BACKGROUND: 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. AIM: To investigate tolerability and safety of an antagonist chimeric monoclonal anti-human CD40 antibody (ch5D12) for treatment of Crohn's disease. METHOD: 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. RESULTS: 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. CONCLUSIONS: Antagonizing CD154-CD40 interactions with ch5D12 is a promising therapeutic approach for remission induction in Crohn's disease.
BACKGROUND: 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. AIM: To investigate tolerability and safety of an antagonist chimeric monoclonal anti-humanCD40 antibody (ch5D12) for treatment of Crohn's disease. METHOD: 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. RESULTS: 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. CONCLUSIONS: Antagonizing CD154-CD40 interactions with ch5D12 is a promising therapeutic approach for remission induction in Crohn's disease.
Authors: Deepa Rana Jamwal; Raji V Marati; Christy A Harrison; Monica T Midura-Kiela; Vanessa R Figliuolo Paz; David G Besselsen; Fayez K Ghishan; Pawel R Kiela Journal: Inflamm Bowel Dis Date: 2020-01-06 Impact factor: 5.325
Authors: Anthony J Michaels; Matteo Stoppato; Walter J Flores; Keith A Reimann; Kathleen D Engelman Journal: Am J Transplant Date: 2019-09-12 Impact factor: 8.086
Authors: Shi-Dong Ma; Xuequn Xu; Julie Plowshay; Erik A Ranheim; William J Burlingham; Jeffrey L Jensen; Fotis Asimakopoulos; Weihua Tang; Margaret L Gulley; Ethel Cesarman; Jenny E Gumperz; Shannon C Kenney Journal: J Clin Invest Date: 2014-12-08 Impact factor: 14.808