Long-acting protein drugs for the treatment of ocular diseases.
Long-acting protein drugs for the treatment of ocular diseases.
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DOI：
10.1038/ncomms14837
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发表时间：
2017-03-23
影响因子：
16.6
通讯作者：
Roguska M
中科院分区：
文献类型：
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作者：
Ghosh JG;Nguyen AA;Bigelow CE;Poor S;Qiu Y;Rangaswamy N;Ornberg R;Jackson B;Mak H;Ezell T;Kenanova V;de la Cruz E;Carrion A;Etemad-Gilbertson B;Caro RG;Zhu K;George V;Bai J;Sharma-Nahar R;Shen S;Wang Y;Subramanian KK;Fassbender E;Maker M;Hanks S;Vrouvlianis J;Leehy B;Long D;Prentiss M;Kansara V;Jaffee B;Dryja TP;Roguska M
中和血管内皮生长因子（VEGF）的蛋白质药物，如阿柏西普或雷珠单抗，可挽救视网膜血管疾病患者的视力。尽管如此，最佳的视力结果需要每月频繁地进行眼内注射。在这里，我们报告了一种方法，以延长玻璃体内半衰期的蛋白质药物作为替代封装或化学修饰的聚合物。我们将联合收割机与治疗性抗体和蛋白质结合，这种97个氨基酸的人源肽结合透明质酸，透明质酸是眼睛玻璃体的主要大分子成分。当施用于兔和猴眼睛时，修饰的蛋白质的半衰期相对于未修饰的蛋白质增加了0.3 -4倍。我们进一步表明，原型长效抗VEGF药物（LAVA），其中包括这种肽减弱VEGF诱导的视网膜病变的新生血管性视网膜疾病的动物模型比未修饰的药物长约3-4倍。这种方法有可能减少与视网膜疾病治疗相关的给药频率。视网膜血管疾病治疗涉及频繁的药物眼内给药。在这里，作者提出了一种方法，通过将这些药物与透明质酸结合肽融合来增加注射药物的半衰期，这可能导致更少的视网膜疾病治疗。
Protein drugs that neutralize vascular endothelial growth factor (VEGF), such as aflibercept or ranibizumab, rescue vision in patients with retinal vascular diseases. Nonetheless, optimal visual outcomes require intraocular injections as frequently as every month. Here we report a method to extend the intravitreal half-life of protein drugs as an alternative to either encapsulation or chemical modifications with polymers. We combine a 97-amino-acid peptide of human origin that binds hyaluronan, a major macromolecular component of the eye's vitreous, with therapeutic antibodies and proteins. When administered to rabbit and monkey eyes, the half-life of the modified proteins is increased ∼3–4-fold relative to unmodified proteins. We further show that prototype long-acting anti-VEGF drugs (LAVAs) that include this peptide attenuate VEGF-induced retinal changes in animal models of neovascular retinal disease ∼3–4-fold longer than unmodified drugs. This approach has the potential to reduce the dosing frequency associated with retinal disease treatments. Retinal vascular disease treatments involve frequent pharmacological intraocular administrations. Here the authors present a method to increase the half-life of injected drugs by fusing these to a hyaluronan-binding peptide, which might lead to less frequent retinal disease treatments.