Transient Cytokine-Induced Liver Injury Following Administration of the Humanized Anti-CD3 Antibody Visilizumab (HuM291) in Crohn's Disease

OBJECTIVES: Monoclonal antibodies for 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 mu g/kg intravenously for 2 consecutive days. Serum hepatic tests for bilirubin, alkaline phosphatase (AP), gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), visilizumab concentrations, and a panel of 16 cytokines were performed before and after administration of visilizumab. RESULTS: Patients experienced CRS symptoms at a median of 45 min post infusion. The cytokine profile was characterized by interferon-inducible protein-10 (IP-10), interleukin-10 (IL-10), tumor necrosis factor-a (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 concentrations peaked on the first day, 1 h post infusion, whereas all others peaked 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 post infusion. 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.