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Antimicrobial Agents and Chemotherapy, May 2005, p. 1808-1812, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1808-1812.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Phase 1 Safety and Pharmacokinetic Study of Chimeric Murine-Human Monoclonal Antibody cStx2 Administered Intravenously to Healthy Adult Volunteers

Pharmacy Practice and Science Department, University of Maryland School of Pharmacy, Allied Health Building, Room 540D, Baltimore, Maryland 21201,¹ Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, Maryland 21201,² Sunol Molecular Corporation, 2810 North Commerce Parkway, Miramar, Florida 33025,³ Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814⁴

Received 4 November 2004/ Returned for modification 13 December 2004/ Accepted 17 January 2005

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 cStx2, that has neutralizing activity in a mouse model was produced and tested in healthy adult volunteers. In this phase I dose escalation study, cStx2 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 cStx2, and innovative clinical trials will be required to measure its efficacy in preventing or treating HUS.

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