Role of Shiga toxin 2 (Stx2)-binding protein, human serum amyloid P component (HuSAP), in Shiga toxin-producing Escherichia coli infections: assumption from in vitro and in vivo study using HuSAP and anti-Stx2 humanized monoclonal antibody TMA-15

Kimura, T.; Tani, Shinobu; Motoki, Masamichi; Matsumoto, Yoh-ichi

doi:10.1016/s0006-291x(03)00901-x

Cited by 21 publications

(12 citation statements)

References 20 publications

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“…Therefore, passive administration of toxin-neutralizing antibodies should be an effective therapy for HUS. A number of Stx-specific mAbs have been developed and tested for their ability to protect animals from Stx-mediated death [23,24,25,26,27,28,29,30,31,32]. However, a detailed toxicokinetic analysis of un-modified Stx2 in the presence or absence of neutralizing antibodies against this toxin in an animal model has not been fully described in the literature.…”

Section: Introductionmentioning

confidence: 99%

Mouse in Vivo Neutralization of Escherichia coli Shiga Toxin 2 with Monoclonal Antibodies

Cheng

Henderson

Patfield

et al. 2013

Toxins

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Shiga toxin-producing Escherichia coli (STEC) food contaminations pose serious health concerns, and have been the subject of massive food recalls. STEC has been identified as the major cause of the life-threatening complication of hemolytic uremic syndrome (HUS). Besides supportive care, there currently are no therapeutics available. The use of antibiotics for combating pathogenic E. coli is not recommended because they have been shown to stimulate toxin production. Clearing Stx2 from the circulation could potentially lessen disease severity. In this study, we tested the in vivo neutralization of Stx2 in mice using monoclonal antibodies (mAbs). We measured the biologic half-life of Stx2 in mice and determined the distribution phase or t1/2 α to be 3 min and the clearance phase or t1/2 β to be 40 min. Neutralizing mAbs were capable of clearing Stx2 completely from intoxicated mouse blood within minutes. We also examined the persistence of these mAbs over time and showed that complete protection could be passively conferred to mice 4 weeks before exposure to Stx2. The advent of better diagnositic methods and the availability of a greater arsenal of therapeutic mAbs against Stx2 would greatly enhance treatment outcomes of life threatening E. coli infections.

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Section: Introductionmentioning

confidence: 99%

Mouse in Vivo Neutralization of Escherichia coli Shiga Toxin 2 with Monoclonal Antibodies

Cheng

Henderson

Patfield

et al. 2013

Toxins

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“…Kimura et al [17] recently reported that intravenous injection of a single dose of 2.5-5.0 mg/kg human SAP did not protect mice against a lethal dose of Stx2 that was 10 times the LD 50 , probably because the 3-h circulating half-life of human SAP in mice means that this trace amount of human SAP was present for only the first few hours of exposure to this massive lethal dose. In contrast, we show here that mice receiving regular 50-mg/kg doses of human SAP twice daily were completely protected against twice the LD 50 of Stx2.…”

mentioning

confidence: 99%

Human Serum Amyloid P Component Protects againstEscherichia coliO157:H7 Shiga Toxin 2 In Vivo: Therapeutic Implications for Hemolytic‐Uremic Syndrome

Armstrong¹,

Mulvey²,

Marcato³

et al. 2006

J INFECT DIS

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Shiga toxin (Stx) 2 causes hemolytic-uremic syndrome (HUS), an intractable and often fatal complication of enterohemorrhagic Escherichia coli O157:H7 infection. Here, we show that serum amyloid P component (SAP), a normal human plasma protein, specifically protects mice against the lethal toxicity of Stx2, both when injected into wild-type mice and when expressed transgenically; in the presence of human SAP, there was greatly reduced in vivo localization of Stx2 to the kidneys, suggesting a possible mechanism of protection. In humans, circulating SAP concentrations did not differ between patients with suspected enterohemorrhagic E. coli infection with antibodies to E. coli O157:H7 lipopolysaccharide and those without antibodies or between patients with HUS and those without it. However, the potent protection conferred by human SAP in the mouse model suggests that infusion of supplemental SAP may be a useful novel therapeutic approach to the treatment of this devastating condition.

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“…It has been shown to neutralize Stx2 in vitro and to completely prevent mortality in animal models of severe STEC infection (23) and Stx2 toxin inoculation (9). We recently conducted two studies designed to examine the safety and pharmacokinetic (PK) profiles of urtoxazumab in healthy adults and STEC-infected pediatric patients.…”

mentioning

confidence: 99%

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

López

Contrini

Glatstein

et al. 2010

Antimicrob Agents Chemother

100

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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.

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Role of Shiga toxin 2 (Stx2)-binding protein, human serum amyloid P component (HuSAP), in Shiga toxin-producing Escherichia coli infections: assumption from in vitro and in vivo study using HuSAP and anti-Stx2 humanized monoclonal antibody TMA-15

Cited by 21 publications

References 20 publications

Mouse in Vivo Neutralization of Escherichia coli Shiga Toxin 2 with Monoclonal Antibodies

Mouse in Vivo Neutralization of Escherichia coli Shiga Toxin 2 with Monoclonal Antibodies

Human Serum Amyloid P Component Protects againstEscherichia coliO157:H7 Shiga Toxin 2 In Vivo: Therapeutic Implications for Hemolytic‐Uremic Syndrome

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

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