Safety and tolerability of antagonist anti‐human CD40 Mab ch5D12 in patients with moderate to severe Crohn's disease
- 12 July 2005
- journal article
- clinical trial
- Published by Wiley in Alimentary Pharmacology & Therapeutics
- Vol. 22 (2), 111-122
- https://doi.org/10.1111/j.1365-2036.2005.02526.x
Abstract
The ligation of CD40 by CD154 is a critical step in the interaction between APC and T cells. In animals, antagonizing CD40L-CD40 has been shown to reduce the severity of several autoimmune and inflammatory disorders, including experimental colitis. To investigate tolerability and safety of an antagonist chimeric monoclonal anti-human CD40 antibody (ch5D12) for treatment of Crohn's disease. ch5D12 was administrated to 18 patients with moderate to severe Crohn's disease in a single dose, open-label dose-escalation phase I/IIa study. ch5D12 plasma concentrations increased dose-dependently after infusion. Two patients developed an anti-ch5D12 antibody response. Overall response and remission rates were 72 and 22%, respectively with no evidence for a dose-response effect. Treatment with ch5D12 reduced microscopic disease activity and intensity of the lamina propria cell infiltrate, but did not alter percentages of circulating T and B cells. ch5D12 was well tolerated, although some patients experienced headache, muscle aches, or joint pains, which may have been related to the study drug. Antagonizing CD154-CD40 interactions with ch5D12 is a promising therapeutic approach for remission induction in Crohn's disease.Keywords
This publication has 42 references indexed in Scilit:
- Inhibition of costimulation allows for repeated systemic administration of adenoviral vector in rhesus monkeysGene Therapy, 2004
- Prevention of kidney allograft rejection using anti-CD40 and anti-CD86 in primatesTransplantation, 2003
- Anti-CD154 monoclonal antibody and thromboembolism revisitedTransplantation, 2002
- CD40 AND CD154 IN CELL-MEDIATED IMMUNITYAnnual Review of Immunology, 1998
- Blocking the CD40L-CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion.The Journal of Experimental Medicine, 1996
- Activated T cells induce interleukin‐12 production by monocytes via CD40‐CD40 ligand interactionEuropean Journal of Immunology, 1995
- Inhibition of Thl responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cellsImmunity, 1994
- Increased macrophage subset in inflammatory bowel disease: apparent recruitment from peripheral blood monocytes.Gut, 1994
- Helper effector function of human T cells stimulated by anti‐CD3 mAb can be enhanced by co‐stimulatory signals and is partially dependent on CD40‐CD40 ligand interactionEuropean Journal of Immunology, 1994
- Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal.The Journal of Experimental Medicine, 1993