title: Phase 1 safety and pharmacokinetic study of chimeric murine-human monoclonal antibody c alpha Stx2 administered intravenously to healthy adult volunteers.
abstract: Hemolytic-uremic syndrome (HUS) is a serious complication of infection by Shiga toxin-producing Escherichia coli. Shiga toxin type 2 (Stx2) is responsible for the renal toxicity that can follow intestinal infection and hemorrhagic colitis due to E. coli. A chimeric mouse-human antibody, designated c alpha Stx2, that has neutralizing activity in a mouse model was produced and tested in healthy adult volunteers. In this phase I dose escalation study, c alpha Stx2 was generally well tolerated. Pharmacokinetic studies indicated that clearance was stable over the dose range of 1.0 to 10 mg/kg of body weight (0.249 +/- 0.023 ml/kg/h) but was higher for the 0.1-mg/kg dose (0.540 +/- 0.078 ml/kg/h), suggesting saturable elimination. A similar nonlinear trend was observed for the volume of distribution, where average values ranged from 0.064 +/- 0.015 liter/kg for the 1.0- to 10-mg/kg doses and 0.043 +/- 0.005 for the 0.01-mg/kg dose. The relatively small volume of distribution suggests that the antibody is limited to the vascular (plasma) compartment. The mean half-life was 165 +/- 66 h, with lowest values observed for the 0.1-mg/kg dose (56.2 +/- 9.7 h) and the highest values reported for the 10.0-mg/kg dose (206.4 +/- 12.4 h). Future studies are needed to confirm the safety of this c alpha Stx2, and innovative clinical trials will be required to measure its efficacy in preventing or treating HUS.
authors.affiliation: Pharmacy Practice and Science Department, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA. tdowling@rx.umaryland.edu
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Dowling
authors.forename: Pierre A
authors.initials: PA
authors.lastname: Chavaillaz
authors.forename: David G
authors.initials: DG
authors.lastname: Young
authors.forename: Angela
authors.initials: A
authors.lastname: Melton-Celsa
authors.forename: Alison
authors.initials: A
authors.lastname: O'Brien
authors.forename: Claire
authors.initials: C
authors.lastname: Thuning-Roberson
authors.forename: Robert
authors.initials: R
authors.lastname: Edelman
authors.forename: Carol O
authors.initials: CO
authors.lastname: Tacket
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D011993:Recombinant Fusion Proteins; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase