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（由申请人提供）：肺气肿是一种流行的慢性阻塞性肺疾病（COPD），主要由吸烟引起，定义为慢性支气管炎（气道）和肺气肿的结合，其特征是肺泡肺结构细胞的过度细胞凋亡和慢性炎症。由于肺泡结构对于肺中的气体交换是必不可少的，因此肺气肿中该组织成分的损失会显著影响生活质量和健康。目前的COPD治疗主要针对气道，并且没有治疗可用于停止实质肺组织的损失。EmphyMAb的创始人发现，促凋亡和单核细胞刺激细胞因子内皮单核细胞激活蛋白（EMAPPI）在当前吸烟者和既往吸烟的COPD患者的人支气管肺泡灌洗液中上调。通过将小鼠暴露于香烟烟雾（CS）可以实验性地诱导小鼠肺中EMAPII水平的提高;此外，EMAPII的肺特异性转基因过表达导致小鼠肺中的肺气肿病理。疾病病理学和EMAPII水平之间的强相关性表明调节这种细胞因子的水平可能是肺气肿中有用的治疗干预。为此，EmphMAb团队开发了一种EMAPII特异性中和大鼠单克隆抗体（mAB），当同时或长期暴露于CS后给药时，该抗体可消除CS诱导的小鼠肺气肿的功能和形态学表现。该团队成功地产生了一种部分人源化的嵌合抗体，与亲本抗体相比，其亲和力和活性仅略低。在该I期申请中，EmphyMAb及其印第安纳州大学的合作伙伴计划完全人源化并增加MAb的亲和力，并确定其生物活性和亲和力 这种重组抗体的性能优于或至少相当于原始单克隆抗体。这里提出的研究，将是未来建立一个高度具体的完全人性化的目标的基础。 EMAP II mAB用于人类COPD患者，作为阻止允许肺组织进行性气体交换损失的首次治疗。