A human monoclonal for RSV prophylaxis

用于预防 RSV 的人单克隆抗体

• 批准号: 8781499
• 负责人: Larry Zeitlin
• 金额: $ 30万
• 依托单位: MAPP BIOPHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781499
• 关键词: Address; Affinity; Amino Acids; Antibodies; Binding; Biological Products; Capital; Cessation of life; Characteristics; Child; Chinese Hamster Ovary Cell; Clinical; Cost Effectiveness Analysis; Cotton Rats; Country; Developing Countries; Development; Dose; Drug Kinetics; Epitopes; Glycoproteins; Goals; Half-Life; Hospitalization; Human; Immunocompromised Host; Immunoglobulin G; In Vitro; Infant; Infection prevention; Injection of therapeutic agent; Lead; Life; Lower respiratory tract structure; Marketing; Measurement; Medicine; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Mutation; Neutralization Tests; Nicotiana; Palivizumab; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Piedra; Population; Premature Infant; Prevention; Production; Prophylactic treatment; Reporting; Resistance; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Respiratory syncytial virus RSV F glycoprotein; Risk; Savings; Seasons; Serum; Small Business Innovation Research Grant; System; Testing; United States; Variant; Virus; Work; college; comparative efficacy; cost; efficacy testing; high risk; in vivo; manufacturing facility; mortality; neonatal Fc receptor; neonate; premature; prevent; product development; public health relevance; resistant strain

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract illness in infants and young children worldwide. In premature neonates, RSV infection results in high levels of morbidity and mortality. In the United States alone, there are more than 125,000 hospitalizations and 500 deaths per year attributable to RSV. The only prophylaxis for RSV is Synagis (palivizumab; MedImmune), a humanized murine monoclonal antibody (mAb) that targets the RSV glycoprotein F and has been shown to reduce the rate of RSV associated hospitalization by 50%. In order to prevent a single hospitalization it has been estimated that 16-18 neonates need to be treated with Synagis. Since a single course of Synagis treatment can cost in excess of $10000 per infant, the resulting cost-effectiveness analysis is not favorable. Moreover, due to this high cost, Synagis is inaccessible to children in developing nations and is unavailable in 4 of the 5 most populous countries - more than half the world's population does not have access to this life-saving treatment. Further, reports of Synagis-resistant RSV strains emphasize the need for additional anti-RSV products against different epitopes. Aridis Pharmaceutical has screened RSV infected patients and identified a naturally occurring human monoclonal IgG ('AR-201') with higher potency than Synagis that neutralizes Synagis-resistant strains. The aim of this proposal is to further the development of AR-201 to address the above mentioned limitations. To this end, Aridis Pharmaceutical has teamed with Mapp Biopharmaceutical to jointly develop a mAb product (AR- 201) with the following characteristics: 1. Fully human (Synagis is a humanized mouse mAb) 2. Higher affinity and in vitro neutralization potency than Synagis 3. Binds a different epitope than Synagis and neutralizes a Synagis-resistant strain 4. Increased serum half-life so injections can be administered less frequently than the monthly dosing required for Synagis 5. Lower cost due to manufacture in Nicotiana benthamiana using the highly scalable Rapid Antibody Manufacturing Platform (RAMP) In Specific Aim 1, we will produce AR-201 in both the RAMP system and in CHO cells. AR-201 will be expressed in Nicotiana benthamiana and CHO cells as both the unmodified sequence and as sequences introducing amino acid mutations that result in increased affinity for FcRn resulting in extended serum half- life. In Specific Aim 2, the mAbs will be compared in vitro. Measurements will assess affinity for glycoprotein F and neutralization activity of the mAbs against a large panel of RSV isolates including Synagis-resistant strains. In Specific Aim 3, the mAbs will be compared in vivo. The cotton rat model will be used to compare the efficacy of the mAb variants to select a lead mAb for continued product development in a subsequent Phase 2 SBIR proposal.

描述（由申请人提供）：呼吸道合胞病毒（RSV）是全世界婴儿和幼儿下呼吸道疾病的主要原因。在过早的新生儿中，RSV感染导致高水平的发病率和死亡率。仅在美国，RSV每年就有超过125,000次住院和500例死亡。 RSV的唯一预防是犹他州（Palivizumab； Medimmune），它是一种人源化的鼠单克隆抗体（MAB），靶向RSV糖蛋白F，已证明可将RSV相关的住院率降低50％。为了防止单个住院治疗，据估计，需要用下姑a治疗16-18名新生儿。由于单一的犹太教堂治疗的费用超过每个婴儿10000美元，因此由此产生的成本效益分析是不利的。此外，由于成本高昂，犹太教堂对于发展中国家的儿童无法接近，在5个人口最多的国家中有4个是无法获得的 - 超过一半的世界人口无法获得这种挽救生命的待遇。此外，耐犹太裔RSV菌株的报道强调了针对不同表位的其他抗RSV产品的需求。 Aridis Pharmaceutical已筛选了RSV感染的患者，并鉴定出比中和犹太氨基酸含量高的自然存在的人类单克隆IgG（'AR-201'），该患者的效力更高，该siNAGIS中和simartical simpectiential suptication。该提案的目的是进一步开发AR-201，以解决上述限制。为此，Aridis Pharmaceutical与MAPP BioPharmaceutical合作，共同开发具有以下特征的MAB产品（AR-201）： 1。完全人类（下沿是人性化的小鼠单元） 2。比下叶酸更高的亲和力和体外中和效力 3。结合一个不同的表位，与下姑息签名并中和耐下议院菌株 4。血清半衰期增加，因此注射量的频率较低，而不是下叶纳那所需的每月给药 5。使用高度可扩展的快速抗体制造平台（RAMP）在Nicotiana Benthamiana制造的成本较低 在特定的目标1中，我们将在坡道系统和CHO细胞中生产AR-201。 AR-2011将以未修饰的序列和引入氨基酸突变的序列表示，在烟草本尼亚尼亚群岛和CHO细胞中表达，从而导致对FCRN的亲和力增加，从而导致血清半衰期延长。在特定的目标2中，将在体外比较mAb。测量将评估对糖蛋白F的亲和力和mAb中和活性的亲和力 针对一系列RSV分离株，包括耐犹太裔抗性菌株。在特定的目标3中，将在体内比较mAb。棉花大鼠模型将用于比较在随后的2阶段SBIR提案中选择铅MAB以继续产品开发的铅MAB的功效。