EVIDENCE THAT ANTIHUMAN TUMOR NECROSIS FACTOR MONOCLONAL... : Transplantation (original) (raw)

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EVIDENCE THAT ANTIHUMAN TUMOR NECROSIS FACTOR MONOCLONAL ANTIBODY PREVENTS OKT3-INDUCED ACUTE SYNDROME

CHARPENTIER, BERNARD2,3; HIESSE, CHRISTIAN2; LANTZ, OLIVIER2; FERRAN, CHRISTIANE4; STEPHENS, SUE; O'SHAUGNESSY, DENIS5; BODMER, MARC5; BENOIT, GERARD2; BACH, JEAN-FRANÇOIS AND4; CHATENOUD, LUCIENNE4

Service de Nephrologie- Urologie, Hôpital Bicêtre, Le Kremlin Bicêtre; INSERM U25, Hôpital Necker, Paris, France; and Celltech Limited, Slough, Berkshire, United Kingdom

2Service de Nephrologie-Urologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France.

3Address correspondence to: B. Charpentier, M.D., Service de Nephrologie, Hôpital Bicêtre, 94275 Le Kremlin Bicêtre, France.

4INSERM U25, Hôpital Necker, Paris, France.

5Celltech Limited, Slough, Berkshire, United Kingdom.

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Abstract

We have used an antihuman tumor necrosis factor monoclonal antibody, CB006 (murine IgG1), to prevent the OKT3-induced acute clinical syndrome. This syndrome is due to the massive, although transient release in the circulation of various cytokines (TNF, interferon gamma, interleukin 2, interleukin 6) and represents one important side effect linked to in vivo use of OKT3. Fourteen kidney allograft recipients undergoing prophylactic OKT3 therapy were treated with CB006 in a single i.v. injection of either 0.4 mg/kg (group I, 7 patients) or 2 mg/kg (group II, 7 patients), 1 hr before the first OKT3 administration. Nineteen consecutive patients formed a historical control group.

None of the CB006-pretreated patients showed any of the common, severe OKTS-associated symptoms (hypotension, respiratory distress, or neurotoxicity), which were observed in 10% of the historical controls. In addition, CB006-treated patients showed a lower frequency of pyrexia (≥39°C) and gastrointestinal symptoms. None of the CB006-treated patients presented severe vomiting or diarrhea, defined as repeated episodes inducing significant fluid and electrolyte loss. Two out of the 7 patients in group I and group II had mild transitory diarrhea. Mild single vomiting episodes occurred in 2 group I patients and 3 group II patients. At variance in all controls, gastrointestinal symptoms were long lasting and associated with major prostration due to electrolyte and fluid loss.

Importantly, CB006-treated patients who presented mild symptoms had detectable bioactive circulating TNF, showing incomplete inactivation of OKT3-induced TNF by CB006. CB006 was perfectly well tolerated, did not induce xenosensitization, and did not affect the biological or clinical effectiveness of OKT3.