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

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.