CDP571, A HUMANIZED ANTIBODY TO HUMAN TUMOR-NECROSIS-FACTOR-ALPHA - SAFETY, PHARMACOKINETICS, IMMUNE-RESPONSE, AND INFLUENCE OF THE ANTIBODY ON CYTOKINE CONCENTRATIONS IN PATIENTS WITH SEPTIC SHOCK

Objectives: To determine the safety of a ''humanized'' antibody to hum an anti-tumor necrosis factor-alpha (TNF-alpha) in patients with septi c shock, and to examine the pharmacokinetics, immune response, and inf luence of the antibody on cytokine concentrations in this patient grou p. Design: Prospective, randomized, placebo-controlled, phase II multi center clinical trial, with escalating doses of a fully humanized anti -TNF-alpha antibody (CDP571). Setting: Seven academic intensive care u nits in Europe. Patients: Forty-two patients with rapidly evolving sep tic shock who received CDP571 in addition to standard supportive care. Interventions: Patients received intravenously either placebo or one of four single doses of CDP571: 0.1, 0.3, 1.0, or 3.0 mg/kg. Measureme nts and Main Results: The humanized anti-TNF-alpha antibody was well t olerated, The overall all-cause 28-day mortality rate was 62%. Mortali ty rate was similar in the placebo and treatment groups, except that a ll six patients who received 0.3 mg/kg of CDP571 died within 7 days. T his outcome, which was not dose-related, is consistent with the poorer prognostic characteristics of this group at baseline. The peak CDP571 concentrations and area under the curve increased proportionately wit h the dose, The low level of the immune response detected had little e ffect on the ability of circulating CDP571 to bind TNF-alpha and on th e pharmacokinetics of the antibody. An abrupt reduction in circulating TNF-alpha concentration was observed 30 mins after CDP571 administrat ion at all active dosage levels. While interleukin-1 beta and interleu kin-6 plasma concentrations decreased with time in all dosage groups, these cytokine concentrations decreased more rapidly during the initia l 24 hrs in the treatment groups than in the placebo group. Conclusion s: The humanized anti-TNF-alpha antibody, CDP571, is well tolerated an d able to cause a dose-dependent reduction in circulating TNF-alpha co ncentrations in patients with septic shock. Further studies are needed to determine the efficacy of this antibody to improve the survival ra tes of critically ill patients with severe sepsis.