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.
"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. "
[Show abstract][Hide abstract] ABSTRACT: During the last decade a large number of biological agents against tumor necrosis factor-α (TNF-α), as well as many biochemical substances and molecules specifically for the medical treatment of patients with inflammatory bowel disease (IBD), have been developed. This enormous progress was a consequence of the significant advances in biotechnology along with the increased knowledge of the underlying pathophysiological mechanisms involved in the pathogenesis of IBD. However, conventional therapies remain the cornerstone of treatment for most patients. During recent years conventional and biologic IBD therapies have been optimized. Newer mesalazine formulations with a reduced pill size and only one dose per day demonstrate similar efficacy to older formulations. New corticosteroids retain the efficacy of older corticosteroids while exhibiting a higher safety profile. The role of antibiotics and probiotics has been further clarified. Significant progress in understanding thiopurine metabolism has improved the effective dose along with adjunctive therapies. Quite a large number of substances and therapies, including biologic agents other than TNF-α inhibitors, unfractionated or low-molecular-weight heparin, omega-3 polyunsaturated fatty acids, microbes and microbial products, leukocytapheresis, and other substances under investigation, could offer important benefits to our patients. In this paper we review the established and emerging therapeutic strategies in patients with Crohn's disease and ulcerative colitis.
Drug Design, Development and Therapy 04/2011; 5:185-210. DOI:10.2147/DDDT.S11290 · 3.03 Impact Factor
"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 "
[Show abstract][Hide abstract] ABSTRACT: Although the remarkable efficacy of biological therapy has resulted in significant success in inflammatory bowel disease (IBD) management, susceptibility to infections remains a concern. The biological agents include the tumor necrosis factor-alpha (TNF-alpha) inhibitors, for instance infliximab, and other immunomodulating agents, such as natalizumab. Progressive multifocal leukoencephalopathy (PML), a rare but mostly fatal opportunistic brain infection caused by reactivation of the human polyomavirus JC virus (JCV), has been found in two patients with multiple sclerosis and one patient with Crohn's disease (CD), linked to treatment with natalizumab. After these cases of PML, the commercial and investigational use of natalizumab was suspended in February 2005 but was subsequently resumed for multiple sclerosis and for CD, only through a special restricted distribution program. This review, starting from an extensive literature search by the PubMed database, resumes the clinical aspects and pathophysiology of CD and focuses on the biologics in current use in CD (infliximab, adalimumab, and natalizumab), in order to provide a reference and gateway to prevention, recognition, and management of JCV, in the early years of biological agents therapy. It also proposed to provide an overview on the hypothetical mechanism of reactivation of JC virus related to the use of these drugs.
Journal of Cellular Physiology 08/2010; 224(2):316-326. · 3.84 Impact Factor
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