BROADLY RSV NEUTRALIZING HUMAN MONOCLONAL ANTIBODIES

广泛 RSV 中和人类单克隆抗体

• 批准号: 2413676
• 负责人: PETER BRAMS
• 金额: $ 32.92万
• 依托单位: IDEC PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-15 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2413676
• 关键词: CHO cells; Cercopithecidae; Macaca fascicularis; antibody formation; antibody specificity; antiviral antibody; chimeric proteins; cross immunity; human tissue; immunoglobulin genes; laboratory mouse; molecular cloning; monoclonal antibody; neutralizing antibody; polymerase chain reaction; respiratory syncytial virus; transfection /expression vector

We propose to clone, express, in vitro characterize and perform preclinical testing of two human monoclonal IgG1, kappa, antibodies, RF-1 and RF-2, that binds specifically and with high affinity to the fusion protein of the human Respiratory Syncytial Virus (RSV). The antibodies have in vitro virus neutralizing activity at concentration as low as 30 and 8 ng/ml, respectively. The antibodies have neutralized all virus strains tested, covering both subtypes A and B and wildtypes and laboratory strains. The antibodies do not cross-react to 4 human RSV negative cell lines, each representing different tissue types. We plan to clone the antibody coding genes and then insert them into a high efficiency CHO expression vector. Two forms of each antibody will be produced, a gamma1 and a gamma4 (PE) form. The antibodies will first be tested in vivo as gamma1 versions in a Balb/c model; the best performing will then be tested as a gamma4 (PE) version. The best antibody will then be tested for cross-reactivity to human tissues. The second animal model, the African green monkey, will be used to assess the efficacy of the antibody in preventing lung damage by RSV. In both animal models, the antibody(ies) will be tested for prophylactic and therapeutic efficacy, and for its effect on the animals response to RSV. PROPOSED COMMERCIAL APPLICATION: approximately 90,000 people are hospitalized each year due to RSV infectious; of these, a majority will suffer lifelong pulmonary problems and approximately 4,500 subsequently die. These patients are the core target population with a therapeutic aim. It is expected that a larger target population of approximately 200,000 subsequently could become applicable for prophylactic treatment. Polyclonal antibody preparations have shown efficacy in prophylacsis and therapy of RSV infection. A monoclonal antibody would have several advantages over such a polyclonal preparation including: consistency, higher effect/dose, ease of production and no possibility for concomitant viral contamination.

我们建议克隆，表达，体外表征和进行临床前 检测两种人单克隆IgG 1 κ抗体RF-1和RF-2， 其特异性地且以高亲和力结合至融合蛋白， 人呼吸道合胞病毒（RSV）。 抗体在体外 在低至30和8 ng/ml的浓度下的病毒中和活性， 分别 抗体已经中和了所有测试过的病毒株， 涵盖亚型A和B以及野生型和实验室菌株。 的 抗体不与4种人RSV阴性细胞系交叉反应， 代表不同的组织类型。 我们计划克隆抗体编码 基因，然后将它们插入高效CHO表达载体中。 每种抗体将产生两种形式，一种γ 1和一种γ 4（PE） form. 这些抗体将首先在体内作为γ 1版本进行测试， Balb/c模型;然后将最佳性能作为gamma4（PE）进行测试 版本. 然后测试最佳抗体的交叉反应性， 人体组织 第二个动物模型，非洲绿色猴，将在 用于评估抗体在预防肺损伤中的功效， RSV。 在两种动物模型中，将检测抗体的 预防和治疗功效，以及对动物的影响 对RSV的反应 建议的商业应用：约90，000人 每年因RSV感染住院;其中，大多数将 患有终生肺部疾病， 死的 这些患者是具有治疗目的的核心目标人群。 预计将有大约20万的更大的目标人口， 随后可适用于预防性治疗。 多克隆抗体制剂已经显示出在大肠杆菌中的功效， RSV感染的治疗。 单克隆抗体将具有几个 相对于这种多克隆制剂的优点包括：一致性， 更高的作用/剂量，易于生产，不可能伴随 病毒污染