Antibody-hyaluronic acid bioconjugates for localized treatment of chronic non-infectious uveitis

抗体-透明质酸生物缀合物用于局部治疗慢性非感染性葡萄膜炎

基本信息

批准号：
10259316
负责人：
Wesley Michael Jackson
金额：
$ 29.93万
依托单位：
VALITOR, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10259316
关键词：
Acute Adrenal Cortex Hormones Adverse effects Adverse event Affect Affective Affinity Aftercare American Anti-Inflammatory Agents Antibodies Antiinflammatory Effect Apoptosis Autoimmune Binding Biological Biological Assay Biological Response Modifier Therapy Biopolymers Biotechnology Blindness Cells Characteristics Chronic Clinical Data Development Dexamethasone Disease Dose Endotoxins Event Exhibits Experimental Models Eye Eye diseases Flare Formulation Frequencies Histopathology Hyaluronic Acid Immune Immune response Implant Infection Inflammation Inflammatory Inflammatory Response Lead Legal patent Long-Term Effects Measures Metabolic Clearance Rate Modeling Molecular Weight Optic Nerve Optics Oryctolagus cuniculus Output Patients Performance Pharmaceutical Preparations Phase Polymers Pre-Clinical Model Privatization Proteins Rattus Retina Risk Safety Small Business Innovation Research Grant Steroids Systemic Therapy TNF gene Technology Testing Therapeutic Therapeutic Effect Time Tissues Uveitis Vertebral column Vision adalimumab base clinical risk cost cytokine design effective therapy efficacy outcomes improved intravitreal injection macromolecule meetings nerve damage novel off-label use pharmacokinetic model residence scaffold side effect treatment duration treatment effect treatment strategy tumor necrosis factor-alpha inhibitor uveoretinitis

项目摘要

Project Summary Uveitis is a group of diseases characterized by sight-threatening intraocular inflammation and responsible for roughly 5-10% of blindness cases worldwide. Uveitis flare-ups can be caused by either an active infection or, in in the case of non-infectious uveitis (NIU), a dysregulated immune response including altered cytokine expression and processing. Thus, there is an urgent and unmet need for more effective treatments. The standard first line therapies for chronic NIU are corticosteroids delivered either topically, systemically, or locally through intravitreal injections or implants. However, long-term use of these treatments is associated with serious side effects. Alternative anti-inflammatory therapeutics are often used to minimize these side-effects and inhibition of the pro-inflammatory cytokine, TNFα has become a key approach. Systemic delivery of TNFα inhibitors is effective but costly and carries a risk of side-effects from long-term use. Valitor, Inc. is developing protein-polymer therapeutics to overcome the vision-threatening effects of chronic ocular inflammation with substantially fewer systemic side effects by enabling intravitreal delivery of a biologic anti-TNFα therapy. We have conjugated single-domain anti-TNFα antibodies (VHH) to linear chains of the natural biopolymer hyaluronic acid to generate multivalent anti-TNFα conjugates (Anti-TNFα MVP) that are substantially larger than any other drugs currently delivered by intravitreal injection. In our previous studies, we verified that the large sizes of our MVPs are sufficient to substantially reduce their clearance rate out of the vitreous, thereby providing a sustained treatment effect to inhibit intraocular TNFα. Thus, our strategy for sustained anti-TNFα therapy has the potential to improve the long-term efficacy, safety, and cost efficacy of anti-TNFα treatment. The overall objective of this Phase I SBIR project is to verify that our Anti-TNFα MVPs exhibit a rapid onset and durable anti-inflammatory treatment for chronic non-infections uveitis. In Specific Aim #1, we will evaluate the ability of an Anti-TNFα MVP to generate a rapid anti-inflammatory response compared to that of a corticosteroid. In Specific Aim #2, we will verify the anti-inflammatory durability of our Anti-TNFα MVP to that of a clinically available TNFα inhibitor. The results of this project will be used to continue the development of our Anti-TNFα MVP drug product and contribute to a productive pre-IND meeting to confirm the additional testing that required for our IND submission.

项目概要葡萄膜炎是一组以威胁视力的眼内炎症为特征的疾病，导致全球大约 5-10% 的葡萄膜炎发作可能是由活动性感染或葡萄膜炎引起的。对于非感染性葡萄膜炎 (NIU)，免疫反应失调，包括细胞因子改变因此，迫切需要更有效的治疗方法。慢性 NIU 的标准一线疗法是局部、全身或局部给予皮质类固醇然而，长期使用这些治疗方法与玻璃体内注射或植入有关。通常使用替代抗炎疗法来尽量减少这些副作用。抑制促炎细胞因子 TNFα 已成为 TNFα 的全身递送的关键方法。 Valitor, Inc. 正在开发抑制剂，虽然有效，但价格昂贵，并且存在长期使用产生副作用的风险。蛋白质聚合物疗法可克服慢性眼部炎症对视力的威胁通过玻璃体内递送生物抗 TNFα 疗法，显着减少全身副作用。将单域抗 TNFα 抗体 (VHH) 缀合至天然生物聚合物的线性链上透明质酸生成更大的多价抗 TNFα 缀合物（抗 TNFα MVP）在我们之前的研究中，我们证实了与目前通过玻璃体内注射输送的任何其他药物相比。我们的 MVP 的大尺寸足以大幅降低其从玻璃体中的清除率，从而提供抑制眼内 TNFα 的持续治疗效果，因此，我们的持续抗 TNFα 策略。疗法有可能提高抗 TNFα 治疗的长期疗效、安全性和成本效益。该 I 期 SBIR 项目的总体目标是验证我们的抗 TNFα MVP 是否表现出快速起效在具体目标#1中，我们将评估慢性非感染性葡萄膜炎的持久抗炎治疗。与抗 TNFα MVP 相比，抗 TNFα MVP 产生快速抗炎反应的能力在具体目标 #2 中，我们将验证抗 TNFα MVP 的抗炎持久性。临床可用的 TNFα 抑制剂该项目的结果将用于继续我们的开发。抗 TNFα MVP 药物产品，并为富有成效的 IND 前会议做出贡献，以确认额外的测试我们提交 IND 所需的信息。