HUMAN-MURINE CHIMERIC ABS TO RESPIRATORY SYNCYTIAL VIRUS

呼吸道合胞病毒的人-鼠嵌合 ABS

• 批准号: 2065544
• 负责人: L Syd Johnson
• 金额: $ 23.26万
• 依托单位: MEDIMMUNE, INC.
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-03-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2065544
• 关键词: Rodentias; antiviral antibody; clone cells; drug design /synthesis /production; human genetic material tag; hybrid antibody; monoclonal antibody; neutralizing antibody; nonhuman therapy evaluation; passive immunization; respiratory syncytial virus

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in young children and is responsible for yearly epidemics of bronchiolitis and pneumonia. At risk of serious RSV morbidity and mortality are children with underlying conditions such as congenital heart disease, broncho-pulmonary dysplasia, other pulmonary diseases, various congenital or acquired immunodeficiency syndromes, and prematurity. In the United States alone, there are over 100,000 such high risk children. Unfortunately, RSV vaccines are unavailable and unlikely to be licensed in the near future. Ribavirin has recently been licensed for therapy of RSV pneumonia and bronchiolitis; however, its value is controversial. Currently, the most promising approach to prophylaxis or therapy of RSV disease in high risk infants is passive immunization. MedImmune Inc. is developing an RSV intravenous hyperimmune globulin product for the prevention and treatment of RSV disease in these children. This product is produced from select plasma containing high titers of neutralizing antibody to RSV, which are pooled and used to prepare immunoglobulin. This product is currently being tested in a NIAlD-sponsored multicenter Phase II efficacy trial for the prophylaxis of RSV lower respiratory tract infection in infants with serious heart and lung disease. However, a more reliable source of a highly defined and standardized product would be more desirable. During our Phase I work, murine monoclonal antibodies to two distinct and conserved neutralizing determinants on the F-glycoprotein of RSV were successfully humanized. The final humanized Mabs bound to the target antigen with similar affinities as the parent molecules, and both neutralized RSV infection in vitro with similar potency as the parent murine Mabs. These humanized antibody molecules represent potential prophylactic and therapeutic products for use in prevention of RSV associated disease. It is therefore the goal of our Phase Il effort to develop these molecules or potentially improved versions of them. These efforts will involve the complete in vitro and in vivo preclinical evaluation of these antibodies, the development of stable antibody production cell lines, and the performance of process development and scale-up production under cGMP conditions of sufficient material for initiation of human clinical trails.

呼吸道合胞病毒（RSV）是最常见的原因， 儿童呼吸道感染， 毛细支气管炎和肺炎的年度流行。存在严重RSV风险 发病率和死亡率是儿童的基本条件， 先天性心脏病、支气管肺发育不良、其他肺 疾病、各种先天性或获得性免疫缺陷综合征，以及 早产仅在美国，就有超过10万人 冒险的孩子。 不幸的是，RSV疫苗是不可用的，不太可能在美国获得许可。 不久的将来利巴韦林最近已获准用于治疗RSV 肺炎和细支气管炎;然而，它的价值是有争议的。 目前，预防或治疗RSV的最有希望的方法是 对高危婴儿进行被动免疫。MedImmune Inc.是 开发RSV静脉内超免疫球蛋白产品， 预防和治疗这些儿童的RSV疾病。这个产品是 由含有高滴度中和 RSV抗体，其被汇集并用于制备免疫球蛋白。这 产品目前正在NIAlD申办的多中心阶段进行测试 II预防RSV下呼吸道感染的疗效试验 严重心肺疾病婴儿的感染。然而，一个更 一个高度定义和标准化的产品的可靠来源将是更多 令人向往 在我们的第一阶段工作中，鼠单克隆抗体对两个不同的， RSV的F-糖蛋白上的保守中和决定簇是 成功的人性化。与靶结合的最终人源化单克隆抗体 抗原与母体分子具有相似的亲和力， 体外中和RSV感染，效力与母体相似 鼠单克隆抗体这些人源化抗体分子代表了潜在的 用于预防RSV的预防和治疗产品 相关疾病。因此，我们第二阶段工作的目标是 开发这些分子或它们的潜在改进版本。这些 这些努力将涉及完整的体外和体内临床前 评价这些抗体，开发稳定的抗体 生产细胞系，以及工艺开发和 在cGMP条件下进行规模化生产， 启动人体临床试验。