A human monoclonal for RSV prophylaxis

描述（由申请人提供）：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，呼吸道合胞病毒感染导致高发病率和死亡率。仅在美国，每年就有超过12.5万人因呼吸道合胞病毒住院，500人死亡。唯一预防RSV的药物是Synagis (palivizumab; MedImmune)，这是一种针对RSV糖蛋白F的人源化小鼠单克隆抗体（mAb），已被证明可将RSV相关住院率降低50%。为了防止一次住院，估计有16-18名新生儿需要接受Synagis治疗。由于单个疗程的Synagis治疗每个婴儿的费用可能超过10000美元，因此由此产生的成本效益分析并不有利。此外，由于成本高昂，发展中国家的儿童无法获得Synagis，在人口最多的5个国家中，有4个国家无法获得Synagis——世界上一半以上的人口无法获得这种救命的治疗。此外，对synagis耐药的RSV菌株的报道强调需要针对不同表位的额外抗RSV产品。Aridis制药公司筛选了RSV感染患者，并鉴定出一种天然存在的人单克隆IgG ('AR-201')，其效力高于Synagis，可以中和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制药与Mapp生物制药合作，共同开发具有以下特点的单抗产品（AR- 201）：

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.