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: 9432704
• 负责人: Matthias Clauss
• 金额: $ 5.2万
• 依托单位: ALLINAIRE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-20 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9432704
• 关键词: Development; Fully; Humanized; Antibody; Treating

 DESCRIPTION (provided by applicant): Emphysema is a prevalent chronic obstructive pulmonary disease (COPD) induced predominantly by cigarette smoking is defined as the combination of chronic bronchitis (in the airways) and emphysema, which characterized by excessive cell apoptotic cell death of alveolar lung structural cells and chronic inflammation. Because alveolar structures are essential for gas exchange in the lungs, loss of this tissue component in emphysema affects life quality and health dramatically. Current COPD therapy targets mainly the airways, and no treatment is available for halting loss of parenchymal lung tissue. The founders of EmphyMAb have made the discovery that pro-apoptotic and monocyte stimulating cytokine endothelial monocyte activating protein (EMAPPI) is upregulated in the human bronchoalveolar lavage of current-smokers and of COPD patients who were ex-smokers. Enhanced levels of EMAPII in the murine lung can be experimentally induced by exposing mice to cigarette smoke (CS); furthermore, lung-specific transgenic overexpression of EMAPII causes emphysematous pathology in mouse lung. The strong correlation between disease pathology and EMAPII levels suggested modulating levels of this cytokine might be a useful therapeutic intervention in emphysema. To this end, the EmphMAb team developed an EMAPII specific neutralizing rat monoclonal antibody (mAB), which abrogated functional and morphometric manifestations of CS-induced emphysema in mice when administered either concomitantly or after prolonged CS exposure. The team succeeded in generation of a partially humanized chimeric antibody with only slightly less affinity and activity in comparison to the parental one. In this Phase I application, EmphyMAb and its partners at Indiana University plan to fully humanize and increase affinity of the MAb, and determine that the bioactivity and affinity of this recombinant antibody are better or at least equivalent to the original MAb. The studies proposed here, will be the basis for future goals of establishing a highly specific fully humanized EMAP II mAB for use in human COPD patients as a first treatment for halting the progressive loss of gas exchange permitting lung tissue.

 描述（由应用提供）：肺气肿是一种普遍的慢性阻塞性肺疾病（COPD），主要是由香烟吸烟引起的，定义为慢性支气管炎（在气道中）和肺气肿的组合，其特征在于过量的细胞凋亡细胞死亡的肺泡结构细胞和慢性注射。由于肺泡结构对于肺中的气体交换至关重要，因此肺气肿中这种组织成分的损失会极大地影响生活质量和健康。当前的COPD治疗主要针对气道，没有用于停止实质性肺组织丧失的治疗。 Emphymab的创始人已经发现，促凋亡和单核细胞刺激细胞因子内皮细胞单核细胞激活蛋白（EMAPPI）在人支气管肺泡灌洗中进行了更新，对当前烟民和前烟患者的COPD患者的支气管肺泡灌洗液进行了更新。可以通过将小鼠暴露于香烟烟雾（CS）来实验诱导鼠肺中的EMAPII水平增强。此外，EMAPII的肺特异性转基因过表达会导致小鼠肺中的杂质病理学。疾病病理学与EMAPII水平之间的强相关性表明调节这种细胞因子水平可能是肺气肿的一种有用的治疗干预措施。为此，Emphmab团队开发了EMAPII特异性中和大鼠单克隆抗体（MAB），当延长CS暴露后，当同时或同时给予CS诱导的小鼠中CS诱导的肺气肿的功能和形态学表现。该团队成功地生成了部分人源化的嵌合抗体，与父母相比，该抗体的亲和力和活动仅略有。在此I阶段应用中，Emphymab及其在印第安纳大学的合作伙伴计划完全人性化和增加MAB的亲和力，并确定生物活性和亲和力 这种重组抗体的更好或至少等同于原始mAb。这里提出的研究将是建立一个高度特定全人源化的未来目标的基础 EMAP II MAB用于人类COPD患者，用作停止逐渐损失的气体交换允许肺组织的治疗方法。