IND-enabling development for IN-002, an inhaled muco-trapping mAb against respiratory syncytial virus

项目摘要 呼吸道合胞病毒（RSV）是婴幼儿病毒性死亡的主要原因， 也是免疫受损的成人和老年人呼吸道疾病的主要原因。不幸的是 目前没有疫苗或有效的治疗可用于RSV。Synagis，每月肌肉注射 单克隆抗体（mAb）帕利珠单抗是唯一FDA批准的干预，但只能用于 这是一种预防措施，只针对极少数高危婴儿。Synagis治疗RSV无效 感染开始后。因此，对于数万名因RSV住院的患者，仅支持性治疗是有效的。 可用;由此产生的发病率和死亡率很高，特别是在免疫功能低下的人群中。 有趣的是，RSV在肺中通过将病毒排到气道中而传播;因此，RSV必须 在感染其他邻近细胞之前穿过气道粘液（AM），并保持局限于气道 几乎没有系统性病毒血症这种独特的病理生理学使得RSV难以通过全身性靶向给药， 剂量疗法我们认为，一种可以直接吸入的RSV特异性、安全有效的抗病毒治疗方法， 进入呼吸道将提供一个强大的选择，解决目前的差距，药理学 干预措施。为了实现这一目标，Inhalon一直在推进IN-002，使用其专有技术和 专利的“粘膜捕获”mAb技术平台。IN-002是一种强效抗F mAb，具有皮摩尔结合 具有亲和力和中和效力，具有最小的病毒逃逸风险，并且具有合适的Fc N-糖基化， 在AM中捕获RSV。反过来，捕获的RSV通过天然的粘膜纤毛从气道中迅速清除， 清除机制。我们进一步配制了IN-002，以使用振动筛稳定雾化 喷雾器通过将IN-002直接浓缩在感染部位，而不是全身递送mAb， 我们期望能够实现有效和具有成本效益的RSV治疗，而由于 限制了肺部递送的全身吸收。在RSV感染的新生羔羊模型中，每日 即使在肺中接近峰值病毒滴度时开始IN-002的雾化治疗也能够降低感染性 肺和BALF中的RSV病毒载量在3天内降至几乎不可检测的水平。Inhalon目前正在积极 从事IN-002的细胞系开发。为了能够快速转化为临床，我们寻求完成 细胞系开发，并生产适合IND使能活动的毒性材料， 组织交叉反应性研究、GLP肺毒性研究和GLP雾化表征研究。 总之，拟议的工作将支持IN-002快速进入临床试验。我们在这里的工作 RSV还将有助于为改善其他呼吸道疾病的分子靶向吸入疗法铺平道路。 病原体

Project Summary Respiratory Syncytial Virus (RSV) is the leading cause of viral death in infants and young children, and is also a major cause of respiratory illness in immune compromised adults and the elderly. Unfortunately, there is currently no vaccine or effective therapy available for RSV. Synagis, a monthly intramuscular injection of the monoclonal antibody (mAb) palivizumab, is the only FDA-approved intervention, but can only be used for prevention and is given only to a very small subset of high-risk infants. Synagis is not effective at treating RSV after infection has begun. Thus, for the tens of thousands hospitalized with RSV, only supportive therapy is available; the resulting morbidity and mortality are substantial, particularly among the immunocompromised. Interestingly, RSV spreads in the lung via shedding of virus exclusively into the airway; thus, RSV must traverse the airway mucus (AM) before infecting other neighboring cells, and remains restricted to the airways with little-to-no systemic viremia. This unique pathophysiology makes RSV difficult to target by systemically dosed therapies. We believe an RSV-specific, safe and effective antiviral therapy that can be inhaled directly into the respiratory tract would provide a powerful option addressing the current gap in pharmacological interventions. To meet this goal, Inhalon has been advancing IN-002, developed using its proprietary and patented “muco-trapping” mAb technology platform. IN-002 is a potent anti-F mAb with picomolar binding affinity and neutralization potency, has minimal risk of viral escape, and possess suitable Fc N-glycosylation for trapping RSV in AM. In turn, trapped RSV are quickly purged from the airways via natural mucociliary clearance mechanisms. We have further formulated IN-002 to be stably nebulized using a vibrating mesh nebulizer. By concentrating IN-002 directly at the site of infection, rather than delivering the mAb systemically, we expect to enable efficacious and cost-effective treatment of RSV, with little risk of adverse side effects due to limited systemic adsorption from pulmonary delivery. In a neonatal lamb model of RSV infection, daily nebulized therapy with IN-002 initiated even at near peak viral titers in the lung was able to reduce infectious RSV viral load in the lungs and BALF to almost non-detectible levels within 3 days. Inhalon is currently actively engaging in cell line development for IN-002. To enable rapid translation into the clinic, we seek to complete the cell line development in this proposal, and produce tox materials suitable for IND-enabling activities such as Tissue Cross Reactivity studies, GLP pulmonary tox studies, and GLP nebulization characterization studies. Together, the proposed work will support rapid advancement of IN-002 into clinical testing. Our work here with RSV will also help pave the way for improved, molecularly-targeted, inhaled therapies for other respiratory pathogens.