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.

我们已经开展了一系列研究，以评估人源化抗il -2受体单克隆抗体（Daclizumab）治疗严重、视力威胁、中期和后部非感染性葡萄膜炎患者的长期安全性和潜在治疗活性。这是基于我们对人类葡萄膜炎动物模型的初步观察。我们在患者中的初始研究是一项非随机、开放标签的研究，以评估daclizumab的长期安全性和潜在治疗活性。在该研究中，患有慢性、非感染性双侧、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，同时最终每4周接受一次Daclizumab输注。在大多数患者中，抗白细胞介素2受体抗体治疗似乎可以预防严重威胁视力的眼内炎症性疾病的表达，主要终点是任何一只眼睛的视力从基线下降10个字母或更多。所有患者都能够耐受研究药物而无需减少剂量。一些接受一年治疗的患者被随机分配到6周的治疗间隔，大多数接受6周治疗间隔的患者出现了疾病复发。目前，7/10的患者接受了长达4年的抗il - 2受体治疗。这些患者的感染率未见明显增加。这些患者转为每月皮下给药，而不是输液。患者能够忍受这种转变，没有任何问题。基于这些发现，我们开始了第二项研究。： 15名接受免疫抑制治疗的视力威胁性葡萄膜炎的研究参与者在3个部位入组，使用皮下daclizumab治疗，每2周2 mg/kg x2，然后维持每2周1 mg/kg的剂量，同时逐渐减少标准免疫抑制治疗。治疗耐受性良好，11/15的患者在12周内消除了50%的标准免疫抑制药物，达到了预定的结果，没有眼炎复发或视力下降。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，而没有明显的视力丧失或疾病活动性增加。一项研究是在少数患者中进行的，这些患者尽管接受了标准的免疫抑制治疗，但仍患有活动性葡萄膜炎。所有患者的疾病均对高剂量（8mg/kg后4mg/kg）治疗有反应。我们正在评估这些数据。讨论继续进行第三期研究。同时，一项探索用这种药物治疗活动性葡萄膜炎的可能性的新方案将很快启动。