Radioimmunotherapy of opportunistic infections

机会性感染的放射免疫治疗

• 批准号: 6627778
• 负责人: EKATERINA DADACHOVA
• 金额: $ 25.05万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-15 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6627778
• 关键词: AIDS; Cryptococcus neoformans; antifungal antibody; autoradiography; biotechnology; bismuth; chromatography; communicable disease control; cytotoxicity; disease /disorder model; drug delivery systems; flow cytometry; immunologic substance development /preparation; immunotherapy; indium; intermolecular interaction; laboratory mouse; nonhuman therapy evaluation; opportunistic infections; pharmacokinetics; protein structure function; radiation therapy; radiation therapy dosage; radionuclides; spectrometry

DESCRIPTION (Provided by the applicant): The existence of certain AIDS-associated opportunistic infections for which there is no cure combined with the emergence of multidrug-resistant strains of bacteria and fungi creates an urgent need for new approaches to antimicrobial therapy. This application proposes to develop radioimmunotherapy as an anti-infective strategy. We have recently suggested the use of radioimmunotherapy as a novel modality for treatment of infections employing C. neoformans as a model opportunistic infection. C. neoformans has several advantages as a model system for radioimmunotherapy of AIDS-associated opportunistic infections that include the existence of excellent animal models and the availability of several well characterized immunological reagents. Furthermore, monoclonal antibody therapy is already in clinical testing for C. neoformans using the monoclonal antibody (mAb) 1887. We have radiolabeled mAb 18B7 with therapeutic radioisotopes 188-Rhenium (1 88-Re) and 21 3-Bismuth (21 3-Bi) and have shown that these radiolabeled antibodies can efficiently eradicate C. neoformans cells in vitro as well as significantly prolong survival of complement-deficient animals lethally infected with C. neoformans. We hypothesize that 18B7 antibody may serve as an efficient delivery vehicle to deliver fungicidal doses of therapeutic radioisotopes to the sites of C. neoformans infection in vivo without radiation injury to the surrounding tissue and major organs. We also hypothesize that while inducing apoptosis and cell cycle arrest in C. neoformans cells through treatment with radiolabeled antibodies, no significant damage will be done to the certain components of immune system such as macrophages. The Specific Aims of this proposal are: 1. To generate radiolabeled derivatives of antibodies to C. neoformans and their fragments. 2. To identify the structural and functional characteristics of immunoglobulins that determine their suitability as anti-infective radioimmunotherapeutic agents in vitro and in vivo. 3. To elucidate the mechanisms of interaction between radiolabeled antibodies and C. neoformans cells in vitro. The research proposed here will contribute to development of a novel therapeutic modality based on radioimmunotherapy for treatment of currently incurable or multidrug-resistant AIDS-associated opportunistic infections. It will also provide some understanding of the fundamentals of interactions between microorganisms and antibodies radiolabeled with particulate-emitting radioisotopes in vitro and in vivo.

描述（申请人提供）：某些人的存在 艾滋病相关的机会感染，没有治愈的合并 随着细菌和真菌多种抗性菌株的出现 迫切需要对抗菌治疗的新方法。此应用程序 建议开发放射免疫疗法作为一种抗感染策略。我们有 最近建议将放射免疫疗法用作一种新型方式 使用C. Neoformans作为模型的机会主义的感染治疗 感染。 C. Neoformans作为模型系统具有多个优势 艾滋病相关的机会感染的放射免疫疗法，包括 存在优秀的动物模型和几个井的可用性 具有免疫学试剂的特征。此外，单克隆抗体疗法 使用单克隆抗体已经在用于新生梭菌的临床测试中 （mab）1887年。我们有放射性标记的mAb 18B7，具有治疗性放射性同位素 188-rhenium（1 88-RE）和21个3-苯甲部（21 3-Bi），并表明这些 放射标记的抗体可以在体外有效地消除新生虫细胞。 以及补体缺乏动物的生存率显着延长 致命感染了新生梭菌。我们假设18B7抗体可能 用作有效的送货工具，可递送杀真菌剂量 在体内感染C. Neoformans感染部位的放射性病 没有对周围组织和主要器官的辐射损伤。我们也是 假设在诱导C中凋亡和细胞周期停滞的同时。 Neoformans细胞通过放射性标记的抗体处理，无显着 免疫系统的某些组件将造成损害 巨噬细胞。该提案的具体目的是：1。生成 抗新生梭菌及其片段的抗体的放射标记衍生物。 2。 确定免疫球蛋白的结构和功能特征 这决定了它们作为抗感染性放射性疗法的适用性 体外和体内的代理。 3。阐明相互作用的机制 放射性标记的抗体和新生孢细胞在体外。研究 这里提出的将有助于发展新型治疗方式 基于放射免疫疗法，用于治疗当前无法治愈或 抗多药相关的机会感染。它也会 提供一些对互动基础的了解 微生物和抗颗粒发射的放射性标记的抗体 放射性病体外和体内。