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.

我们进行了一系列研究，以评价人源化抗IL-2受体单克隆抗体（Daclizumab）治疗严重、危及视力、中间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。这是基于我们在人类葡萄膜炎动物模型中的初步观察。我们在患者中进行的初步研究是一项非随机、开放标签研究，旨在评估达克珠单抗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时间表停用免疫抑制剂，最终每4周接受一次Daclizumab输注。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，其主要终点是每只眼睛的视力从基线丧失10个字母或更多。所有患者均能够耐受研究药物，无需降低剂量。一些患者在治疗一年时被随机分配到6周的治疗间隔，其中大多数以6周间隔接受治疗的患者的疾病复发。7/10例患者目前已接受抗IL 2受体治疗长达4年。在这些患者中未观察到感染率明显增加。这些患者改为每月皮下给药，而不是输注。患者可以耐受这种过渡，没有任何问题。根据这些发现，我们开始了第二项研究。15名在免疫抑制治疗中静止的具有威胁视力的葡萄膜炎的研究参与者在3个地点入组，并接受皮下达克珠单抗治疗，每2周一次2 mg/kg x2，然后维持每2周一次1 mg/kg，治疗耐受性良好，11/15例患者通过消除50%的免疫抑制剂达到预设结果。标准免疫抑制药物治疗12周后，眼部炎症性疾病未复发或视力下降。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。所有患者的疾病对给予高剂量（8 mg/kg，随后4 mg/kg）治疗均产生反应。我们正在评估这些数据。讨论继续进行III期研究。此外，一项新的协议，以探索治疗活动性葡萄膜炎与这种药物的可能性将很快开始。