A phase I study of visilizumab a humanized anti-CD3, monoclonal antibody, in severe steroid-refractory ulcerative colitis

Leiden University, Leyden, South Holland, Netherlands
Gastroenterology (Impact Factor: 13.93). 11/2007; 133(5):1414-22. DOI: 10.1053/j.gastro.2007.08.035
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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    • "The early results from clinical trials using anti-CD3 antibodies, i.e. Otelixizumab (ChAgly CD3), Tepilizumab [hOKT3γ1(Ala-Ala)], and Visilizumab, in a variety of autoimmune disorders are encouraging (Keymeulen et al., 2005; Bisikirsha et al., 2005; Plevy et al., 2007). Second, agents that block T cell costimulation are currently being tested as maintenance drug in transplant patients. "
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    • "Anti-CD4 antibodies CD4 depleting antibody cM-T412 Stronkhorst et al. (1997) CD4 non-depleting antibody MAX.16H5 Emmrich et al. (1995) B-F5 Canva-Delcambre et al. (1996) Anti-CD3 antibodies Anti-CD3e chain of TCR Visulizumab (UhM291) humanized Plevy et al. (2007) Anti-inflammatory cytokines IL-10 rHuIL-10 recombinant human Schreiber et al. (2000), Fedorak et al. (2001), Steidler et al. (2000) IL-11 rhIL-11 recombinant human Sands et al. (2002), Herrlinger et al. (2006) Inhibitors of pro-inflammatory cytokines TNF-a blockers Anti-human TNF-a (soluble and membrane-bound), composed of a human constant region IgG1k light chain (75%), linked to a mouse variable region (25%) Infliximab chimeric Papadakis et al. (2003), Ardizzone and Bianchi Porro (2002), Hanauer et al. (2002), Sands et al. (2004), Hommes et al. (2005) IgG4 anti-TNF-a with 95% human and 5% murine protein CDP571 humanized Sandborn et al. (2001a) TNF-a Fab' antibody fragment linked to polyethylene glycol "
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    • "It has been studied in a phase I study in severe steroid-refractory UC. On day 30, 84% of patients demonstrated a clinical response, 41% achieved clinical remission, and 44% achieved endoscopic remission [Plevy et al. 2007]. However, the phase III study was suspended in 2007 when interim analysis showed no benefit. "
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