An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo.

人鼻病毒（human rhinoviruses, HRV）是引发绝大多数普通感冒以及哮喘、慢性阻塞性肺疾病（chronic obstructive pulmonary disease, COPD）急性加重的病原体。目前亟需有效的治疗手段，但尚无获批的治疗药物或疫苗上市。在已鉴定的100种血清型中，约90%以人细胞间黏附分子-1（human intercellular adhesion molecule-1, ICAM-1）的结构域1作为细胞受体，这使得该结构域成为治疗开发的极具吸引力的靶点；然而，ICAM-1结构域1同时也是宿主防御以及主要通过其主要配体淋巴细胞功能相关抗原1（lymphocyte function-associated antigen-1, LFA-1）调控细胞迁移所必需的。本研究使用一株可特异性结合人ICAM-1结构域1的小鼠抗人ICAM-1抗体（14C11），证实经局部或全身给药的14C11可阻断两大主要鼻病毒群（HRV16与HRV14）的入侵，并在体内减轻细胞炎症、促炎细胞因子诱导反应与病毒载量。此外，在主要群鼻病毒诱导的哮喘急性加重模型中，14C11同样可减轻细胞炎症并降低Th2型细胞因子/趋化因子的产生。值得注意的是，14C11在体外并未阻断人ICAM-1/LFA-1相互介导的细胞黏附，这表明14C11所靶向的表位仅针对病毒入侵过程。综上，靶向人ICAM-1结构域1的抗体可在体内阻断主要群鼻病毒的入侵，并抑制气道炎症的诱导。