Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis

C. J. Fisher, S. M. Opal, J. F. Dhainaut, S. Stephens, J. L. Zimmerman, P. Nightingale, S. J. Harris, R. M H Schein, Edward A Panacek, J. L. Vincent -, G. E. Foulke, E. L. Warren, C. Garrard, G. Park, M. W. Bodmer, J. Cohen, C. Van der Linden, A. S. Cross, J. C. Sadoff

Research output: Contribution to journalArticle

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Abstract

Objectives: To determine the safety, pharmacokinetics, and activity of an anti-tumor necrosis factor (TNF)-α monoclonal antibody in severe sepsis. Design: Open-label, prospective, phase II multicenter trial with escalating doses of a murine monoclonal antibody (CB0006). Setting: Twelve academic medical center intensive care units in the United States and Europe. Patients: Eighty patients with severe sepsis or septic shock who received standard supportive care and antimicrobial therapy in addition to the anti- TNF antibody. Interventions: Patients were treated intravenously with one of four dosing regimens with CB0006: 0.1 mg/kg, 1.0 mg/kg, 10 mg/kg or two doses of 1 mg/kg 24 hrs apart. Measurements and Main Results: The murine monoclonal anti-TNF antibody was well tolerated despite the development of anti-murine antibodies in 98% of patients. No survival benefit was found for the total study population, but patients with increased circulating TNF concentrations at study entry appeared to benefit by the high dose anti-TNF antibody treatment. Increased interleukin (IL)-6 levels predicted a fatal outcome (p = .003), but TNF levels were not found to be a prognostic indicator. TNF levels were higher (206.7 ± 60.7 vs. 85.9 ± 26.1 pg/mL; p < .001) and outcome was poor (41% vs. 71% survival; p = .007) in patients who were in shock at study entry when compared with septic patients not in shock. Conclusions: The murine anti-TNF-α monoclonal antibody CB0006 has proven to be safe in this clinical trial and may prove to be useful in septic patients with increased circulating TNF concentrations. Further studies are needed to determine efficacy and the ultimate clinical utility of this immunotherapeutic agent in sepsis.

Original languageEnglish (US)
Pages (from-to)318-327
Number of pages10
JournalCritical Care Medicine
Volume21
Issue number3
StatePublished - 1993
Externally publishedYes

Fingerprint

Sepsis
Tumor Necrosis Factor-alpha
Monoclonal Antibodies
Cytokines
Antibodies
Shock
Fatal Outcome
Survival
Septic Shock
Multicenter Studies
Intensive Care Units
Anti-Idiotypic Antibodies
Interleukin-6
Pharmacokinetics
Clinical Trials
Safety
Therapeutics
Population

Keywords

  • anti-cytokine
  • critical illness
  • immunotherapy
  • infection
  • interleukin-1
  • interleukin-6
  • monoclonal antibody
  • sepsis
  • shock, septic
  • tumor necrosis factor

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Fisher, C. J., Opal, S. M., Dhainaut, J. F., Stephens, S., Zimmerman, J. L., Nightingale, P., ... Sadoff, J. C. (1993). Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. Critical Care Medicine, 21(3), 318-327.

Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. / Fisher, C. J.; Opal, S. M.; Dhainaut, J. F.; Stephens, S.; Zimmerman, J. L.; Nightingale, P.; Harris, S. J.; Schein, R. M H; Panacek, Edward A; Vincent -, J. L.; Foulke, G. E.; Warren, E. L.; Garrard, C.; Park, G.; Bodmer, M. W.; Cohen, J.; Van der Linden, C.; Cross, A. S.; Sadoff, J. C.

In: Critical Care Medicine, Vol. 21, No. 3, 1993, p. 318-327.

Research output: Contribution to journalArticle

Fisher, CJ, Opal, SM, Dhainaut, JF, Stephens, S, Zimmerman, JL, Nightingale, P, Harris, SJ, Schein, RMH, Panacek, EA, Vincent -, JL, Foulke, GE, Warren, EL, Garrard, C, Park, G, Bodmer, MW, Cohen, J, Van der Linden, C, Cross, AS & Sadoff, JC 1993, 'Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis', Critical Care Medicine, vol. 21, no. 3, pp. 318-327.
Fisher CJ, Opal SM, Dhainaut JF, Stephens S, Zimmerman JL, Nightingale P et al. Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. Critical Care Medicine. 1993;21(3):318-327.
Fisher, C. J. ; Opal, S. M. ; Dhainaut, J. F. ; Stephens, S. ; Zimmerman, J. L. ; Nightingale, P. ; Harris, S. J. ; Schein, R. M H ; Panacek, Edward A ; Vincent -, J. L. ; Foulke, G. E. ; Warren, E. L. ; Garrard, C. ; Park, G. ; Bodmer, M. W. ; Cohen, J. ; Van der Linden, C. ; Cross, A. S. ; Sadoff, J. C. / Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. In: Critical Care Medicine. 1993 ; Vol. 21, No. 3. pp. 318-327.
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abstract = "Objectives: To determine the safety, pharmacokinetics, and activity of an anti-tumor necrosis factor (TNF)-α monoclonal antibody in severe sepsis. Design: Open-label, prospective, phase II multicenter trial with escalating doses of a murine monoclonal antibody (CB0006). Setting: Twelve academic medical center intensive care units in the United States and Europe. Patients: Eighty patients with severe sepsis or septic shock who received standard supportive care and antimicrobial therapy in addition to the anti- TNF antibody. Interventions: Patients were treated intravenously with one of four dosing regimens with CB0006: 0.1 mg/kg, 1.0 mg/kg, 10 mg/kg or two doses of 1 mg/kg 24 hrs apart. Measurements and Main Results: The murine monoclonal anti-TNF antibody was well tolerated despite the development of anti-murine antibodies in 98{\%} of patients. No survival benefit was found for the total study population, but patients with increased circulating TNF concentrations at study entry appeared to benefit by the high dose anti-TNF antibody treatment. Increased interleukin (IL)-6 levels predicted a fatal outcome (p = .003), but TNF levels were not found to be a prognostic indicator. TNF levels were higher (206.7 ± 60.7 vs. 85.9 ± 26.1 pg/mL; p < .001) and outcome was poor (41{\%} vs. 71{\%} survival; p = .007) in patients who were in shock at study entry when compared with septic patients not in shock. Conclusions: The murine anti-TNF-α monoclonal antibody CB0006 has proven to be safe in this clinical trial and may prove to be useful in septic patients with increased circulating TNF concentrations. Further studies are needed to determine efficacy and the ultimate clinical utility of this immunotherapeutic agent in sepsis.",
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T1 - Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis

AU - Fisher, C. J.

AU - Opal, S. M.

AU - Dhainaut, J. F.

AU - Stephens, S.

AU - Zimmerman, J. L.

AU - Nightingale, P.

AU - Harris, S. J.

AU - Schein, R. M H

AU - Panacek, Edward A

AU - Vincent -, J. L.

AU - Foulke, G. E.

AU - Warren, E. L.

AU - Garrard, C.

AU - Park, G.

AU - Bodmer, M. W.

AU - Cohen, J.

AU - Van der Linden, C.

AU - Cross, A. S.

AU - Sadoff, J. C.

PY - 1993

Y1 - 1993

N2 - Objectives: To determine the safety, pharmacokinetics, and activity of an anti-tumor necrosis factor (TNF)-α monoclonal antibody in severe sepsis. Design: Open-label, prospective, phase II multicenter trial with escalating doses of a murine monoclonal antibody (CB0006). Setting: Twelve academic medical center intensive care units in the United States and Europe. Patients: Eighty patients with severe sepsis or septic shock who received standard supportive care and antimicrobial therapy in addition to the anti- TNF antibody. Interventions: Patients were treated intravenously with one of four dosing regimens with CB0006: 0.1 mg/kg, 1.0 mg/kg, 10 mg/kg or two doses of 1 mg/kg 24 hrs apart. Measurements and Main Results: The murine monoclonal anti-TNF antibody was well tolerated despite the development of anti-murine antibodies in 98% of patients. No survival benefit was found for the total study population, but patients with increased circulating TNF concentrations at study entry appeared to benefit by the high dose anti-TNF antibody treatment. Increased interleukin (IL)-6 levels predicted a fatal outcome (p = .003), but TNF levels were not found to be a prognostic indicator. TNF levels were higher (206.7 ± 60.7 vs. 85.9 ± 26.1 pg/mL; p < .001) and outcome was poor (41% vs. 71% survival; p = .007) in patients who were in shock at study entry when compared with septic patients not in shock. Conclusions: The murine anti-TNF-α monoclonal antibody CB0006 has proven to be safe in this clinical trial and may prove to be useful in septic patients with increased circulating TNF concentrations. Further studies are needed to determine efficacy and the ultimate clinical utility of this immunotherapeutic agent in sepsis.

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KW - critical illness

KW - immunotherapy

KW - infection

KW - interleukin-1

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KW - sepsis

KW - shock, septic

KW - tumor necrosis factor

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