Minagawa Shunsuke, Lou Jianlong, Seed Robert I, Cormier Anthony, Wu Shenping, Cheng Yifan, Murray Lynne, Tsui Ping, Connor Jane, Herbst Ronald, Govaerts Cedric, Barker Tyren, Cambier Stephanie, Yanagisawa Haruhiko, Goodsell Amanda, Hashimoto Mitsuo, Brand Oliver J, Cheng Ran, Ma Royce, McKnelly Kate J, Wen Weihua, Hill Arthur, Jablons David, Wolters Paul, Kitamura Hideya, Araya Jun, Barczak Andrea J, Erle David J, Reichardt Louis F, Marks James D, Baron Jody L, Nishimura Stephen L
Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA.
Sci Transl Med. 2014 Jun 18;6(241):241ra79. doi: 10.1126/scitranslmed.3008074.
Airway remodeling, caused by inflammation and fibrosis, is a major component of chronic obstructive pulmonary disease (COPD) and currently has no effective treatment. Transforming growth factor-β (TGF-β) has been widely implicated in the pathogenesis of airway remodeling in COPD. TGF-β is expressed in a latent form that requires activation. The integrin αvβ8 (encoded by the itgb8 gene) is a receptor for latent TGF-β and is essential for its activation. Expression of integrin αvβ8 is increased in airway fibroblasts in COPD and thus is an attractive therapeutic target for the treatment of airway remodeling in COPD. We demonstrate that an engineered optimized antibody to human αvβ8 (B5) inhibited TGF-β activation in transgenic mice expressing only human and not mouse ITGB8. The B5 engineered antibody blocked fibroinflammatory responses induced by tobacco smoke, cytokines, and allergens by inhibiting TGF-β activation. To clarify the mechanism of action of B5, we used hydrodynamic, mutational, and electron microscopic methods to demonstrate that αvβ8 predominantly adopts a constitutively active, extended-closed headpiece conformation. Epitope mapping and functional characterization of B5 revealed an allosteric mechanism of action due to locking-in of a low-affinity αvβ8 conformation. Collectively, these data demonstrate a new model for integrin function and present a strategy to selectively target the TGF-β pathway to treat fibroinflammatory airway diseases.
由炎症和纤维化引起的气道重塑是慢性阻塞性肺疾病（COPD）的主要组成部分，目前尚无有效治疗方法。转化生长因子-β（TGF-β）在COPD气道重塑的发病机制中具有广泛影响。TGF-β以一种需要激活的潜伏形式表达。整合素αvβ8（由itgb8基因编码）是潜伏性TGF-β的受体，对其激活至关重要。在COPD患者的气道成纤维细胞中，整合素αvβ8的表达增加，因此是治疗COPD气道重塑的一个有吸引力的治疗靶点。我们证明，一种针对人αvβ8的工程优化抗体（B5）在仅表达人而非小鼠ITGB8的转基因小鼠中抑制了TGF-β的激活。B5工程抗体通过抑制TGF-β的激活，阻断了由烟草烟雾、细胞因子和过敏原诱导的纤维炎症反应。为了阐明B5的作用机制，我们使用了流体动力学、突变和电子显微镜方法来证明αvβ8主要采用一种组成型激活的、延伸闭合的头部构象。B5的表位作图和功能表征揭示了一种由于锁定低亲和力αvβ8构象而产生的变构作用机制。总的来说，这些数据证明了整合素功能的新模型，并提出了一种选择性靶向TGF-β途径以治疗纤维炎症性气道疾病的策略。
