastname: van Haperen
authors.forename: Joyce H G
authors.initials: JH
authors.lastname: Lebbink
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Gilles
authors.initials: G
authors.lastname: Prévost
authors.forename: Frank
authors.initials: F
authors.lastname: Grosveld
authors.forename: Dubravka
authors.initials: D
authors.lastname: Drabek
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology*; D000915:Antibody Affinity; D000918:Antibody Specificity; D004797:Enzyme-Linked Immunosorbent Assay; D005098:Exotoxins / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000276:immunology*; D008969:Molecular Sequence Data; D011817:Rabbits; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus / Q000378:metabolism*
chemical_list: D018033:Antibodies, Bispecific; D057134:Antibodies, Neutralizing; D005098:Exotoxins; D007143:Immunoglobulin Heavy Chains; C018579:leukotoxin