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

Dowling TC,Chavaillaz PA,Young DG,Melton-Celsa A,O'Brien A,Thuning-Roberson C,Edelman R,Tacket CO

doi

10.1128/AAC.49.5.1808-1812.2005

subject

Has Abstract

pub_date

2005-05-01 00:00:00

pages

1808-12

issue

5

eissn

0066-4804

issn

1098-6596

pii

49/5/1808

journal_volume

49

pub_type

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