Treatment of Diabetic Macular Edema With a Designed Ankyrin Repeat Protein That Binds Vascular Endothelial Growth Factor: A Phase I/II Study
Treatment of Diabetic Macular Edema With a Designed Ankyrin Repeat Protein That Binds Vascular Endothelial Growth Factor: A Phase I/II Study
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DOI：
10.1016/j.ajo.2012.09.032
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发表时间：
2013-04-01
影响因子：
4.2
通讯作者：
Stumpp, Michael T.
中科院分区：
文献类型：
--
作者：
Campochiaro, Peter A.;Channa, Roomasa;Stumpp, Michael T.
目得：评价MP 0112（一种设计的锚蛋白重复序列蛋白（DARPin），可特异性结合血管内皮生长因子（VEGF））治疗糖尿病性黄斑水肿（DME）患者的安全性和生物活性。DARPins是一种新型的蛋白质，选择特定的，高亲和力的结合到一个目标protein.DESIGN：I/II期，开放标签，多中心剂量递增trial.METHODS：后一个单一的玻璃体内注射的MP 0112，主要的结果是安全性评估，水MP 0112水平，最佳矫正视力（BCVA）的变化，并通过光学相干断层扫描测量中心凹厚度。计划了6个组群，但只有3个组群（0.04，0.15，0.4 mg）被登记，因为在平行的年龄相关性黄斑变性试验中确定了1.0 mg的最大耐受剂量。队列1、2和3第12周时的中位BCVA改善分别为4、6和10个字母。在11名患者（61%）中观察到眼部炎症，其中1名为重度。高分辨率色谱分离促炎性杂质从MP 0112，导致在一个新的formulation.CONCLUSIONS：一个单一的眼内注射0.4毫克MP 0112导致在水平以上的半最大抑制浓度和中和的血管内皮生长因子在房水为8-12周。尽管在一些患者中存在炎症，但在一些患者中存在长期水肿减轻和视力改善。从一种正在进行的临床试验中测试的新制剂中消除了炎症的来源。(Am J Ophthalmol 2013;155：697-704. (C)2013年，Elsevier Inc.版权所有© 2016
PURPOSE: To evaluate the safety and bioactivity of MP0112, a designed ankyrin repeat protein (DARPin) that specifically binds vascular endothelial growth factor (VEGF) in patients with diabetic macular edema (DME). DARPins are a novel class of proteins selected for specific, high-affinity binding to a target protein.DESIGN: Phase I/II, open-label, multicenter dose-escalation trial.METHODS: After a single intravitreal injection of MP0112, the main outcomes were safety assessments, aqueous MP0112 levels, change in best-corrected visual acuity (BCVA), and foveal thickness measured by optical coherence tomography. Six cohorts were planned, but only 3 were enrolled (0.04, 0.15, 0.4 mg), because a maximally tolerated dose of 1.0 mg was identified in a parallel age-related macular degeneration trial.RESULTS: Median aqueous concentration of MP0112 was 555 nM 1 week and > 10 nM in 3 of 4 patients 12 weeks post injection of 0.4 mg. Median BCVA improvement at week 12 was 4, 6, and 10 letters in cohorts 1, 2, and 3. Ocular inflammation was observed in 11 patients (61%) and was severe in 1. High-resolution chromatography separated proinflammatory impurities from MP0112, resulting in a new formulation.CONCLUSIONS: A single intraocular injection of 0.4 mg MP0112 resulted in levels above the half-maximal inhibitory concentration and neutralization of VEGF in aqueous humor for 8-12 weeks. Despite inflammation in several patients, there was prolonged edema reduction and improvement in vision in several patients. The source of the inflammation was eliminated from a new preparation that is being tested in an ongoing clinical trial. (Am J Ophthalmol 2013;155:697-704. (C) 2013 by Elsevier Inc. All rights reserved.)