title: Protective efficacy and pharmacokinetics of human/mouse chimeric anti-Stx1 and anti-Stx2 antibodies in mice.
abstract: In the United States, Shiga toxin (Stx)-producing Escherichia coli (STEC) is the most frequent infectious cause of hemorrhagic colitis. Hemolytic uremic syndrome (HUS) is a serious sequela that may develop after STEC infection that can lead to renal failure and death in up to 10% of cases. STEC can produce one or more types of Stx, Stx1 and/or Stx2, and Stx1 and Stx2 are responsible for HUS-mediated kidney damage. We previously generated two monoclonal antibodies (MAbs) that neutralize the toxicity of Stx1 or Stx2. In this study, we evaluated the protective efficacy of human/mouse chimeric versions of those monoclonal antibodies, named cαStx1 and cαStx2. Mice given an otherwise lethal dose of Stx1 were protected from death when injected with cαStx1 either 1 h before or 1 h after toxin injection. Additionally, streptomycin-treated mice fed the mouse-lethal STEC strain B2F1 that produces the Stx2 variant Stx2d were protected when given a dose of 0.1 mg of cαStx2/kg of body weight administered up to 72 h post-oral bacterial challenge. Since many STEC strains produce both Stx1 and Stx2 and since either toxin may lead to the HUS, we also assessed the protective efficacy of the combined MAbs. We found that both antibodies were required to protect mice from the presence of both Stx1 and Stx2. Pharmacokinetic studies indicated that cαStx1 and cαStx2 had serum half-lives (t1/2) of about 50 and 145 h, respectively. We propose that cαStx1 and cαStx2, both of which have been tested for safety in humans, could be used therapeutically for prevention or treatment early in the development of HUS.
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Melton-Celsa
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Carvalho
authors.affiliation: Thallion Pharmaceuticals Inc., Laval, Quebec, Canada.
authors.forename: Claire
authors.initials: C
authors.lastname: Thuning-Roberson
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA alison.obrien@usuhs.edu.
authors.forename: A D
authors.initials: AD
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000235:genetics / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D000992:Antitoxins / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000517:prevention & control*; D005260:Female; D006207:Half-Life; D008297:Male; D051379:Mice; D011041:Poisoning / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D022622:Shiga Toxin 1 / Q000037:antagonists & inhibitors*; D022641:Shiga Toxin 2 / Q000037:antagonists & inhibitors*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000992:Antitoxins; D011994:Recombinant Proteins; D022622:Shiga Toxin 1; D022641:Shiga Toxin 2