title: Transient cytokine-induced liver injury following administration of the humanized anti-CD3 antibody visilizumab (HuM291) in Crohn's disease.
abstract: OBJECTIVE
  Monoclonal antibodies to CD3 and CD4 T-cell receptors are evolving for Crohn's disease (CD) and ulcerative colitis. Their administration is often associated with a cytokine release syndrome (CRS).
  
  
  METHODS
  We evaluated data from two prospective clinical trials (NCT00267709 and NCT00267722) of visilizumab (HuM291), a novel humanized anti-CD3 antibody, in 34 patients with CD who received 10 microg/kg intravenously on 2 consecutive days. Serum hepatic tests including bilirubin, alkaline phosphatase (AP), gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), visilizumab concentrations, and a panel of 16 cytokines were measured pre- and postadministration of visilizumab.
  
  
  RESULTS
  Patients experienced CRS symptoms at a median of 45 min postinfusion. The cytokine profile was characterized by interferon-inducible protein-10 (IP-10), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, monocyte chemotactic protein 1 (MCP-1), interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin-2 (IL-2), and interleukin 1 receptor antagonist (IL-1Ra), which were elevated between 6 (IL-1Ra) and 870 (IP-10) times their baseline concentrations. TNF-alpha and IL-2 peaked at the first day 1 h post infusion, whereas all others peaked at 6 h post infusion. Eighty-six percent of patients experienced an elevation above the upper limit of normal in hepatic enzymes (GGT 73%, AST 73%, ALT 64%, and AP 42% of patients), but not bilirubin, within 6 h postinfusion.
  
  
  CONCLUSIONS
  Transient elevation of hepatic enzymes occurred frequently in patients with CD treated with visilizumab and was associated with CRS. CD patients could be predisposed due to an aberrant expression of adhesion molecules in the liver that promotes CRS upon engagement of the T-cell receptor and may relate to extraintestinal disease manifestations such as primary sclerosing cholangitis.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical School, Humboldt University of Berlin, Berlin, Germany. daniel.baumgart@charite.de
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Baumgart
authors.forename: James N
authors.initials: JN
authors.lastname: Lowder
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
authors.forename: William J
authors.initials: WJ
authors.lastname: Sandborn
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Frankel
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D017252:CD3 Complex / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy*; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007275:Injections, Intravenous; D008107:Liver Diseases / Q000097:blood; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D055815:Young Adult; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex; D016207:Cytokines; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; C456519:visilizumab; D001663:Bilirubin