Efficacy of Urtoxazumab (TMA-15 Humanized Monoclonal Antibody Specific for Shiga Toxin 2) Against Post-Diarrheal Neurological Sequelae Caused by Escherichia coli O157:H7 Infection in the Neonatal Gnotobiotic Piglet Model

Rodney Moxley,Mizuho Tamura,Mojun Zhao,Kristina Santiago-Mateo,David Marx,David Francis

doi:10.3390/toxins9020049

Abstract

Enterohemorrhagic Escherichia coli (EHEC) is the most common cause of hemorrhagic colitis and hemolytic uremic syndrome in human patients, with brain damage and dysfunction the main cause of acute death. We evaluated the efficacy of urtoxazumab (TMA-15, Teijin Pharma Limited), a humanized monoclonal antibody against Shiga toxin (Stx) 2 for the prevention of brain damage, dysfunction, and death in a piglet EHEC infection model. Forty-five neonatal gnotobiotic piglets were inoculated orally with 3 × 109 colony-forming units of EHEC O157:H7 strain EDL933 (Stx1+, Stx2+) when 22–24 h old. At 24 h post-inoculation, piglets were intraperitoneally administered placebo or TMA-15 (0.3, 1.0 or 3.0 mg/kg body weight). Compared to placebo (n = 10), TMA-15 (n = 35) yielded a significantly greater probability of survival, length of survival, and weight gain (p <0.05). The efficacy of TMA-15 against brain lesions and death was 62.9% (p = 0.0004) and 71.4% (p = 0.0004), respectively. These results suggest that TMA-15 may potentially prevent or reduce vascular necrosis and infarction of the brain attributable to Stx2 in human patients acutely infected with EHEC. However, we do not infer that TMA-15 treatment will completely protect human patients infected with EHEC O157:H7 strains that produce both Stx1 and Stx2.

Highlights

Strains of Shiga toxin (Stx)-producing Escherichia coli (STEC) are important foodborne pathogens, causing severe illness in humans, including hemorrhagic colitis and hemolytic uremic syndrome (HUS) [1]
The results of this study demonstrate that the humanized anti-Stx2 monoclonal antibody TMA-15 is highly protective against neuropathological sequelae of Escherichia coli (EHEC) infection in the neonatal gnotobiotic piglet model when administered within 24 h after the onset of infection
This study extends the observations made by Yamagami et al [26] who reported that TMA-15 increased the survival of mice when administered 24 h after challenge with 1010 colony forming units (CFU) EHEC

Summary

Introduction

Strains of Shiga toxin (Stx)-producing Escherichia coli (STEC) are important foodborne pathogens, causing severe illness in humans, including hemorrhagic colitis and hemolytic uremic syndrome (HUS) [1]. STEC isolates from cases of hemorrhagic colitis and/or HUS, or those strains that contain the genes for production of Shiga toxin (Stx), and an adhesin known as intimin, are classified as enterohemorrhagic E. coli (EHEC) [2]. Based on data from 2000–2008, the estimated annual incidence of STEC infection in the United States was 175,905 cases, resulting in 2409 hospitalizations and 20 deaths [4]. EHEC are thought to infect the human intestine by a mechanism that includes intimate attachment to and effacement of intestinal microvilli [8,9], as was originally demonstrated in a neonatal gnotobiotic piglet model [10,11]. The attaching-and-effacing (A/E) lesions seen in the gnotobiotic piglet [12,13] and other models are dependent upon the production of the outer membrane protein, intimin

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