A phase I study of visilizumab, a humanized anti-CD3 monoclonal antibody, in severe steroid-refractory ulcerative colitis.
OBJECTIVE
To evaluate the safety and biological activity of visilizumab (a humanized anti-CD3 monoclonal antibody) and to determine a maximum tolerated dose in patients with severe ulcerative colitis that had not responded to 5 days of treatment with intravenous corticosteroids.


METHODS
In this open-label phase 1 study, 32 subjects received visilizumab at a dose of 10 or 15 microg/kg, administered intravenously on 2 consecutive days. Clinical response was defined as a Modified Truelove and Witts Severity Index <10 with a minimum decrease of 3 points; remission was <4 points. Endoscopic remission was a Mayo endoscopic subscore of 0 or 1.


RESULTS
Eight patients received 15 microg/kg visilizumab. Because of dose-limiting toxicities (T-cell recovery >30 days in 2 of 8 patients), the dose was reduced to 10 microg/kg in 24 patients. On day 30, 84% of patients demonstrated a clinical response, 41% achieved clinical remission, and 44% achieved endoscopic remission. Forty-five percent of patients did not require salvage therapies or colectomy during the first year postdose. Mild to moderate symptoms of cytokine release occurred in 100% and 83% of patients in the 15- and 10-microg/kg dose groups, respectively. All patients exhibited a rapid decrease in circulating CD4(+) T-cell counts, which returned to baseline values by day 30 in 26 of 30 evaluable patients (86%). There were no serious infections.


CONCLUSIONS
Visilizumab had an acceptable safety profile at the 10-microg/kg dose level and may be clinically beneficial in patients with severe intravenous corticosteroid-refractory ulcerative colitis.
Plevy
Scott
S
Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA. scott_plevy@med.unc.edu
Salzberg
Bruce
B
Van Assche
Gert
G
Regueiro
Miguel
M
Hommes
Daniel
D
Sandborn
William
W
Hanauer
Stephen
S
Targan
Stephan
S
Mayer
Lloyd
L
Mahadevan
Uma
U
Frankel
Matthew
M
Lowder
James
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D016099:Endoscopy, Gastrointestinal; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex; C456519:visilizumab