Liver and Biliary Tract
Subject Category: Liver and Biliary Tract
Am J Gastroenterol 2009; 104:868–876; doi:10.1038/ajg.2008.138; published online 24 February 2009
Transient Cytokine-Induced Liver Injury Following Administration of the Humanized Anti-CD3 Antibody Visilizumab (HuM291) in Crohn's Disease
Daniel C Baumgart MD, PhD1, James N Lowder MD2, Stephan R Targan MD3, William J Sandborn MD4 and Matthew B Frankel MD2
- 1Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical School, Humboldt University of Berlin, Berlin, Germany
- 2PDL BioPharma, Redwood City, California, USA
- 3Division of Gastroenterology and Hepatology, Department of Medicine, Cedars Sinai Medical Center, University of California, Los Angeles, California, USA
- 4Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
Correspondence: Daniel C. Baumgart, MD, PhD, Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical Center–Virchow Hospital, Medical School of the Humboldt University, D-13344 Berlin, Germany. E-mail: daniel.baumgart@charite.de
Received 28 July 2008; Accepted 13 October 2008; Published online 24 February 2009.
Abstract
OBJECTIVES:
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 
g/kg intravenously on 2 consecutive days. Serum hepatic tests including bilirubin, alkaline phosphatase (AP), 
-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-
(TNF-), interferon-, 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- 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.
