Resource for Nonhuman Primate Cell Depleting Antibodies

非人灵长类细胞耗竭抗体资源

• 批准号: 7900648
• 负责人: KEITH A. REIMANN
• 金额: $ 37.62万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2010-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900648
• 关键词: Resource; Nonhuman; Primate; Cell; Depleting

DESCRIPTION (provided by applicant): Nonhuman primates (NHPs) provide powerful animal models for exploring the pathogenesis of infectious and noninfectious diseases, and for testing of new therapies and vaccines that cannot be evaluated in rodents. Over the past decade, the number of NIH grants employing nonhuman primates has doubled. However, the utility of these models in many cases is limited by the availability of reagents for in vitro diagnostics and for in vivo modulation of specific immune functions. During the previous funding period of this grant, we established the NIH Nonhuman Primate Reagent Resource, a program for identifying and/or developing monoclonal antibodies, including new mouse-human chimeric recombinant monoclonal antibodies, fully-human monoclonal antibodies and rhesus receptor/human Ig fusion proteins that deplete specific lymphocyte subpopulations or target specific immune functions in vivo. We also established processes for large-scale production of reagents and optimized their use. During this initial award period, we distributed 90,000 milligrams of purified monoclonal antibody supporting more than 60 NIH grants or intramural programs representing 8 NIH institutes or centers. The need for these unique reagents has grown steadily since the initiation of this program. In addition, the potential has emerged to develop new reagents with reduced antigenicity, longer duration of effect in vivo and more focused targeting of lymphocyte subpopulations. To continue support of nonhuman primate models across multidisciplinary scientific programs we will: 1) Produce and distribute recombinant antibodies and fusion proteins developed during the previous funding period, 2) Identify and/or develop reagents, including recombinant (chimeric, humanized and primatized) mAbs, with new specificities and functions as directed by a scientific advisory committee, 3) Develop macaque IgG vectors for generating recombinant rhesus antibodies and rhesus Ig-Fc fusion proteins, and assess the in vivo biological properties of recombinant rhesus lgG1, lgG2 and lgG4 antibodies, 4) Explore methods of increasing recombinant antibody plasma half-life by increasing affinity for FcRn, and 5) Determine if experimental lymphocyte depletion reactivates viruses that are endemic in captive NHPs potentially affecting experimental outcome or having public health considerations.

描述（由申请人提供）：非人灵长类动物（NHP）为探索感染性和非感染性疾病的发病机制以及测试无法在啮齿动物中评价的新疗法和疫苗提供了强大的动物模型。在过去的十年里，NIH资助的非人灵长类动物的数量翻了一番。然而，在许多情况下，这些模型的实用性受到体外诊断试剂和体内调节特异性免疫功能试剂的可用性的限制。在该资助的上一个资助期内，我们建立了NIH非人灵长类动物试剂资源，这是一个用于鉴定和/或开发单克隆抗体的项目，包括新的小鼠-人嵌合重组单克隆抗体、全人单克隆抗体和恒河猴受体/人IG融合蛋白，这些抗体可消耗特定的淋巴细胞亚群或靶向体内特定的免疫功能。我们还建立了大规模生产试剂的流程并优化了其使用。在最初的奖励期间，我们分发了90，000毫克纯化的单克隆抗体，支持代表8个NIH研究所或中心的60多个NIH赠款或校内项目。 自该计划启动以来，对这些独特试剂的需求稳步增长。此外，已经出现了开发新试剂的潜力，这些新试剂具有降低的抗原性、更长的体内作用持续时间和更集中的淋巴细胞亚群靶向。为了继续支持跨多学科科学项目的非人类灵长类动物模型，我们将：1）生产和分销在上一个资助期内开发的重组抗体和融合蛋白，2）鉴定和/或开发试剂，包括重组（嵌合的、人源化的和灵长类化的）mAb，具有科学咨询委员会指导的新的特异性和功能，3）开发用于产生重组恒河猴抗体和恒河猴Ig-Fc融合蛋白的猕猴IgG载体，并评估重组恒河猴IgG 1、IgG 2和IgG 4抗体的体内生物学特性，4）探索通过增加对FcRn的亲和力来增加重组抗体血浆半衰期的方法，和5）确定实验性淋巴细胞耗竭是否重新激活圈养NHP中流行的病毒，这些病毒可能影响实验结果或具有公共卫生考虑。