Phase 1 Safety and Pharmacokinetic Study of Chimeric Murine-Human Monoclonal Antibody caStx2 Administered Intravenously to Healthy Adult Volunteers
AuthorDowling, Thomas C.
Chavaillaz, Pierre A.
Young, David G.
Thuninz- Roberson, Claire
Tacket, Carol O.
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AbstractHemolytic-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 cαStx2, that has neutralizing activity in a mouse model was produced and tested in healthy adult volunteers. In this phase I dose escalation study, cαStx2 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 cαStx2, and innovative clinical trials will be required to measure its efficacy in preventing or treating HUS.
CitationDowling, T. C., Chavaillaz, P. A., Young, D. G., Melton-Celsa, A., O’Brien, A., Thuninz-Roberson, C., Edelman, R., & Tacket, C. O. (2005). Phase 1 Safety and Pharmacokinetic Study of Chimeric Murine-Human Monoclonal Antibody caStx2 Administered Intravenously to Healthy Adult Volunteers. Antimicrobial Agents and Chemotherapy, 49(5), 1808-1812, DOI: 10.1128/AAC.49.5.1808-1812.2005.
Keywordchimeric murine-human monoclonal antibody
Hemolytic-Uremic Syndrome--prevention & control
Shiga-Toxigenic Escherichia coli
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/690
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