Strain-Independent Therapeutic Antibodies for Influenza

流感病毒毒株无关的治疗性抗体

基本信息

批准号：
10338076
负责人：
Lawrence Michael Kauvar
金额：
$ 99.98万
依托单位：
TRELLIS BIOSCIENCE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338076
关键词：
Address Advanced Development Aerosols Affinity Agreement Amantadine Antibiotic Resistance Antibody-Dependent Enhancement Antiviral Agents Award Bacterial Proteins Binding Biological Assay Biological Sciences Birds Buffers Cardiotoxicity Cities Clinical Communicable Diseases Cytomegalovirus Development Disease Dose Drug Industry Drug Kinetics Drug resistance Formulation Funding Grant Guidelines Human Human Cloning In Vitro Industry Infection Inflammatory Influenza Influenza A Virus, H7N9 Subtype Influenza A virus Influenza B Virus Influenza Hemagglutinin Influenza Therapeutic Inhalation Legal patent Licensing Malignant Neoplasms Microbial Biofilms Monoclonal Antibodies Mus Nebulizer Neuraminidase inhibitor Oseltamivir Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Phase II Clinical Trials Polymerase Predisposition Privatization Production Property Proteins Rattus Resistance Respiratory System Respiratory syncytial virus Safety Serum Small Business Innovation Research Grant Technology Testing Therapeutic antibodies Toxic effect Toxicology Vaccines Ventilator Virus Work antibody test biosafety level 3 facility cell bank clinical development cohort comparative efficacy efficacy study expectation experience flu activity follow-up high risk human monoclonal antibodies human tissue improved improved outcome in vivo influenza virus strain influenzavirus inhibitor innovation mouse model neutralizing antibody nonhuman primate pandemic disease phase III trial physical property preclinical development programs resistant strain response small molecule small molecule therapeutics symposium

项目摘要

SUMMARY In this Phase IIB proposal, we seek funding to complete the IND-enabling development of CF-404, a mixture of three native human monoclonal antibodies (mAbs). Activity has been established in mouse models against representatives of all major circulating strains of influenza A and B. By providing a pan-influenza treatment, we avoid delays associated with strain typing, with improved outcomes expected from the prompt treatment. We specifically propose here to address regulatory issues relating to delivery of the mAb mixture by inhalation. Our background work demonstrated that inhaled delivery provides superior efficacy compared to systemic delivery, at ~10-fold lower dose. The inhalation technology from industry leader Aerogen Pharma is established as suitable for hospitalized patients, including those on a ventilator. Due to drug resistance to the existing influenza therapeutic drugs, there is a high need for our product. The first class of small molecule therapeutics, the amantadines, are now largely useless due to drug resistance. The second class, neuraminidase inhibitors, are currently experiencing similar emergence of resistance. The newest class, polymerase inhibitors, has already shown worrisome signs of early emergence of drug resistant strains (10% in the Phase 3 trials). By contrast, intensive selection in vitro for virus that escapes our mAbs has shown that resistance is likely to be far less common than for the small molecule antivirals. The impact of CF-404 is thus expected to be high.

概括在此 IIB 期提案中，我们寻求资金来完成 CF-404 的 IND 开发，CF-404 是三种天然人单克隆抗体 (mAb)。已在小鼠模型中建立了针对甲型和乙型流感所有主要流行毒株的代表。通过提供泛流感治疗，我们避免与菌株分型相关的延误，及时治疗有望改善结果。我们在此特别建议解决与吸入单克隆抗体混合物相关的监管问题。我们的背景工作表明，与全身给药相比，吸入给药具有更优越的功效，剂量低约 10 倍。行业领导者 Aerogen Pharma 的吸入技术被确立为适用于住院患者，包括使用呼吸机的患者。由于对现有流感产生耐药性治疗药物，对我们的产品有很高的需求。第一类小分子疗法，由于耐药性，金刚烷胺现在基本上没有用处。第二类是神经氨酸酶抑制剂目前也出现了类似的阻力。最新的一类聚合酶抑制剂已经显示出早期出现耐药菌株的令人担忧的迹象（3 期试验中为 10%）。相比之下，对逃离我们的单克隆抗体的病毒进行的体外强化选择表明，耐药性可能要低得多比小分子抗病毒药物更常见。因此，CF-404 的影响预计会很大。