Development of a Fully Humanized Antibody for Treating Lung Emphysema

项目摘要 慢性阻塞性肺疾病是一种常见而严重的疾病，无法治愈，其特征是慢性进行性肺损伤， 肺功能下降和生活质量下降，通常是死亡。慢性阻塞性肺疾病的两个主要临床特征是 肺气肿和慢性支气管炎。慢性阻塞性肺病主要与吸烟(CS)有关，然而， 大约3%的COPD患者存在α-1抗胰蛋白酶(AATD)的遗传缺陷。AATD患者代表 肺气肿是导致死亡的主要原因的孤儿疾病人群，是一种相对 与广泛的COPD相比，同质组具有更有效和更低成本的临床开发路径 人口。Allinaire Treateutics，LLC已经证明EMAP II(内皮单核细胞激活 蛋白质)是治疗肺气肿COPD的新靶点，它在推动潜在的 本病的病理表现包括肺部炎症和肺泡破坏。EMAP II在小鼠肺组织中的水平 患者与COPD的严重程度呈正相关，即使在戒烟后仍保持升高。 此外，肺组织特异性过表达EMAP II可诱导小鼠肺气肿的改变，并且工具大鼠 抗EMAP II抗体(M7/1)可阻断CS诱导的小鼠慢性肺气肿的进展。工作 在第一阶段SBIR的支持下，赠款导致合成了大鼠M7/1单抗的完全人源化版本。 几个铅被确定为具有适当的潜力和可开发性属性，以供考虑 优化。此外，申请书中提供的初步数据表明，使用以下一种方法进行治疗 人源化EMAP II单抗预防亚慢性(4周)CS暴露后肺巨噬细胞的浸润 模特。本二期研究计划的具体目标是：目标1.选择优化的、高亲和力的 EMAP II单抗开发候选。将确定4个电流导联中最有效的(通过SPR)和 用于进行先导优化、亲和力成熟和稳定的细胞系开发，以产生临床 具有亚纳摩尔亲和力和合适的可制造性的候选者；目标。2小鼠的体内试验 铅单抗在慢性CS暴露小鼠肺气肿模型中的作用的剂量-反应效应 临床开发候选单抗将在慢性CS暴露模型中进行测试，以确认减少 肺气肿终点。单抗将通过临床相关的皮下注射进行治疗。 在AATD患者样本、小鼠弹性蛋白酶模型和人类中对EMAP II的靶向验证 肺细胞。对不同严重程度的慢性阻塞性肺疾病患者进行血清EMAP II检测 AATD以确定EMAP II与疾病严重程度的相关性。EMAP II的进一步目标验证 在AATD的背景下，将通过测试mAb在弹性蛋白酶小鼠模型中的作用来确定- 诱发肺气肿和人肺细胞。第二阶段里程碑的完成将为Allinaire提供 强大的临床前数据包以支持与制药公司的项目合作或 额外筹资，以支持项目向制造业和支持工业的研究的进展，这是至关重要的 最初在AATD患者中使用EMAP II单抗进行临床试验的步骤，随后在更广泛的范围内进行 患有肺气肿的慢性阻塞性肺病患者。

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.