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）是全世界婴幼儿下呼吸道疾病的主要原因。在早产儿中，RSV 感染导致高发病率和死亡率。仅在美国，每年就有超过 125,000 人因 RSV 住院治疗，并有 500 人死亡。 RSV 的唯一预防方法是 Synagis（帕利珠单抗；MedImmune），这是一种针对 RSV 糖蛋白 F 的人源化鼠单克隆抗体 (mAb)，已被证明可以将 RSV 相关住院率降低 50%。为了防止单次住院，估计有 16-18 名新生儿需要接受 Synagis 治疗。由于 Synagis 治疗的单个疗程的费用可能超过每个婴儿 10000 美元，因此由此产生的成本效益分析并不理想。此外，由于成本高昂，发展中国家的儿童无法获得 Synagis，并且在 5 个人口最多的国家中的 4 个国家也无法获得 Synagis——世界上一半以上的人口无法获得这种挽救生命的治疗。此外，Synagis 抗性 RSV 菌株的报告强调需要针对不同表位的额外抗 RSV 产品。 Aridis Pharmaceutical 筛选了 RSV 感染患者，并鉴定出一种天然存在的人单克隆 IgG (“AR-201”)，其中和 Synagis 耐药菌株的效力比 Synagis 更高。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点的mAb产品（AR-201）： 1. 完全人源化（Synagis 是人源化小鼠单克隆抗体） 2. 比Synagis具有更高的亲和力和体外中和能力 3. 结合与 Synagis 不同的表位并中和 Synagis 抗性菌株 4. 血清半衰期延长，因此注射次数可以低于 Synagis 所需的每月剂量 5. 使用高度可扩展的快速抗体制造平台 (RAMP) 在本塞姆氏烟草中进行制造，从而降低成本 在具体目标 1 中，我们将在 RAMP 系统和 CHO 细胞中生产 AR-201。 AR-201将在本塞姆氏烟草和CHO细胞中以未修饰的序列和引入氨基酸突变的序列表达，所述氨基酸突变导致对FcRn的亲和力增加，从而导致血清半衰期延长。在具体目标 2 中，将在体外对 mAb 进行比较。测量将评估糖蛋白 F 的亲和力以及 mAb 的中和活性 针对大量 RSV 分离株，包括 Synagis 抗性菌株。在具体目标 3 中，将在体内比较 mAb。棉鼠模型将用于比较 mAb 变体的功效，以选择主要 mAb，用于后续 2 期 SBIR 提案中的持续产品开发。