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Sustained Intravitreal Delivery of Ranibizumab Mediated by ECM Binding

ECM 结合介导的雷珠单抗玻璃体内持续递送

基本信息

批准号：
9765322
负责人：
Michael S Yu
金额：
$ 22.88万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765322
关键词：
Adenovirus Vector Affinity Age related macular degeneration Antibodies Antibody Therapy Antibody-drug conjugates Avastin Binding Biological Assay Blindness Cells Chemicals Choroidal Neovascularization Clinical Collagen Collagen Type II Cornea Corneal Diseases Data Diagnostic Diffusion Disease Disease model Doctor of Philosophy Drainage procedure Drug Delivery Systems Encapsulated Engineering Extracellular Matrix Eye Eye diseases Fab Immunoglobulins Formulation Gel Goals Growth Factor Half-Life Human Hyaluronan Hybrids Immune In Vitro Injections Joints Link Liposomes Longitudinal Studies Lucentis Macular degeneration Mediating Membrane Modeling Molecular Ophthalmology Optics Oryctolagus cuniculus Pain Paper Pathologic Patients Peptides Pharmaceutical Preparations Pharmacologic Substance Polymers Procedures Protein Denaturation Proteins Publishing Regimen Research Retina Retinal Retinal Diseases Skin Stress Structure Surface System Testing Therapeutic Tissues Toxic effect Vascular Endothelial Growth Factors Vegf inhibition Vitrectomy Vitreous body structure Water angiogenesis anterior chamber base bevacizumab biomaterial compatibility blood vessel development design drug clearance experience histological studies humanized antibody improved in vivo infection risk innovation intravitreal injection nano nanofiber neovasculature particle peptidomimetics prevent proliferative diabetic retinopathy protein aminoacid sequence ranibizumab response side effect uptake

项目摘要

PROJECT SUMMARY Antibody-based therapies have emerged as an important treatment for many eye diseases with pathological blood vessel formation, including the wet form of aged related macular degeneration (AMD), proliferative diabetic retinopathy, and choroidal neovascularization. Avastin (bevacizumab) and Lucentis (ranibizumab) are humanized antibody and its Fab fragments, respectively, that prevent angiogenesis by blocking VEGF. They have shown remarkable clinical response in treating these eye diseases; however current therapeutic regimens require monthly intravitreal injections because of fast diffusion-mediated clearance of drugs from the eye. Frequent injections result in severe patient burden in terms of increased risk of infection and repeated stress and pain associated with the injection. Prolonging the activity of antibody in the eye would greatly improve the therapeutic utility and efficacy, and decrease toxicity. The overall objective of this application is to develop ranibizumab (Ran) derivatives that can engage the extracellular matrix of the vitreous with high affinity, particularly through engineering peptide conjugates that can interact with type II collagen (Coll) and hyaluronan (HA). The long-term goal is to explore their sustained delivery for treating macular degeneration and other disease of the posterior eye. The central hypothesis is that the Ran derivatives which interact with the vitreous ECM will have significantly extended duration and improved therapeutic activity after intravitreal injection. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims. The focus of Aim 1 is to synthesize peptide-Ran conjugates that can bind to type II collagen or hyaluronan (HA) while maintaining their anti-VEGF activity. The conjugates will be tested for ECM binding affinity and VEGF inhibiting activity using in vitro molecular- and cell-level assays. Aim 1 also includes plans to develop self-assembled peptide nanofibers that can be co-injected with peptide-Ran conjugates for high level of drug loading particularly for patients with low level of ECM in the vitreous. Aim 2 focuses on testing the sustained delivery of the Ran formulation and ultimately the long-term efficacy in delaying the neovasculature formation using induced choroidal neovascularization (CNV) model in rabbit. Aim 2 also includes the long-term biocompatibility study of the Ran formulations. The proposal is significant because localization and sustained release of antibody drugs made possible by ECM binding and ECM-like nanofibers can be applied to other pathologic conditions in the skin and joints which are rich in collagen and HA.

项目摘要基于抗体的疗法已经成为许多具有病理性眼病的重要治疗方法。血管形成，包括湿性的老年性黄斑变性（AMD）、增殖性黄斑变性、糖尿病视网膜病和脉络膜新生血管形成。Avastin（贝伐单抗）和Lucentis（雷珠单抗）是人源化抗体及其Fab片段，其通过阻断VEGF来预防血管生成。他们在治疗这些眼病中显示出显著的临床反应;然而，目前的治疗方法方案需要每月玻璃体内注射，因为药物从玻璃体中快速扩散介导的清除，眼睛频繁注射会导致严重的患者负担，增加感染和反复感染的风险。压力和注射带来的疼痛延长抗体在眼睛中的活性将大大提高治疗效用和疗效，降低毒性。本申请的总体目标是开发了可以高亲和力结合玻璃体细胞外基质的雷珠单抗（Ran）衍生物，特别是通过工程肽缀合物，其可以与II型胶原（科尔）和透明质酸相互作用，（民政事务局）。长期目标是探索其用于治疗黄斑变性和其他疾病的持续递送。眼睛后部的疾病。中心假设是与玻璃体相互作用的Ran衍生物 ECM在玻璃体内注射后将具有显著延长的持续时间和改善的治疗活性。在强有力的初步数据的指导下，这一假设将通过追求两个具体目标来检验。的焦点目的1是合成肽-Ran缀合物，其可以结合II型胶原或透明质酸（HA），维持其抗VEGF活性。将测试缀合物的ECM结合亲和力和VEGF抑制性。活性使用体外分子和细胞水平测定。Aim 1还包括开发自组装可与肽-Ran缀合物共注射以实现高水平药物负载的肽纳米纤维特别是对于玻璃体中ECM水平较低的患者。目标2侧重于测试持续提供 Ran制剂和最终使用Ran制剂延迟新血管形成的长期功效诱导兔脉络膜新生血管（CNV）模型。目标2还包括长期生物相容性 Ran制剂的研究。该提案意义重大，因为本地化和持续释放通过ECM结合和ECM样纳米纤维使抗体药物成为可能，胶原蛋白和透明质酸的含量丰富，可以有效地改善皮肤和关节的状况。