Safety and tolerability of antagonist anti-human CD40 Mab ch5D12 in patients with moderate to severe 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.


OBJECTIVE
To investigate tolerability and safety of an antagonist chimeric monoclonal anti-human CD40 antibody (ch5D12) for treatment of Crohn's disease.


METHODS
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.
Kasran
A
A
Laboratory of Experimental Immunology, Catholic University of Leuven, Belgium.
Boon
L
L
Wortel
C H
CH
Hogezand
R A
RA
Schreiber
S
S
Goldin
E
E
Boer
M
M
Geboes
K
K
Rutgeerts
P
P
Ceuppens
J L
JL
D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000009:adverse effects / Q000276:immunology*; D023201:CD40 Ligand / Q000009:adverse effects / Q000276:immunology*; D015331:Cohort Studies; D003424:Crohn Disease / Q000628:therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D023201:CD40 Ligand