Development of a Fully Humanized Antibody for Treating Lung Emphysema

开发治疗肺气肿的全人源化抗体

• 批准号: 9409634
• 负责人: Matthias Clauss
• 金额: $ 71.51万
• 依托单位: ALLINAIRE 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: 2015-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409634
• 关键词: Affinity; Animals; Antibodies; Apoptosis; Automobile Driving; Bacteriophages; Binding; Biological Markers; Cause of Death; Cells; Cessation of life; Characteristics; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Clinical Data; Clinical Trials; Complement; Data; Development; Disease; Dose; Drug Exposure; Drug Kinetics; Elastases; Evaluation; Fund Raising; Funding; Generations; Genetic; Goals; Grant; Hereditary Disease; Human; Individual; Infiltration; Inflammation; Kinetics; Lead; Libraries; Link; Lung; Lung Inflammation; Lung diseases; Measures; Medical; Medicine; Modeling; Monoclonal Antibodies; Morphology; Mus; Nature; Orphan; Outcome; Pathology; Patients; Pharmacologic Substance; Phase; Play; Population; Production; Property; Proteins; Pulmonary Emphysema; Quality of life; Rare Diseases; Rattus; Research; Role; Route; Sampling; Schedule; Serum; Severities; Severity of illness; Small Business Innovation Research Grant; Solubility; Structure of parenchyma of lung; Surface Plasmon Resonance; System; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic Uses; Validation; Variant; Work; alpha 1-Antitrypsin Deficiency; alveolar destruction; cigarette smoke-induced; cigarette smoking; clinical candidate; clinical development; clinical effect; clinically relevant; commercialization; cost; cost efficient; cytokine; environmental tobacco smoke exposure; humanized antibody; humanized monoclonal antibodies; in vivo; innovation; macrophage; monocyte; mouse model; nanomolar; new therapeutic target; overexpression; pre-clinical; prevent; product development; pulmonary function; response; smoking cessation; stable cell line; subcutaneous; therapeutic effectiveness; therapeutic evaluation; tool

Project Summary COPD is a common and serious disease with no cure that is characterized by chronic, progressive lung damage, a decline in pulmonary function and quality of life, and often death. The two major clinical features of COPD are emphysema and chronic bronchitis. COPD is mainly associated with exposure to cigarette smoke (CS), however, about 3% of COPD patients have a genetic deficiency of alpha-1 antitrypsin (AATD). AATD patients represent an orphan disease population for which emphysema is the primary cause of death, and is a relatively homogenous group with a more efficient and less costly clinical development path compared to the broad COPD population. Allinaire Therapeutics, LLC, has demonstrated that EMAP II (endothelial monocyte-activating protein) is a novel therapeutic target for emphysematous COPD that plays a central role in driving the underlying pathology of the disease, including lung inflammation and alveolar destruction. EMAP II levels in the lungs of patients positively correlate with the severity of COPD and remain elevated even after smoking cessation. Furthermore, lung-specific overexpression of EMAP II induces emphysematous changes in mice, and a tool rat antibody to EMAP II (M7/1) blocks the progression of chronic CS-induced lung emphysema in mice. Work supported by the phase 1 SBIR grant resulted in the synthesis of fully humanized versions of the rat M7/1 mAb. Several leads were identified with appropriate potency and developability properties to be considered for optimization. In addition, preliminary data presented in the application demonstrates that treatment with one of the humanized EMAP II mAbs prevented lung macrophage infiltration in a sub-chronic (4 week) CS-exposure model. The specific aims of this Phase II research plan are: Aim 1. Selection of an optimized, high-affinity EMAP II mAb development candidate. The most potent of the 4 current leads will be identified (by SPR) and used to perform lead optimization, affinity maturation, and stable cell line development to produce a clinical candidate with sub-nanomolar affinity and suitable manufacturability properties; Aim. 2 In vivo testing of the lead mAb in a chronic CS-exposure model of emphysema in mouse. The dose-response effects of the clinical development candidate mAb will be tested in a model of chronic CS exposure to confirm a reduction in emphysema endpoints. The mAb will be administered therapeutically via the clinically relevant subcutaneous route; Aim 3. Target validation for EMAP II in AATD patient samples, mouse elastase model, and human lung cells. Serum EMAP II will be measured in individuals with COPD of different severities with or without AATD to determine the correlation between EMAP II and disease severity. Further target validation of EMAP II in the context of AATD will be determined by testing the effects of the mAb in the mouse model of elastase- induced emphysema and human lung cells. Completion of the Phase II milestones will provide Allinaire with a strong pre-clinical data package to enable either partnering of the project with a Pharmaceutical company or additional fund-raising to support progression of the project to manufacturing and IND-enabling studies, as critical steps towards clinical trials with an EMAP II mAb in AATD patients initially, and subsequently in the broader COPD population with emphysema.

项目摘要 COPD是一种常见的严重疾病，无法治愈，其特征是慢性进行性肺损伤， 肺功能和生活质量下降，经常死亡。COPD的两个主要临床特征是 肺气肿和慢性支气管炎。COPD主要与暴露于香烟烟雾（CS）有关，然而， 约3%的COPD患者具有α-1抗胰蛋白酶（AATD）的遗传缺陷。AATD患者 一个孤儿疾病人群，肺气肿是主要死亡原因， 与广泛的COPD相比，同质组具有更有效和成本更低的临床开发路径 人口Allinaire Therapeutics，LLC已经证明EMAP II（内皮单核细胞活化 蛋白）是肺气肿性COPD的一种新的治疗靶点，在驱动潜在的 疾病的病理学，包括肺部炎症和肺泡破坏。EMAP II在肺中的水平 患者的吸烟量与COPD的严重程度呈正相关，即使在戒烟后仍保持升高。 此外，肺特异性EMAP II过表达诱导小鼠肺气肿变化，工具大鼠 EMAP II抗体（M7/1）阻断小鼠中慢性CS诱导的肺气肿的进展。工作 在1期SBIR资助的支持下，合成了大鼠M7/1 mAb的完全人源化版本。 确定了几种具有适当效价和可开发性的先导化合物， 优化.此外，本申请中提供的初步数据表明， 人源化EMAP II mAb在亚慢性（4周）CS暴露中防止肺巨噬细胞浸润 模型第二阶段研究计划的具体目标是：目标1。选择一种优化的、高亲和力的 EMAP II mAb开发候选物。将识别4种当前电极导线中最有效的电极导线（通过SPR）， 用于进行先导物优化、亲和力成熟和稳定细胞系开发，以产生临床 具有亚纳摩尔亲和力和合适的可制造性特性的候选物;目的。2体内试验 在小鼠肺气肿慢性CS暴露模型中的先导mAb。的剂量反应效应。 临床开发候选mAb将在慢性CS暴露模型中进行检测，以确认 肺气肿终点。mAb将通过临床相关的皮下给药进行治疗。 路线;目标3. EMAP II在AATD患者样本、小鼠弹性蛋白酶模型和人中的靶点验证 肺细胞将在患有不同严重程度的COPD的个体中测量血清EMAP II， AATD，以确定EMAP II和疾病严重程度之间的相关性。EMAP II的进一步目标验证 将通过测试mAb在弹性蛋白酶的小鼠模型中的作用来确定在AATD的情况下的抗肿瘤活性。 诱发肺气肿和人类肺细胞。第二阶段里程碑的完成将为Allinaire提供 强大的临床前数据包，使项目与制药公司合作， 额外的资金筹集，以支持该项目向制造和IND赋能研究的进展， EMAP II mAb最初在AATD患者中进行临床试验，随后在更广泛的 COPD肺气肿人群。