Radioimmunotherapy of opportunistic infections

描述（由申请人提供）：存在某些 无法治愈的艾滋病相关机会性感染 随着细菌和真菌的多重耐药菌株的出现， 迫切需要新的抗菌治疗方法。本申请 建议开发放射免疫疗法作为抗感染策略。我们有 最近建议使用放射免疫治疗作为一种新的方式， 使用C.新形式主义者作为一种模式， 感染C. neoformans作为模型系统有几个优点， 艾滋病相关机会性感染的放射免疫治疗，包括 优秀的动物模型的存在和几个良好的可用性 特征免疫学试剂。此外，单克隆抗体治疗 已经在进行C的临床试验使用单克隆抗体 (mAb)1887年我们用治疗性放射性同位素放射性标记mAb 18 B7， 188-铼（188-Re）和213-铋（213-Bi），并已表明，这些 放射性标记的抗体可以有效地根除C.体外新生儿细胞 并显著延长了缺乏补体的动物的存活时间 致死性感染C.新人类我们假设18 B7抗体可能 用作有效的递送载体以递送杀真菌剂量的 治疗性放射性同位素对C.体内新生菌感染 而不会对周围组织和主要器官造成辐射损伤。我们也 假设在诱导C. 通过放射性标记抗体处理新生儿细胞， 免疫系统的某些组成部分会受到损害， 巨噬细胞该提案的具体目标是：1。完成网站 放射性标记的抗C.新人类及其碎片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放射免疫制剂的适用性 体外和体内的药剂。3.阐明相互作用的机制 放射性标记抗体与C. neoformans细胞体外培养。研究 本文提出的方法将有助于开发一种新的治疗方式 基于放射免疫疗法治疗目前无法治愈或 多重耐药艾滋病相关的机会性感染。它还将 提供了一些相互作用的基础知识， 放射性标记的微生物和抗体 放射性同位素在体外和体内。

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.