GMP manufacturing and IND Filing of IN-002, a potent inhaled muco-trapping antibody therapy for Respiratory Syncytial Virus

标题：IN-002的GMP制造和IND申报，一种有效的吸入性“粘液捕获”抗体疗法 呼吸道合胞病毒 项目总结(限行30行) 呼吸道合胞病毒(RSV)是婴幼儿病毒性住院和死亡的主要原因 对儿童和儿童来说，也是免疫功能受损的成年人和老年人呼吸道疾病的主要原因。 不幸的是，目前有有效的治疗方法可以防止RSV住院。为数百万受感染的人 在美国，RSV每年都会出现，除了症状管理之外，没有其他治疗选择。 像许多呼吸道病原体一样，RSV通过从受感染的儿童身上脱落病毒粒子在肺部传播 细胞被排入呼吸道。从那里，呼吸道合胞病毒必须穿过呼吸道粘液(AM)之前 感染其他邻近细胞，仅限于呼吸道，很少或根本没有全身性病毒血症。这 重要的传播机制使RSV难以通过系统剂量的治疗来靶向；抗病毒药物 药物需要进入呼吸道粘液，以灭活病毒粒子，阻止感染。我们相信 一种针对RSV的安全有效的抗病毒疗法，可通过以下方式直接吸入呼吸道 在家里使用手持设备将提供一个强大的治疗选择。 为了实现这一目标，Inhalon正在推进IN-002，一种能与RSV F蛋白结合并中和RSV F蛋白的单抗 皮摩尔结合亲和力和中和效力，并具有最小的病毒逃逸风险。重要的是，在 除了公认的免疫球蛋白Fc效应器功能外，IN-002还被设计为具有Fc N-糖链 针对捕获AM中的RSV进行了优化一旦被困住，RSV病毒粒子就会通过天然的 粘液纤毛清除机制。我们进一步配制了IN-002，可以使用便携式喷雾器稳定地雾化 振动网状雾化器。通过将IN-002直接输送到感染部位(呼吸道)，我们希望 用较低剂量的单抗达到较高的药物浓度，节省成本，并有可能提高疗效。在……里面 雾化吸入IN-002降低呼吸道合胞病毒病毒载量的新生羔羊呼吸道合胞病毒感染模型 和BALF几乎检测不到的水平，与安慰剂治疗的动物不同。Inhalon是第一家 成功完成吸入性单抗疗法(IN-006)治疗CoVID的第一阶段研究，取得了非常高的成就 呼吸道中的药物水平，具有极好的安全性。Inhalon已收到FDA对其Pre-IND的反馈 提交IN-002，目前正在完成IN-002的启用IND的临床前活动，包括GLP 吸入毒物、GLP组织交叉反应和GLP雾化特性。此外，Inhalon已经 建立了一个符合GMP的主细胞库，用于生产IN-002，并由此扩大了毒素的生产 材料已经生成。在这里，我们正在寻求支持以完成：(I)生产、包装 和根据GMP(目标1)生产的IN-002临床试验材料的特征，和(Ii)IND提交给 获得批准启动第一阶段临床研究(目标2)。圆满完成拟议活动 将使我们的IN-002进入人类研究的第一阶段。

Title: GMP manufacturing and IND Filing of IN-002, a potent inhaled “muco-trapping” antibody therapy for Respiratory Syncytial Virus Project Summary (30 line limit) Respiratory Syncytial Virus (RSV) is the leading cause of viral hospitalization and 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 effective therapy that can prevent RSV-hospitalization. For the millions infected with RSV in the U.S. every year, there is no treatment option available aside from symptom-management. Like many respiratory pathogens, RSV spreads in the lungs by shedding daughter virions from infected cells exclusively back into the airways. From there, RSV must traverse the airway mucus (AM) before infecting other neighboring cells, remaining restricted to the airways with little-to-no systemic viremia. This important mechanism of spread makes RSV difficult to target by systemically dosed therapies; the antiviral drugs need to make their way to the airway mucus in order to inactivate virions and halt infection. We believe an RSV-specific, safe, and effective antiviral therapy that can be inhaled directly into the respiratory tract using a hand-held device at home would provide a powerful treatment option. To meet this goal, Inhalon is advancing IN-002, a mAb that binds and neutralizes RSV F protein with picomolar binding affinity and neutralization potency, and has minimal risks of viral escape. Importantly, in addition to the well-established IgG Fc effector functions, IN-002 is also engineered to possess Fc N-glycans optimized to trap RSV in AM. Once trapped, RSV virions are quickly purged from the airways via natural mucociliary clearance mechanisms. We have further formulated IN-002 to be stably nebulized using a portable vibrating mesh nebulizer. By delivering IN-002 directly to the site of infection (the airways), we expect to achieve high drug concentrations with a lower dose of mAb, saving costs and potentially improving efficacy. In a neonatal lamb model of RSV infection, nebulized therapy with IN-002 reduced RSV viral load in the lungs and BALF to almost non-detectible levels, unlike placebo-treated animals. Inhalon is the first company to successfully complete a Phase 1 study for an inhaled mAb therapy (IN-006) for COVID, achieving very high levels of drug in the airways with an excellent safety profile. Inhalon has received FDA feedback on its pre-IND submission for IN-002, and is currently completing IND-enabling preclinical activities for IN-002, including GLP inhalation tox, GLP tissue cross reactivity, and GLP nebulization characterization. Further, Inhalon has already established a GMP-compliant master cell bank for production of IN-002, from which scaled up production of tox materials have already been generated. Here, we are seeking support to complete: (i) the production, vialing and characterization of IN-002 clinical trial materials produced under GMP (Aim 1), and (ii) IND submission to receive approval to initiate Phase 1 clinical studies (Aim 2). Successful completion of the proposed activities would allow us to advance IN-002 into first-in-human studies.