A Phase II Study of Chimeric Monoclonal Antibodies to Shiga Toxins 1 (cαStx1) and 2 (cαStx2) Administered Concomitantly to Children With Shiga Toxin-Producing Bacterial (STPB) Infection and Bloody Diarrhea (SHIGATEC Trial)

This study is designed to evaluate the safety and efficacy of cαStx1 and cαStx2 administered concomitantly in children presenting early signs of Shiga Toxin-Producing Bacterial (STPB) Infection.

开始日期2010-11-01

申办/合作机构

Thallion Pharmaceuticals, Inc.

100 项与 cαStx1/cαStx2 相关的临床结果

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100 项与 cαStx1/cαStx2 相关的转化医学

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100 项与 cαStx1/cαStx2 相关的专利（医药）

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项与 cαStx1/cαStx2 相关的文献（医药）

2015-04-01·Clinical and Vaccine Immunology

Protective Efficacy and Pharmacokinetics of Human/Mouse Chimeric Anti-Stx1 and Anti-Stx2 Antibodies in Mice

Article

作者: Melton-Celsa, Angela R ; Thuning-Roberson, Claire ; O'Brien, A D ; Carvalho, H M

ABSTRACTIn the United States, Shiga toxin (Stx)-producingEscherichia coli(STEC) is the most frequent infectious cause of hemorrhagic colitis. Hemolytic uremic syndrome (HUS) is a serious sequela that may develop after STEC infection that can lead to renal failure and death in up to 10% of cases. STEC can produce one or more types of Stx, Stx1 and/or Stx2, and Stx1 and Stx2 are responsible for HUS-mediated kidney damage. We previously generated two monoclonal antibodies (MAbs) that neutralize the toxicity of Stx1 or Stx2. In this study, we evaluated the protective efficacy of human/mouse chimeric versions of those monoclonal antibodies, named cαStx1 and cαStx2. Mice given an otherwise lethal dose of Stx1 were protected from death when injected with cαStx1 either 1 h before or 1 h after toxin injection. Additionally, streptomycin-treated mice fed the mouse-lethal STEC strain B2F1 that produces the Stx2 variant Stx2d were protected when given a dose of 0.1 mg of cαStx2/kg of body weight administered up to 72 h post-oral bacterial challenge. Since many STEC strains produce both Stx1 and Stx2 and since either toxin may lead to the HUS, we also assessed the protective efficacy of the combined MAbs. We found that both antibodies were required to protect mice from the presence of both Stx1 and Stx2. Pharmacokinetic studies indicated that cαStx1 and cαStx2 had serum half-lives (t1/2) of about 50 and 145 h, respectively. We propose that cαStx1 and cαStx2, both of which have been tested for safety in humans, could be used therapeutically for prevention or treatment early in the development of HUS.

2009-07-01·Antimicrobial Agents and Chemotherapy2区 · 医学

Safety and Pharmacokinetics of Chimeric Anti-Shiga Toxin 1 and Anti-Shiga Toxin 2 Monoclonal Antibodies in Healthy Volunteers

2区 · 医学

Article

作者: Thuning-Roberson, Claire ; Brockus, Catherine ; Sicard, Eric ; Poole, Ruth ; Bitzan, Martin ; Mehran, Mariam ; Rivière, Marc

ABSTRACT Shiga toxin (Stx)-producing Escherichia coli (STEC) causes hemorrhagic colitis and hemolytic-uremic syndrome (HUS). The rates of STEC infection and complications, including death, are highest among young children and elderly individuals. There are no causal therapies. Because Stx is the primary pathological agent leading to organ injury in patients with STEC disease, therapeutic antibodies are being developed to neutralize systemically absorbed toxin during the early phase of the infection. Two phase I, single-dose, open-label, nonrandomized studies were conducted to evaluate the safety and pharmacokinetics of the chimeric monoclonal antibodies (antitoxins) against Stx 1 and 2 (cαStx1 and cαStx2, respectively). In the first study, 16 volunteers received 1 or 3 mg/kg of body weight of cαStx1 or cαStx2 as a single, short (1-h) intravenous infusion ( n = 4 per group). In a second study, 10 volunteers received a 1-h infusion of cαStx1 and cαStx2 combined at 1 or 3 mg/kg ( n = 5 per group). Treatment-emergent adverse events were mild, resolved spontaneously, and were generally unrelated to the antibody infusion. No serious adverse events were observed. Human antichimeric antibodies were detected in a single blood sample collected on day 57. Antibody clearance was slightly greater for cαStx1 (0.38 ± 0.16 ml/h/kg [mean ± standard deviation]) than for cαStx2 (0.20 ± 0.07 ml/h/kg) ( P = 0.0013, t test). The low clearance is consistent with the long elimination half-lives of cαStx1 (190.4 ± 140.2 h) and cαStx2 (260.6 ± 112.4 h; P = 0.151). The small volume of distribution (0.08 ± 0.05 liter/kg, combined data) indicates that the antibodies are retained within the circulation. The conclusion is that cαStx1 and cαStx2, given as individual or combined short intravenous infusions, are well tolerated. These results form the basis for future safety and efficacy trials with patients with STEC infections to ameliorate or prevent HUS and other complications.

2005-05-01·Antimicrobial Agents and Chemotherapy2区 · 医学

Phase 1 Safety and Pharmacokinetic Study of Chimeric Murine-Human Monoclonal Antibody cαStx2 Administered Intravenously to Healthy Adult Volunteers

2区 · 医学

Article

作者: Melton-Celsa, Angela ; Chavaillaz, Pierre A. ; Thuning-Roberson, Claire ; Young, David G. ; Edelman, Robert ; Tacket, Carol O. ; Dowling, Thomas C. ; O'Brien, Alison

ABSTRACT 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 cαStx2, that has neutralizing activity in a mouse model was produced and tested in healthy adult volunteers. In this phase I dose escalation study, cαStx2 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 cαStx2, and innovative clinical trials will be required to measure its efficacy in preventing or treating HUS.

100 项与 cαStx1/cαStx2 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
细菌感染	临床2期	智利	Thallion Pharmaceuticals, Inc.	2010-11-01
细菌感染	临床2期	秘鲁	Thallion Pharmaceuticals, Inc.	2010-11-01
细菌感染	临床2期	阿根廷	Thallion Pharmaceuticals, Inc.	2010-11-01
腹泻	临床2期	阿根廷	Thallion Pharmaceuticals, Inc.	2010-11-01
腹泻	临床2期	智利	Thallion Pharmaceuticals, Inc.	2010-11-01
腹泻	临床2期	秘鲁	Thallion Pharmaceuticals, Inc.	2010-11-01