Humanized Anti-tac In The Treatment Of Uveitis

我们进行了一系列研究，以评估人源化抗IL-2受体单抗(Daclizumab)治疗严重、威胁视力、中度和后部非感染性葡萄膜炎患者的长期安全性和潜在的治疗活性。这是基于我们在人类葡萄膜炎动物模型中的初步观察。我们最初在患者中进行的研究是一项非随机、开放标签的研究，以评估Daclizumab的长期安全性和潜在的治疗活性。在这项研究中，患有慢性、非传染性双眼、威胁视力的葡萄膜炎的患者根据标准化的时间表停用免疫抑制剂，同时最终接受每4周一次的Daclizumab输液。抗白细胞介素2受体抗体治疗似乎可以预防大多数患者严重威胁视力的眼内炎性疾病的表达，这是基于双眼视力从基线开始丧失10个字母或更多的主要终点。所有患者都能够耐受研究中的药物，而不需要减少剂量。一些患者在一年的治疗中被随机分为6周的治疗间隔，其中大多数接受6周间隔治疗的患者疾病复发。7/10的患者现在已经接受了长达4年的抗IL-2受体治疗。这些患者的感染率没有明显增加。这些患者被转换为每月皮下给药，而不是输液。患者已经毫无问题地忍受了这种过渡。基于这些发现，我们启动了第二项研究。：15名患有视力威胁的葡萄膜炎患者在3个地点接受免疫抑制治疗，皮下注射Daclizumab，每2周x2次，2 mg/kg，然后每2周维持1 mg/kg，同时逐渐减少标准免疫抑制治疗。治疗耐受性良好，15名患者中有11名在12周内取消了50%的标准免疫抑制药物，达到了预定的结果，而他们的眼部炎症性疾病没有复发或视力下降。在完成6个月随访的10名参与者中，9名能够减少或维持50%的基线药物负荷，而不会显著丧失视力或增加疾病活动性。使用Daclizumab治疗白塞病的随机掩蔽试验已经完成，该试验已提交审查。一项研究是在少数尽管接受标准免疫抑制治疗但仍有活动期葡萄膜炎的患者中进行的。所有患者均对大剂量(8 mg/kg后4 mg/kg)治疗有效。一项使用大剂量Daclizumab方案治疗幼年类风湿性关节炎的初步研究已经开始，初步结果表明这种方法可能具有有益的临床效果。关于制定第三阶段研究的讨论仍在继续。Daclizumab/雷帕霉素诱导外周免疫耐受的研究也在继续。

We have engaged in a series of studies to evaluate the long term safety and potential therapeutic activity of humanized anti-IL-2 receptor monoclonal antibody (Daclizumab) therapy in the treatment of patients with severe, sight-threatening, intermediate and posterior non-infectious uveitis. This was based on our initial observations in an animal model for human uveitis. Our initial study in patients was a non-randomized, open-label study to evaluate the long term safety and potential therapeutic activity of daclizumab. In that study, patients with chronic, non-infectious bilateral, sight-threatening uveitiswere weaned off their immunosuppressive agents according to a standardized schedule, while ultimately receiving Daclizumab infusions every 4 weeks. Anti-Interleukin 2 receptor antibody therapy appeared to prevent the expression of severe sight-threatening intraocular inflammatory disease in most patients, based on the primary end point of a loss of vision of 10 letters or more from baseline in either eye. All patients were able to tolerate the study medications without the need for dose reduction. Some patients at one year of therapy were randomized to therapy intervals of 6 weeks, with most of those receiving therapy at 6 week intervals having recurrences of their disease. 7/10 Patients have now received anti-IL2 receptor therapy for up to 4 years. No apparent increase in the infection rate has been seen in these patients. Those patients were converted to monthly subcutaneous administration of the medication instead of infusions. Patients have tolerated this transition with no problems. Based on these findings we have initiated a second study. : Fifteen study participants with sight-threatening uveitis quiescent on immunosuppressive therapy were enrolled at 3 sites and treated with subcutaneous daclizumab, 2 mg/kg every 2 weeks x2, then maintenance at 1 mg/kg every 2 weeks, with simultaneous tapering of the standard immunosuppressive therapy. Treatments were well tolerated and 11/15 patients reached the preset outcome by eliminating 50% of their standard immunosuppressive medications by 12 weeks without recurrence of their ocular inflammatory disease or reduction in visual acuity. Of the 10 participants that have completed 6 months of followup, 9 were able to reduce or maintain 50% of their baseline medication load without significant loss of vision or increase in disease activity. A randomized masked trial using Daclizumab in the treatment of Behcet's disease was completed and the mansucript has been submitted for review. A study was performed in a small number of patients who had active uveitis in spite of standard immunosuppressive therapy. All the patients' disease responded to the administration of high dose (8mg/kg followed by 4mg/kg) therapy with good results. A pilot study using the high dose regimen of daclizumab in the treatment of juvenile rheumatoid arthritis has started with initial findings suggesting that this approach may have beneficial clinical effects. Discussions continue at developing a Phase III study. The Daclizumab/rapamycin study to induce peripheral immune tolerance continues as well.