A human monoclonal for RSV prophylaxis

描述（由申请方提供）：呼吸道合胞病毒（RSV）是全球婴幼儿下呼吸道疾病的主要原因。在早产儿中，RSV感染会导致高发病率和死亡率。仅在美国，每年就有超过125，000例住院和500例死亡可归因于RSV。RSV的唯一预防是Synagis（帕利珠单抗; MedImmune），一种靶向RSV糖蛋白F的人源化鼠单克隆抗体（mAb），已显示可将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。由于单疗程Synagis治疗的成本可能超过10000美元每名婴儿，由此产生的成本效益分析是不利的。此外，由于价格昂贵，发展中国家的儿童无法获得Synagis，5个人口最多的国家中有4个无法获得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毒株的报道强调了对针对不同表位的另外的抗RSV产品的需要。Aridis制药公司已经筛选了RSV感染的患者，并鉴定了一种天然存在的人单克隆IgG（“AR-201”），其效力高于Synagis，可中和Synagis耐药菌株。本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性的mAb产品（AR- 201）： 1.完全人源化（Synagis是一种人源化小鼠mAb） 2.比Synagis更高的亲和力和体外中和效力 3.结合与Synagis不同的表位，并中和Synagis耐药菌株 4.增加血清半衰期，因此注射频率可以低于Synagis所需的每月给药频率 5.使用高度可扩展的快速抗体生产平台（RAMP）在本氏烟草中生产，降低了成本 在特定目标1中，我们将在RAMP系统和CHO细胞中生产AR-201。AR-201将在本氏烟草和CHO细胞中表达为未修饰的序列和引入氨基酸突变的序列，所述氨基酸突变导致对FcRn的亲和力增加，从而延长血清半衰期。在特定目标2中，将在体外比较mAb。测量将评估mAb对糖蛋白F的亲和力和中和活性 针对包括耐Synagis菌株在内的一大组RSV分离株。在特异性目的3中，将在体内比较mAb。棉鼠模型将用于比较mAb变体的有效性，以选择先导mAb用于后续II期SBIR提案中的持续产品开发。

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.