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Antimicrobial Agents and Chemotherapy, July 2009, p. 3081-3087, Vol. 53, No. 7
0066-4804/09/$08.00+0 doi:10.1128/AAC.01661-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Safety and Pharmacokinetics of Chimeric Anti-Shiga Toxin 1 and Anti-Shiga Toxin 2 Monoclonal Antibodies in Healthy Volunteers
Martin Bitzan,1*
Ruth Poole,2
Mariam Mehran,2,
Eric Sicard,3
Catherine Brockus,4
Claire Thuning-Roberson,2 and
Marc Rivière2,
Department of Pediatrics, McGill University, Montreal Children's Hospital, 2300 rue Tupper, Room E-222, Montréal, Québec, Canada H3H 1P3,1 Thallion Pharmaceuticals Inc., 7150 rue Alexander-Fleming, Montréal, Québec, Canada H4S 2C8,2 Algorithme Pharma Inc., 200 av. Beaumont, Mount-Royal, Québec, Canada H3P 3P1,3 Department of Immunology, MPI Research Inc., 54943 North Main St., Mattawan, Michigan 490714
Received 17 December 2008/ Returned for modification 22 March 2009/ Accepted 22 April 2009
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 (c
Stx1 and cStx2, respectively). In the first study, 16 volunteers received 1 or 3 mg/kg of body weight of cStx1 or cStx2 as a single, short (1-h) intravenous infusion (n = 4 per group). In a second study, 10 volunteers received a 1-h infusion of cStx1 and cStx2 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 cStx1 (0.38 ± 0.16 ml/h/kg [mean ± standard deviation]) than for cStx2 (0.20 ± 0.07 ml/h/kg) (P = 0.0013, t test). The low clearance is consistent with the long elimination half-lives of cStx1 (190.4 ± 140.2 h) and cStx2 (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 cStx1 and cStx2, 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.
* Corresponding author. Mailing address: Montreal Children's Hospital, Room E-222, 2300, Rue Tupper, Montréal, Québec, Canada H3H 1P3. Phone: (514) 412-4461. Fax: (514) 412-4359. E-mail: martin.bitzan{at}mcgill.ca
Published ahead of print on 4 May 2009.
Present address: MethylGene Inc., 7220, Rue Frederick-Banting, Montréal, Québec, Canada H4S 2A1.
Present address: Axcan Pharma Inc., 597, Boul. Laurier, Mont-Saint-Hilaire, Québec, Canada J3H 6C4.
Antimicrobial Agents and Chemotherapy, July 2009, p. 3081-3087, Vol. 53, No. 7
0066-4804/09/$08.00+0 doi:10.1128/AAC.01661-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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