Immunotherapy for Ocular Surface Diseases

摘要 我们发现了眼表发炎的新机制。首先，我们 发现干眼症患者眼表面存在中性粒细胞外陷阱(Net) 疾病(DED)患者和随后，瓜氨酸蛋白和抗- 瓜氨酸蛋白抗体(ACPA)。ACPAs不仅会导致眼表疾病，还会 刺激Net的形成，从而造成慢性炎症的自我延续循环 眼表。我们提出了一个创新的病理生理学概念：DED具有 通过产生自身抗体来破坏自身对瓜氨酸抗原的耐受性 (ACPA)和NETs可能代表为ACPA提供燃料的瓜氨酸抗原的来源 眼表上的自身免疫反应。我们进行了首例人类飞行员临床试验。 并显示，眼表免疫球蛋白(OSIG)滴眼液，由混合 人免疫球蛋白制品(IVIG)治疗DED安全有效。我们的 这些发现改变了目前以T细胞介导的炎症为中心的范式 DED的病理生理学也包括由后遗症驱动的自身免疫性炎症 自身蛋白(瓜氨酸化)和自身抗体(ACPA)的翻译修饰。这个 此R24应用程序的目的是产生支持商业应用的临床前数据 向美国食品和药物管理局(FDA)提交的研究性新药(IND)申请。这个 较长期的目标是在临床试验中测试OSIG滴眼液的疗效并定位OSIG 滴眼液作为DED患者新的局部生物免疫疗法。因此，在目标A中，我们 寻求利用设计质量(QBD)原则开发OSIG滴眼液的最佳配方， 测试关键质量属性(CQA)和GMP生产临床用品。为了使用OSIG 在人类的眼科配方中，FDA的IND是先决条件，因此，在目标B中，我们建议 使用OSIG进行临床前、体外和体内毒理学和疗效研究 眼科配方，以满足IND研究的法规要求。在目标C中，我们建议 进行临床研究以确定DED亚型、临床表现和患者特征 与ACPA或NETs最相关的，因此最有可能显示出治疗益处的 OSIG疗法。为了成功实现这三个目标，我们建立了一支高素质的， 在眼科药物开发和FDA流程方面经验丰富的多学科团队 和规定。如果这项拨款建议的目标成功实现，我们将迈出一步 更接近于将首个针对眼表疾病的免疫疗法引入临床实践。

ABSTRACT We have discovered a new mechanism for inflammation on the ocular surface. First, we discovered the presence of neutrophil extracellular traps (NETs) on the ocular surface of dry eye disease (DED) patients and subsequently, the presence of citrullinated proteins and anti- citrullinated protein antibodies (ACPAs). ACPAs not only cause ocular surface disease, but also stimulate formation of NETs, thus creating a self-perpetuating cycle of chronic inflammation on the ocular surface. We present an innovative pathophysiological concept: DED is characterized by breach of self-tolerance towards citrullinated antigens with generation of autoantibodies (ACPAs) and NETs could represent a source of citrullinated antigens fueling the ACPA autoimmune response over the ocular surface. We performed a first-in-human pilot clinical trial and showed that ocular surface immune globulin (OSIG) eye drops, formulated from pooled human immune globulin products (IVIG), were safe and efficacious in treating DED patients. Our findings shift the current paradigm that focuses on T-cell mediated inflammation as central to the pathophysiology of DED to also include autoimmune inflammation that is driven by post- translational modifications in self-proteins (citrullination) and autoantibodies (ACPAs). The purpose of this R24 application is to produce preclinical data that supports a commercial Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA). The longer-term goal is for testing the efficacy of OSIG eye drops in clinical trials and positioning OSIG eye drops as a new topical biologic immunotherapy for DED patients. Therefore, in Aim A, we seek to develop an optimum OSIG eye drop formulation using Quality by Design (QbD) principles, test critical quality attributes (CQAs) and GMP manufacture clinical supplies. In order to use OSIG ophthalmic formulation in human, an FDA IND is a prerequisite, therefore, in Aim B, we propose to perform pre-clinical in vitro and in vivo toxicology and efficacy studies using the OSIG ophthalmic formulation to meet regulatory requirements for IND studies. In Aim C, we propose to perform a clinical study to identify DED subtypes, clinical presentations and patient characteristics that are most associated with ACPAs or NETs, hence most likely to show therapeutic benefit with OSIG therapy. To successfully achieve these three Aims, we have established a highly qualified, multi-disciplinary team that is experienced in ophthalmic drug development, and FDA processes and regulations. If the aims of this grant proposal are successfully achieved, we will be one-step closer to introducing the first immunotherapy for ocular surface diseases into clinical practice.