Passive Immunotherapeutics for Select Agents

特定药物的被动免疫治疗

• 批准号: 7649817
• 负责人: Clarence J. Peters
• 金额: $ 26.93万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7649817
• 关键词: Active immunity; Animal Model; Antibodies; Antiviral Agents; B lymphocyte immortalization; Biological Assay; Cavia; Cell Line; Cells; Clinical; Data; Disease; Epitopes; Evaluation; Fever; Freezing; Goals; Guanosine Monophosphate; Hamsters; Human; Human Herpesvirus 4; Hybridomas; Immunotherapeutic agent; Infection; Junin virus; Laboratories; Limes; Monoclonal Antibodies; Nipah Virus; Non-Hodgkin' s Lymphoma; Passive Immunotherapy; Pathogen detection; Peripheral Blood Lymphocyte; Production; Prophylactic treatment; Rabies; Reagent; Recombinant Proteins; Rift Valley fever virus; Role; Safety; Screening procedure; Serological; Serum; Smallpox Viruses; Specificity; Testing; Therapeutic; Tissues; United States Food and Drug Administration; Vaccines; Virus; Virus Diseases; Work; World Health Organization; base; human monoclonal antibodies; immunoreactivity; improved; neutralizing antibody; pathogen; prevent; respiratory; success; uptake

Post exposure prophylaxis and treatment are aitical challenges in the management of emerging viral diseases. Vaccines may be helpful in post exposure prophylaxis where agents replicate s10wty or are initially sequestered in the periphery. However, in most instances, active immunity does not occur in a lime frame wherein disease can be prevented or ameliorated. Passive immunotherapy has an established track record in management of infections with rabies. respiratory syncytial, and variola viruses. Except in rare instances where antibodies cross react with host tissues to cause disease or enhance virus uptake to accelerate progression of infection, the effects of passive immunotherapy are specific. Anlivirals have been used with success in many infections, and the repertoire of effective compounds will undoubtedly improve; nonetheless. passive immunotherapy will continue to be a significant primary or complementary line of defense. Reagents for passive immunotherapy include both convalescent serum and monoclonal antibodies (MAbs). MAbs have the advantages of defined reactivity and specificity. and enhanced safety profiles. Through previous work in pathogen detection in context of the WHO laboratory network we have access to peripheral blood lymphocytes (PBL) from victims recovered from infection with high.risk pathogens. We have established that PBL can be stored frozen and used for fusion several months after ootlection with only insignificant loss of Ig production. This Trans-RCE project will exploit human PBL and direct fusion with an effICient human hybridoma fusion partner cell line (MFP¿2), as well as immortalization of B cells using EBV and CpG followed by e1eeuofusion with a HMMA2.5 fusion partner cell line to produce fully human MAbs (fhMAB) SpecifIC for three select agents: Junin virus, Nipah virus, and Rift. VaHey fever virus. The choice of targets is based on data indicating a potential therapeutic role for passive immunotherapy and the avaHability well-characterized clinical materials. A limited evaluation of MFP-2 has been oonducted in the context of ding an INO with the FDA. Furthennore, a commercial relationship has been established with the goal of producing GMP grade fhMAbs for treatment of non-Hodgkin lymphomas. These factors will enable transition of fhMAbs with antiviral activity from animal models to clinical use. Specific aims include: 1. Establish serologic assays for screening of convalescent donor sera and human hybridoma supernatants; 2. Characterize donor sera and PBl, and generate human hybridoma lines; and 3. Test neutraliZing fhMAbs for protective activity in animal models.

暴露后预防和治疗是新发病毒管理中面临的严峻挑战 疫苗可能有助于暴露后预防，其中病原体会复制或最初复制。 然而，在大多数情况下，主动免疫不会发生在石灰框架中。 因此，被动免疫疗法可以预防或改善疾病。 用于治疗狂犬病和天花病毒感染。 抗体与宿主组织发生交叉反应，导致疾病或增强病毒摄取以加速 随着感染的进展，被动免疫疗法的效果是特异性的。 在许多感染方面取得成功，有效化合物的储备无疑将得到改善； 尽管如此，被动免疫疗法仍将是重要的主要或补充疗法。 被动免疫治疗的试剂包括恢复期血清和单克隆抗体。 (MAb) 具有明确的反应性和特异性以及增强的安全性的优点。 通过之前在世界卫生组织实验室网络背景下进行的病原体检测工作，我们可以访问 感染高危病原体后恢复的受害者的外周血淋巴细胞（PBL）。 已经确定 PBL 可以冷冻保存，并在采摘后几个月用于融合，只需 该 Trans-RCE 项目将利用人类 PBL 并与 Ig 生产直接融合。 高效的人杂交瘤融合伴侣细胞系 (MFP¿2)，以及使用 EBV 的 B 细胞永生化 和 CpG，然后与 HMMA2.5 融合伙伴细胞系进行电子融合，以产生完全人源 MAb (fhMAB) 特定于三种选择的病毒：胡宁病毒、尼帕病毒和裂谷热病毒。 目标基于表明被动免疫疗法潜在治疗作用和可用性的数据 对 MFP-2 进行了有限的评估。 此外，还与 FDA 建立了商业关系，目标是： 生产 GMP 级 fhMAb 用于治疗非霍奇金淋巴瘤这些因素将实现转型。 从动物模型到临床应用具有抗病毒活性的fhMAb的具体目标包括： 1. 建立。 筛选恢复期供体血清和人杂交瘤上清液的血清学测定；2. 表征供体血清和PB1，并产生人杂交瘤系；以及3.测试中和fhMAb 动物模型中的保护活性。