title: 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.
abstract: EnterohemorrhagicEscherichia 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 × 10⁸ 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.
authors.affiliation: School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA. rmoxley1@unl.edu.
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Moxley
authors.affiliation: Department of Veterinary and Biomedical Sciences, South Dakota State University, Brookings, SD 57007, USA. David.Francis@sdstate.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Francis
authors.affiliation: Teijin Pharma Limited, Pharmacology Research Department, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan. miz.tamura@teijin.co.jp.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Tamura
authors.affiliation: Department of Statistics, University of Nebraska-Lincoln, Lincoln, NE 68583, USA. dmarx1@unl.edu.
authors.forename: David B
authors.initials: DB
authors.lastname: Marx
authors.affiliation: Canadian Food Inspection Agency, Lethbridge Laboratory, Box 640 TWP Rd 9-1, Lethbridge, AB T1J 3Z4, Canada. Kristina.Santiago-Mateo@inspection.gc.ca.
authors.forename: Kristina
authors.initials: K
authors.lastname: Santiago-Mateo
authors.affiliation: Valley Pathologists, Inc., 1100 South Main Street, Suite 308, Dayton, OH 45409, USA. zhaomojun@gmail.com.
authors.forename: Mojun
authors.initials: M
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D020520:Brain Infarction / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D003967:Diarrhea / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology; D004195:Disease Models, Animal; D019453:Escherichia coli O157 / Q000187:drug effects* / Q000276:immunology / Q000472:pathogenicity; D005856:Germ-Free Life; D006463:Hemolytic-Uremic Syndrome / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D020814:Meningitis, Escherichia coli / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D009336:Necrosis; D012720:Severity of Illness Index; D022641:Shiga Toxin 2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D034421:Sus scrofa; D013997:Time Factors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D022641:Shiga Toxin 2; C437063:urtoxazumab
keywords: Shiga toxin; enterohemorrhagic E. coli; gnotobiotic piglets; monoclonal antibody