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制造和IND提交，这是一种潜在的遗传“粘液捕获”抗体疗法 用于呼吸综合病毒 项目摘要（30行限制） 呼吸综合病毒（RSV）是婴儿和年轻人的病毒住院和死亡的主要原因 儿童，也是免疫疾病的呼吸道疾病的主要原因。 不幸的是，目前有有效的疗法可以防止RSV院子里化。对于数百万感染了 每年在美国使用RSV，符号管理中没有可用的治疗选择。 像许多呼吸道病原体一样，RSV通过感染的女儿病毒在肺部传播 细胞专门回到气道。从那里开始，RSV必须在此之前穿越气道粘液（AM） 感染其他邻近细胞，仅限于无数全身性病毒性的气道。这 扩散的重要机制使RSV难以通过全身性剂量的疗法靶向；抗病毒 为了使病毒失活和停止感染，药物需要前往气道粘液。我们相信 RSV特异性，安全且有效的抗病毒疗法，可以直接纳入呼吸道 家里的手持设备将提供强大的治疗选择。 为了实现这一目标，Inhalon正在进步IN-002，一种mab，将RSV F蛋白结合和中和的mAb与 皮摩尔结合亲和力和神经刺激效力，并且病毒逃生的风险很小。重要的是，在 除了完善的IgG FC效应器功能外，IN-002还经过设计为具有FC N-Glycans 优化可在AM中捕获RSV。一旦被困，RSV病毒就会通过天然从气道迅速清除 粘毛清除机制。我们已经进一步配制了002，可以使用便携式 振动网状雾化器。通过将IN-002直接传递到感染部位（气道），我们希望 通过较低剂量的mAb实现高药物浓度，可节省成本并可能提高效率。在 RSV感染的新生儿羔羊模型，In-002的雾化治疗减少了肺中的RSV病毒载量 与安慰剂治疗的动物不同，BALF几乎不可检测的水平。 Inhalon是第一家 成功完成了用于遗传的MAB疗法（IN-006）的1期研究，以实现很高 气道中的药物水平具有出色的安全性。伊哈隆（Inhalon）已收到FDA的反馈 IN-002的提交，目前正在完成IN-002的临床前活动，包括GLP 吸入TOX，GLP组织交叉反应性和GLP雾化表征。此外，Inhalon已经 建立了一家符合GMP的大型细胞库以生产IN-002，从中扩展了Tox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，瓶 以及在GMP（AIM 1）和（ii）提交的IN-002 IN-002临床试验材料的表征 获得批准以启动第1阶段的临床研究（AIM 2）。成功完成拟议活动 将使我们能够将IN-002推进到人类的第一研究。