Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin.
BACKGROUND
Selective blockade of interactions between leukocytes and vascular endothelium in the gut is a promising strategy for the treatment of inflammatory bowel diseases.


METHODS
We conducted a multicenter, double-blind, placebo-controlled trial of MLN02, a humanized antibody to the alpha4beta7 integrin, in patients with active ulcerative colitis. We randomly assigned 181 patients to receive 0.5 mg of MLN02 per kilogram of body weight, 2.0 mg per kilogram, or an identical-appearing placebo intravenously on day 1 and day 29. Eligible patients also received concomitant mesalamine or no other treatment for colitis. Ulcerative colitis clinical scores and sigmoidoscopic assessments were evaluated six weeks after randomization.


RESULTS
Clinical remission rates at week 6 were 33 percent, 32 percent, and 14 percent for the group receiving 0.5 mg of MLN02 per kilogram, the group receiving 2.0 mg per kilogram, and the placebo group, respectively (P=0.03). The corresponding proportions of patients who improved by at least 3 points on the ulcerative colitis clinical score were 66 percent, 53 percent, and 33 percent (P=0.002). Twenty-eight percent of patients receiving 0.5 mg per kilogram and 12 percent of those receiving 2.0 mg per kilogram had endoscopically evident remission, as compared with 8 percent of those receiving placebo (P=0.007). For the minority of patients in whom an MLN02 antibody titer greater than 1:125 developed, incomplete saturation of the alpha4beta7 receptor on circulating lymphocytes was observed and no benefit of treatment was identifiable.


CONCLUSIONS
In this short-term study, MLN02 was more effective than placebo for the induction of clinical and endoscopic remission in patients with active ulcerative colitis.
Feagan
Brian G
BG
Robarts Research Institute, London, ON N6A 5K8, Canada. bfeagan@robarts.ca
Greenberg
Gordon R
GR
Wild
Gary
G
Fedorak
Richard N
RN
Paré
Pierre
P
McDonald
John W D
JW
Dubé
Rejean
R
Cohen
Albert
A
Steinhart
A Hillary
AH
Landau
Steven
S
Aguzzi
Rasha A
RA
Fox
Irving H
IH
Vandervoort
Margaret K
MK
D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use* / Q000652:urine*; D061067:Antibodies, Monoclonal, Humanized; D000917:Antibody Formation; D001323:Autoantibodies; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D016023:Integrins / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001323:Autoantibodies; D016023:Integrins; C501380:MLN02 antibody, human; C071777:integrin alpha4beta7