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， 也是免疫功能低下的成年人和老年人患呼吸系统疾病的主要原因。不幸的是，有 目前还没有针对RSV的疫苗或有效疗法。Synagis，每月肌肉注射一次 单抗(MAb)palivizumab是FDA批准的唯一干预措施，但只能用于 预防，只适用于极少数高危婴儿。Synagis在治疗RSV方面无效 在感染开始后。因此，对于成千上万因呼吸道合胞病毒而住院的人来说，唯一的支持性治疗是 因此导致的发病率和死亡率很高，特别是在免疫功能受损的人群中。 有趣的是，呼吸道合胞病毒通过将病毒排入呼吸道而在肺部传播；因此，呼吸道合胞病毒必须 在感染其他邻近细胞之前穿过呼吸道粘液(AM)，并保持对呼吸道的限制 几乎没有全身性病毒血症。这种独特的病理生理机制使RSV很难系统地靶向 用药治疗。我们相信一种可以直接吸入的针对RSV的、安全有效的抗病毒疗法 进入呼吸道将提供一个强有力的选择，解决目前在药物方面的差距 干预措施。为了实现这一目标，Inhalon一直在推进IN-002，使用其专有和 获得专利的“粘液诱捕”单抗技术平台。IN-002是一种具有皮摩尔结合力的抗F单抗 亲和力和中和效力，病毒逃逸风险最小，并具有合适的Fc N-糖基化 在AM中捕获RSV反过来，捕获的呼吸道合胞病毒通过天然粘液纤毛迅速从呼吸道中排出。 许可机制。我们进一步配制了IN-002，以便使用振动筛稳定地雾化 雾化器。通过将IN-002直接集中在感染部位，而不是系统地传递mAb， 我们希望能够对RSV进行有效和成本效益高的治疗，并且几乎没有副作用的风险 从肺部给药到有限的全身吸收。在RSV感染的新生羔羊模型中，每天 即使在肺部病毒滴度接近高峰时也开始使用IN-002雾化治疗，能够减少感染性 肺和BALF中的RSV病毒载量在3天内几乎检测不到。因哈龙目前正在积极 从事IN-002细胞系开发工作。为了能够快速转化为临床，我们寻求完成 该提案中的细胞系开发，并生产适合于IND使能活动的毒素材料，如 作为组织交叉反应研究、GLP肺毒性研究和GLP雾化特性研究。 总之，拟议的工作将支持IN-002进入临床测试的快速发展。我们在这里的工作是 RSV还将有助于为改进的、分子靶向的、吸入性的其他呼吸道疗法铺平道路 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.