Safety and Pharmacokinetics of Urtoxazumab, a Humanized Monoclonal Antibody, against Shiga-Like Toxin 2 in Healthy Adults and in Pediatric Patients Infected with Shiga-Like Toxin-Producing Escherichia coli

Abstract

Shiga-like toxin-producing Escherichia coli (STEC) infection causes diarrhea, which is often bloody and which can result in potentially life-threatening hemolytic-uremic syndrome (HUS). Urtoxazumab, a humanized monoclonal antibody directed against the Shiga-like toxin 2 (Stx2) produced by STEC, has been developed as a promising agent for the prevention of HUS. Single randomized, intravenous, double-blind, placebo-controlled doses of urtoxazumab were administered to assess its safety and pharmacokinetics in healthy adults (0.1 to 3.0 mg/kg of body weight) and STEC-infected pediatric patients (1.0 and 3.0 mg/kg). No dose-related safety trends were noted, nor were antiurtoxazumab antibodies detected. The disposition of urtoxazumab showed a biexponential decline, regardless of the dose. In healthy adults, the mean terminal elimination half-life was consistent across the dose groups and ranged from 24.6 days (3.0-mg/kg dose group) to 28.9 days (0.3-mg/kg dose group). The mean maximum serum drug concentration (C max ) ranged from 2.6 g/ml at 0.1 mg/kg to 71.7 g/ml at 3.0 mg/kg. The disposition of urtoxazumab following the administration of doses of 1.0 and 3.0 mg/kg in pediatric patients showed mean C max s of 19.6 and 56.1 g/ml, respectively. Urtoxazumab was well tolerated, appears to be safe at doses of up to 3.0 mg/kg, and is a potential candidate for the prevention of HUS in pediatric patients.

Adenovirus Vector Expressing Stx1/Stx2-Neutralizing Agent Protects Piglets Infected with Escherichia coli O157:H7 against Fatal Systemic Intoxication

“…With this in mind, we developed HuMAbs to neutralize Stx (17)(18)(19), which were shown to be highly effective in protecting STEC-infected piglets (17,20,21). Other investigators have also developed Stx-neutralizing chimeric (47) or humanized (48,49) MAbs. HuMAb 5C12, specific for Stx2, was found to be highly effective in protecting piglets 48 h after STEC infection; a dose of 0.4 mg/kg of body weight protected 80% of piglets (20).…”

Identification of Anti-Alpha Toxin Monoclonal Antibodies That Reduce the Severity of Staphylococcus aureus Dermonecrosis and Exhibit a Correlation between Affinity and Potency

“…Although there is only one anti-infective MAb currently approved for use in humans, there are other MAbs targeting pathogens being tested in human clinical trials (21,23,25,37). These anti-infective MAbs, which are specific for pathogen and not human antigens, are anticipated to have relatively few off-target toxicities.…”

Recent Advances in Understanding Enteric Pathogenic Escherichia coli

“…Monoclonal antibodies (MAbs) have been shown to reduce the cytotoxicity of Stx1 and Stx2 in vitro (381), while Urtoxazumab, a humanized MAb against Stx2, was shown to be safe in a phase 1 study (382). Similarly, phase 1 clinical trials of chimeric monoclonal Stx1-and Stx2-neutralizing antibodies were also shown to be generally well tolerated in injected volunteers (383,384).…”