title: A fully human monoclonal antibody to Staphylococcus aureus iron regulated surface determinant B (IsdB) with functional activity in vitro and in vivo.
abstract: A fully human monoclonal antibody (CS-D7, IgG1) specific for the iron regulated surface determinant B (IsdB) of Staphylococcus aureus was isolated from the Cambridge Antibody Technology (CAT) scFv antibody library. As compared to previously described IsdB specific murine monoclonals, CS-D7 has a unique, non-overlapping binding site on IsdB, and exhibits increased in vivo activity. The antibody recognizes a conformational epitope spanning amino acids 50 to 285 and has a binding affinity of 340 (± 75) pM for IsdB. CS-D7 bound to a wide variety of S. aureus strains, but not to an isdB deletion mutant. The antibody mediated opsonophagocytic (OP) killing in vitro and mediated significant protection in vivo. In a murine lethal sepsis model, the antibody conferred protection from death when dosed prior to challenge, but not when dosed after challenge. Importantly, in a central venous catheter (CVC) model in rats, the antibody reduced bacteremia and prevented colonization of indwelling catheters. Protection was observed when rats were dosed with CS-D7 prior to challenge as well as post challenge. IsdB is currently being investigated for clinical efficacy against S. aureus infection, and the activity of this human IsdB specific antibody supplements the growing body of evidence to support targeting this antigen for vaccine development.
authors.affiliation: Merck Research Labs, Merck and Co. Inc., West Point, PA 19486, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Ebert
authors.forename: Sharon
authors.initials: S
authors.lastname: Smith
authors.forename: Greg
authors.initials: G
authors.lastname: Pancari
authors.forename: Desmond
authors.initials: D
authors.lastname: Clark
authors.forename: Richard
authors.initials: R
authors.lastname: Hampton
authors.forename: Susan
authors.initials: S
authors.lastname: Secore
authors.forename: Victoria
authors.initials: V
authors.lastname: Towne
authors.forename: Hongxia
authors.initials: H
authors.lastname: Fan
authors.forename: Xin-Min
authors.initials: XM
authors.lastname: Wang
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Wu
authors.forename: Robin
authors.initials: R
authors.lastname: Ernst
authors.forename: Barrett R
authors.initials: BR
authors.lastname: Harvey
authors.forename: Adam C
authors.initials: AC
authors.lastname: Finnefrock
authors.forename: Fubao
authors.initials: F
authors.lastname: Wang
authors.forename: Charles
authors.initials: C
authors.lastname: Tan
authors.forename: Eberhard
authors.initials: E
authors.lastname: Durr
authors.forename: Leslie
authors.initials: L
authors.lastname: Cope
authors.forename: Annaliesa
authors.initials: A
authors.lastname: Anderson
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: An
authors.forename: Tessie
authors.initials: T
authors.lastname: McNeely
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use*; D000918:Antibody Specificity; D016470:Bacteremia / Q000276:immunology / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D002405:Catheterization, Central Venous / Q000009:adverse effects; D027682:Cation Transport Proteins / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009895:Opsonin Proteins / Q000378:metabolism; D010587:Phagocytosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D013203:Staphylococcal Infections / Q000382:microbiology / Q000401:mortality* / Q000517:prevention & control*; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D027682:Cation Transport Proteins; C510010:IsdB protein, Staphylococcus aureus; D009895:Opsonin Proteins