Nanobodies for topical delivery to inhibit abnormal choroidal angiogenesis
Nanobodies for topical delivery to inhibit abnormal choroidal angiogenesis
批准号:
8832369
负责人:
Hiep T Tran
金额:
$22.49万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-02-03 至 2017-01-31
关键词:
Adverse effectsAffectAffinityAge related macular degenerationAngiogenesis InhibitionAnimalsAntibodiesAntigen TargetingAntigensBindingBiological AssayBispecific AntibodiesBlindnessCatalytic AntibodiesCataractCell SeparationCell surfaceCellsChoroidChoroidal NeovascularizationCloning VectorsDeteriorationDisease ProgressionDrug KineticsERBB2 geneElderlyEndophthalmitisEnzyme-Linked Immunosorbent AssayEpidermal Growth Factor ReceptorEscherichia coliEyeEyedropsFluorescenceGenesHospitalsHumanIndividualInfectionInflammationInvestigationLibrariesMediatingModelingMouse ProteinMusOutcomeOutpatientsPatientsPeriplasmic ProteinsPharmaceutical PreparationsPhasePhysiologic Intraocular PressurePreparationProductionProtein IsoformsRetinaRetinalRetinal DetachmentRiskSerumSurfaceSurface Plasmon ResonanceTherapeuticTimeTopical applicationTransferrin ReceptorTreatment CostVEGF121 geneValidationVascular Endothelial Growth Factor ReceptorVascular Endothelial Growth FactorsVascular PermeabilitiesVisualVisual AcuityVitreous HemorrhageVitreous humorYeastsangiogenesisantiangiogenesis therapybasechoroidal angiogenesiscompliance behaviordesignexpression cloningexpression vectorhuman VEGF proteinhumanized antibodyimprovedintravitreal injectionmesothelinmouse modelnanobodiesneovascularizationnovelnovel therapeuticspreventprotein expressionpublic health relevancereceptortranscytosisvector
中文摘要
描述(由申请人提供):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)是老年人失明的主要原因。血管内皮生长因子(VEGF)调节血管生成,增强血管通透性,导致视力下降。阻断VEGF的作用是目前预防脉络膜血管生成和降低血管通透性最有效的策略。玻璃体内注射抗vegf药物已被广泛应用于减少疾病进展和改善患者视力。不幸的是,玻璃体内注射需要在医院给药,存在严重感染、视网膜脱离、白内障、眼内炎、眼内炎症、眼压升高和玻璃体出血的风险,并且患者依从性较低。Abzyme Therapeutics LLC提议开发一种新的治疗方法,用于自我给药的无创局部递送,以抑制视网膜和脉络膜中的异常血管生成。用于AMD治疗的抗新生血管治疗将被设计为克服视网膜和脉络膜障碍,使治疗可以以滴眼液的形式提供。主动抗血管生成疗法将通过转铁蛋白受体(TfR)介导的经细胞作用和经角膜运输到达玻璃体中的VEGF靶点。在第一阶段,将生产人类单域高亲和力抗VEGF中和纳米体和对TfR低亲和力和对VEGF高亲和力的双特异性VEGF/TfR纳米体。在接受局部滴眼液的小鼠模型中,纳米体在玻璃体和视网膜中的积累将被确定。在II期,转铁蛋白受体介导的抗vegf疗法的抗新生血管活性将在动物AMD模型中进行表征和验证,以寻求IND应用。
英文摘要
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.
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