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

IN-002 是一种针对呼吸道合胞病毒的吸入性粘膜捕获单克隆抗体，可进行 IND 开发

基本信息

批准号：
10663797
负责人：
JEFF T HUTCHINS
金额：
$ 101.9万
依托单位：
INHALON BIOPHARMA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-12 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10663797
关键词：
Address Adsorption Adult Affinity Age Animals Antibodies Antibody Therapy Antigens Antiviral Therapy Apical Back Binding Biological Biological Assay Bronchiolitis Cell Line Cells Cessation of life Child Chinese Hamster Ovary Cell Clinic Clinical Clinical Research Clinical Trials Contracts Cotton Rats Coupled Critical Pathways Cyclic GMP Data Development Dose Effectiveness Elderly Engineering Evaluation FDA approved Formulation Functional disorder Gel Goals Government Hospitalization Human Immune Immunocompromised Host Immunoglobulin G In Vitro Infant Infection Inhalation Inhalation Therapy Injections Intervention Intramuscular Injections Investigation Legal patent Lung Mediating Modality Molecular Target Monoclonal Antibodies Morbidity - disease rate Mucins Mucociliary Clearance Mucous body substance Mus Nebulizer Neonatal Neutrophil Infiltration Palivizumab Persons Phase Pneumonia Polysaccharides Positioning Attribute Pregnancy Prevention Rattus Research Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory System Respiratory syncytial virus Risk Running Serum Side Site Supportive care Therapeutic Tissues Toxicology Translations Vaccine Therapy Vaccines Viral Viral Load result Viral load measurement Viremia Virion Virus Virus Diseases Virus Shedding Vulnerable Populations Work airway epithelium antiviral drug development cell bank cost cost effective cost effective treatment cross reactivity crosslink effective therapy glycosylation high risk high risk infant improved lamb model meetings minimal risk mortality necrotic tissue pathogen pharmacologic phase 1 study pre-Investigational New Drug meeting pre-clinical prophylactic research clinical testing respiratory respiratory pathogen side effect technology platform transmission process vibration

项目摘要

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.

项目摘要呼吸道合胞病毒（RSV）是婴儿和幼儿病毒死亡的主要原因，是在免疫受损的成年人中，也是呼吸道疾病的主要原因。不幸的是，有目前尚无RSV的疫苗或有效疗法。 simagis，每月肌内注射单克隆抗体（MAB）Palivizumab是唯一的FDA批准干预措施，但只能用于预防，仅给了一小部分高风险婴儿。下沿无效治疗RSV 感染后开始。对于数以万计的RSV住院，只有支持疗法是可用的;由此产生的发病率和死亡率是实质的，尤其是在免疫功能低下的人中。有趣的是，RSV通过仅将病毒脱落到气道中而在肺部传播。因此，RSV必须在感染其他相邻细胞之前，穿过气道粘液（AM），并限制在气道上几乎没有系统性的病毒血症。这种独特的病理生理学使RSV难以通过系统地靶向剂量疗法。我们认为可以直接吸入RSV特异性，安全有效的抗病毒疗法进入呼吸道将提供一个强大的选择，以解决药理当前差距干预措施。为了实现这一目标，Inhalon一直在使用其专有和获得专利的“粘液捕获” MAB技术平台。 IN-002是具有皮摩尔结合的潜在抗F mAb 亲和力和神经化效力，病毒逃逸的风险很小，并且具有合适的FC N-糖基化将RSV捕获在AM。反过清除机制。我们已经进一步制定了IN-002，以稳定地使用振动网格喷雾器。通过直接将IN-002集中在感染部位，而不是全身传递mAb，我们期望能够对RSV进行有效且具有成本效益的治疗，几乎没有副作用的风险从肺部递送中有限的全身吸附。在RSV感染的新生儿羔羊模型中即使在肺部接近峰值病毒滴度也能够减少感染肺部的RSV病毒载荷在3天内至几乎不可检测的水平。 Inhalon目前正在积极积极从事IN-002的细胞系开发。为了快速转化为诊所，我们试图完成该提案中的细胞系开发，并生产适用于辅助活动的托克斯材料作为组织交叉反应性研究，GLP肺托克斯研究和GLP雾化表征研究。拟议中的工作将共同支持IN-002的快速发展晋级临床测试。我们在这里的工作 RSV还将为改进，靶向分子的遗传疗法铺平道路病原体。