title: A phase 1 study of PAmAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers.
abstract: BACKGROUND
  Inhibition of the binding of Bacillus anthracis protective antigen (PA) to its cellular receptor can abrogate the downstream toxin-mediated deleterious effects of the anthrax toxin. A fully human monoclonal antibody against B. anthracis PA, PAmAb, was previously shown to provide a survival advantage in rabbit and monkey models of inhalational anthrax.
  
  
  METHODS
  A randomized, single-blind, placebo-controlled, dose-escalation study with 105 healthy volunteers was conducted to evaluate the safety, pharmacokinetics, and biological activity of PAmAb. Subjects received PAmAb or placebo as a single intramuscular injection (11 subjects/cohort) or intravenous infusion (10 subjects/cohort). Three intramuscular dose levels (0.3, 1.0, and 3.0 mg/kg) and 5 intravenous dose levels (1.0, 3.0, 10, 20, and 40 mg/kg) were studied. Two separate intramuscular injection sites (gluteus maximus and vastus lateralis) were evaluated in the cohorts (hereafter, the "IM-GM" and "IM-VL" cohorts, respectively).
  
  
  RESULTS
  PAmAb was well tolerated, with no dose-limiting adverse events. All adverse events were transient and mild to moderate in incidence and/or severity. The pharmacokinetics of PAmAb were linear within each route and site of administration but were significantly different between the IM-GM and IM-VL cohorts. The mean terminal elimination half-life ranged from 15 to 19 days. The bioavailability of PAmAb is approximately 50% for IM-GM injection and 71%-85% for IM-VL injection. The biological activity of PAmAb in serum, assessed using a cyclic adenosine monophosphate assay, correlated with serum concentrations.
  
  
  CONCLUSIONS
  PAmAb is safe, well tolerated, and bioavailable after a single intramuscular or intravenous dose, which supports further clinical development of PAmAb as a novel therapeutic agent for inhalational anthrax.
authors.affiliation: Human Genome Sciences, Rockville, MD 20850, USA. Mani_Subramanian@hgsi.com
authors.forename: G Mani
authors.initials: GM
authors.lastname: Subramanian
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Cronin
authors.forename: Gerald
authors.initials: G
authors.lastname: Poley
authors.forename: Andrea
authors.initials: A
authors.lastname: Weinstein
authors.forename: Susan M
authors.initials: SM
authors.lastname: Stoughton
authors.forename: John
authors.initials: J
authors.lastname: Zhong
authors.forename: Ying
authors.initials: Y
authors.lastname: Ou
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Zmuda
authors.forename: Blaire L
authors.initials: BL
authors.lastname: Osborn
authors.forename: William W
authors.initials: WW
authors.lastname: Freimuth
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000881:Anthrax / Q000517:prevention & control*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000942:Antigens, Bacterial / Q000276:immunology*; D001408:Bacillus anthracis / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D016037:Single-Blind Method; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial