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

IN-002 的 GMP 生产和 IND 备案，这是一种针对呼吸道合胞病毒的有效吸入粘液捕获抗体疗法

• 批准号: 10761398
• 负责人: JEFF T HUTCHINS
• 金额: $ 99.98万
• 依托单位: INHALON BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761398
• 关键词: 2019-nCoV; Address; Adult; Affinity; Age; Animal Model; Animals; Antibody Therapy; Antiviral Agents; Antiviral Therapy; Award; Back; Binding; Biological Assay; Blood; Bronchiolitis; COVID-19 treatment; Cell Line; Cells; Cessation of life; Child; Chinese Hamster Ovary Cell; Clinic; Clinical; Clinical Research; Clinical Trials; Cost Savings; Cyclic GMP; Data; Daughter; Dose; Early treatment; Elderly; Engineering; Epithelium; Fc domain; Feedback; Focal Infection; Formulation; Funding; Goals; Good Manufacturing Process; Home; Hospitalization; Human; Immune; Immunocompromised Host; Immunoglobulin G; Infant; Infection; Inhalation; Intervention; Intramuscular Injections; Lung; Monoclonal Antibodies; Monoclonal Antibody Therapy; Morbidity - disease rate; Mucins; Mucociliary Clearance; Mucous body substance; Nebulizer; Necrosis; Neonatal; Nose; Palivizumab; Pharmaceutical Preparations; Phase; Phase Ia Clinical Trial; Phase Ia Trial; Placebos; Pneumonia; Polysaccharides; Population; Production; Prophylactic treatment; Respiratory Syncytial Virus Infections; Respiratory System; Respiratory syncytial virus; Respiratory syncytial virus RSV F proteins; Risk Reduction; Running; SARS-CoV-2 antibody; Safety; Schedule; Serious Adverse Event; Site; Specimen; Structure of parenchyma of lung; Testing; Therapeutic; Tissues; Vial device; Viral; Viral Load result; Viremia; Virion; Virus; Work; cell bank; clinical development; clinical material; clinical translation; coronavirus disease; cost; cross reactivity; design; drug testing; effective therapy; experience; first-in-human; handheld equipment; healthy volunteer; human monoclonal antibodies; improved; lamb model; manufacture; manufacturing run; manufacturing scale-up; minimal risk; mortality; neutralizing monoclonal antibodies; phase 1 study; portability; pre-Investigational New Drug meeting; pre-clinical; premature; prevent; programs; respiratory; respiratory pathogen; safety assessment; symptom management; vibration; virtual

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.

标题：IN-002的GMP生产和IND备案，一种强效吸入“粘膜捕获”抗体疗法 呼吸道合胞病毒的 项目摘要（30行限制） 呼吸道合胞病毒（RSV）是导致婴幼儿住院和死亡的主要原因 它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，目前有有效的治疗方法可以防止RSV住院。为了数百万感染者 美国每年都会出现呼吸道合胞病毒（RSV），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通过从感染的病毒中脱落子病毒体在肺中传播。 细胞专门返回气道。从那里，RSV必须穿过气道粘液（AM），然后才能进入呼吸道。 感染其他邻近细胞，保持局限于呼吸道，几乎没有系统性病毒血症。这 一种重要的传播机制使得RSV难以通过全身给药治疗靶向;抗病毒药物 药物需要进入呼吸道粘液，以消灭病毒粒子并阻止感染。我们认为 一种RSV特异性、安全有效的抗病毒治疗，可直接吸入呼吸道， 在家中的手持设备将提供强大的治疗选择。 为了实现这一目标，Inhalon正在推进IN-002，这是一种结合并中和RSV F蛋白的mAb， 在一些实施方案中，该化合物具有皮摩尔结合亲和力和中和效力，并且具有最小的病毒逃逸风险。重要的是在 除了公认的IgG Fc效应子功能外，IN-002还被工程改造为具有Fc N-聚糖 优化以捕获AM中的RSV。一旦被捕获，RSV病毒粒子通过天然的呼吸道感染从气道中迅速清除。 粘液纤毛清除机制。我们进一步配制了IN-002，以便使用便携式雾化器稳定雾化 振动网孔雾化器。通过将IN-002直接递送至感染部位（气道），我们期望 以较低剂量的mAb实现高药物浓度，节省成本并可能提高疗效。在 RSV感染的新生羔羊模型，IN-002雾化治疗降低了肺中的RSV病毒载量 和BALF几乎不可检测的水平，不像安慰剂治疗的动物。Inhalon是第一家 成功完成了一项针对新型冠状病毒的吸入性mAb治疗（IN-006）的I期研究， 气道中的药物水平，具有良好的安全性。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IND使能临床前活动，包括GLP 吸入毒性、GLP组织交叉反应性和GLP雾化表征。此外，Inhalon已经 建立了符合GMP要求的主细胞库，用于生产IN-002，并由此扩大了毒素的生产 材料已经产生。在这里，我们寻求支持，以完成：（一）生产，装瓶 根据GMP（目标1）生产的IN-002临床试验材料的特性和（ii）IND提交给 获得批准启动1期临床研究（目标2）。圆满完成拟议活动 将使我们能够将IN-002推进到首次人体研究中。