HUMAN-MURINE CHIMERIC ABS TO RESPIRATORY SYNCYTIAL VIRUS

呼吸道合胞病毒(RSV)是引起下呼吸道感染的最常见原因 幼儿的呼吸道感染，并对 毛细支气管炎和肺炎的年度流行。面临严重呼吸道合胞病毒的风险 发病率和死亡率是有潜在疾病的儿童，如 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 早产儿。仅在美国，就有超过10万个这样的高 冒着孩子的风险。 不幸的是，RSV疫苗无法获得，而且不太可能在#年获得许可。 在不久的将来。利巴韦林最近已被批准用于治疗呼吸道合胞病毒 肺炎和毛细支气管炎；然而，其价值是有争议的。 目前，预防或治疗呼吸道合胞病毒最有前途的方法 高危婴儿的疾病是被动免疫。医疗免疫公司是 呼吸道合胞病毒静脉注射高免疫球蛋白制剂的研制 预防和治疗这些儿童的呼吸道合胞病毒病。这个产品是 由精选的含有高滴度中和作用的等离子体产生 RSV抗体，这些抗体被汇集并用于制备免疫球蛋白。这 该产品目前正在NIAlD赞助的多中心阶段进行测试 预防呼吸道合胞病毒下呼吸道感染的疗效试验 患有严重心肺疾病的婴儿感染。然而，一个更多的 高度定义和标准化的产品的可靠来源将更多 令人向往。 在我们的第一阶段工作中，小鼠针对两种不同的和 RSV F-糖蛋白上的保守中和决定簇是 成功地人性化了。最终与目标绑定的人性化单抗 具有与亲本分子相似亲和力的抗原，并且两者 体外中和RSV感染，效力与亲本相似 小鼠单抗。这些人源化抗体分子代表了潜在的 用于预防呼吸道合胞病毒的预防和治疗产品 相关疾病。因此，我们第一阶段工作的目标是 开发这些分子或它们的潜在改进版本。这些 努力将包括完整的体外和体内临床前 对这些抗体进行评价，研制稳定的抗体 生产单元线，以及工艺开发和性能的 在cGMP条件下的放大生产 启动人类临床试验。

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.