Nanobodies for topical delivery to inhibit abnormal choroidal angiogenesis

用于局部递送以抑制异常脉络膜血管生成的纳米抗体

• 批准号: 8832369
• 负责人: Hiep T Tran
• 金额: $ 22.49万
• 依托单位: ABZYME THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-03 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832369
• 关键词: Adverse effects; Affect; Affinity; Age related macular degeneration; Angiogenesis Inhibition; Animals; Antibodies; Antigen Targeting; Antigens; Binding; Biological Assay; Bispecific Antibodies; Blindness; Catalytic Antibodies; Cataract; Cell Separation; Cell surface; Cells; Choroid; Choroidal Neovascularization; Cloning Vectors; Deterioration; Disease Progression; Drug Kinetics; ERBB2 gene; Elderly; Endophthalmitis; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor Receptor; Escherichia coli; Eye; Eyedrops; Fluorescence; Genes; Hospitals; Human; Individual; Infection; Inflammation; Investigation; Libraries; Mediating; Modeling; Mouse Protein; Mus; Outcome; Outpatients; Patients; Periplasmic Proteins; Pharmaceutical Preparations; Phase; Physiologic Intraocular Pressure; Preparation; Production; Protein Isoforms; Retina; Retinal; Retinal Detachment; Risk; Serum; Surface; Surface Plasmon Resonance; Therapeutic; Time; Topical application; Transferrin Receptor; Treatment Cost; VEGF121 gene; Validation; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascular Permeabilities; Visual; Visual Acuity; Vitreous Hemorrhage; Vitreous humor; Yeasts; angiogenesis; antiangiogenesis therapy; base; choroidal angiogenesis; compliance behavior; design; expression cloning; expression vector; human VEGF protein; humanized antibody; improved; intravitreal injection; mesothelin; mouse model; nanobodies; neovascularization; novel; novel therapeutics; prevent; protein expression; public health relevance; receptor; transcytosis; vector

DESCRIPTION (provided by applicant): The age-related macular degeneration (AMD) characterized by the formation of subretinal choroidal neovascularization is the main cause of blindness in the elderly. Vascular endothelial growth factor (VEGF) regulates angiogenesis and enhances vascular permeability that results in visual acuity deterioration. Blockade of VEGF action is currently the most effective strategy in preventing choroidal angiogenesis and reducing vascular permeability. The intravitreal injection of anti-VEGF drugs has been widely employed to reduce the disease progression and improve the visual outcomes of the affected patients. Unfortunately, intravitreal injection requires the administration in hospital, poses a risk of sevee infection, retinal detachment, cataract, endophthalmitis, intraocular inflammation, increase of intraocular pressure and vitreous hemorrhage as well as has low patient compliance. Abzyme Therapeutics LLC proposes to develop a new therapeutic for self-administrable noninvasive topical delivery to inhibit abnormal angiogenesis in the retina and choroid. The anti-neovascularization therapeutic for AMD treatment will be designed to overcome the retinal and choroidal barriers such that the therapeutic can be delivered in the form of eye drop. Active anti-angiogenesis therapeutics will reach the VEGF target in the vitreous humor via transferrin receptor (TfR) mediated transcytosis and transcorneal transport. In Phase I, human single domain high affinity anti-VEGF neutralizing nanobodies and bispecific VEGF/TfR nanobodies with low affinity to TfR and high affinity to VEGF will be produced. The accumulation of nanobodies in the vitreous humor and retina will be determined in a mouse model that receives topical eye drops. In Phase II, the anti-neovascularization activity of transferrin receptor- mediated anti-VEGF therapeutics will be characterized and validated in animal AMD models pursuing the IND application.

描述（申请人提供）：以视网膜下脉络膜新生血管形成为特征的年龄相关性黄斑变性（AMD）是老年人致盲的主要原因。血管内皮生长因子（VEGF）调节血管生成并增强血管通透性，导致视力恶化。阻断VEGF作用是目前预防脉络膜血管生成和降低血管通透性的最有效策略。玻璃体内注射抗VEGF药物已被广泛用于减缓疾病进展并改善受影响患者的视力结果。不幸的是，玻璃体内注射需要在医院给药，造成眼内感染、视网膜脱离、白内障、眼内炎、眼内炎症、眼内压升高和玻璃体出血的风险，并且患者依从性低。Abzyme Therapeutics LLC建议开发一种新的治疗方法，用于自我管理的非侵入性局部给药，以抑制视网膜和脉络膜中的异常血管生成。用于AMD治疗的抗新生血管形成治疗剂将被设计为克服视网膜和脉络膜屏障，使得治疗剂可以以滴眼剂的形式递送。活性抗血管生成治疗剂将通过转铁蛋白受体（TfR）介导的转胞吞作用和经角膜转运到达玻璃体液中的VEGF靶标。在I期，将产生人单结构域高亲和力抗VEGF中和纳米抗体和对TfR具有低亲和力和对VEGF具有高亲和力的双特异性VEGF/TfR纳米抗体。纳米抗体在玻璃体液和视网膜中的积累将在接受局部滴眼剂的小鼠模型中确定。在II期，转铁蛋白受体介导的抗VEGF治疗剂的抗新血管形成活性将在寻求IND申请的动物AMD模型中表征和验证。