Humanized Anti-tac in the Treatment of Uveitis

人源化 Anti-tac 治疗葡萄膜炎

• 批准号: 6968519
• 负责人: ROBERT B. NUSSENBLATT
• 金额: --
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6968519
• 关键词: antibody receptor; antireceptor antibody; biotechnology; clinical trials; cytokine receptors; eye disorder chemotherapy; human subject; human therapy evaluation; immunosuppressive; immunotherapy; interleukin 2; longitudinal human study; monoclonal antibody; patient oriented research; uveitis

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 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. We are evaluating this data. Discussions continue at developing a Phase III study. As well, a new protocol to explore the possibility of treating active uveitis with this medication will start shortly.

我们已经进行了一系列研究，以评估人源化抗IL-2受体单克隆抗体（Daclizumab）治疗的长期安全性和潜在的治疗活性，以治疗严重，视力危险，中间和后非感染性葡萄膜炎的患者。这是基于我们在人类葡萄膜炎的动物模型中的最初观察结果。我们在患者中的最初研究是一项非随机的开放标签研究，用于评估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，非感染双侧，视力危险性葡萄膜炎的患者根据标准化的时间表使他们的免疫抑制剂断奶，同时最终每4周接受Daclizumab的输注。基于大多数患者，抗Interleukin 2受体抗体疗法似乎可以防止大多数患者的严重视力危及眼内炎症性疾病的表达，这是根据两只眼睛中基线的10个字母或更多视力丧失的主要终点。所有患者都能忍受研究药物而无需降低剂量。一些治疗中的患者被随机分配为6周的治疗间隔，大多数患者以6周的间隔接受治疗，患有其疾病的复发。 7/10例患者现在已接受抗IL2受体疗法长达4年。这些患者没有看到感染率明显增加。这些患者被转化为每月皮下给药，而不是输注。患者可以忍受这种过渡，没有任何问题。根据这些发现，我们开始了第二项研究。 ：在3个地点接受了15个对免疫抑制治疗的视力降低葡萄膜炎的研究参与者，并用皮下daclizumab进行治疗，每2周x2每2周2 mg/kg x2，然后以1 mg/kg的速度维持每2周，同时进行了1毫克，并及时进行了1 mg/kg。通过消除其标准免疫抑制药物的50％，而不会复发其眼部炎症性疾病或视力降低。在完成6个月随访的10名参与者中，有9位能够减少或维持其基线药物负荷的50％，而不会大大丧失视力或增加疾病活动。尽管有标准的免疫抑制治疗，但对少数患有葡萄膜炎的患者进行了一项研究。所有患者的疾病都对高剂量（8mg/kg，4mg/kg）治疗的给药做出了反应。我们正在评估这些数据。讨论继续进行III期研究。同样，探索这种药物治疗活性葡萄膜炎的可能性的新方案将很快开始。