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 随着多重耐药细菌和真菌菌株的出现， 迫切需要新的抗菌治疗方法。此应用程序 建议发展放射免疫疗法作为一种抗感染策略。我们有 最近建议使用放射免疫疗法作为一种新的治疗方式 以新生葡萄球菌为模型机会主义治疗感染 感染。新生葡萄球菌作为一种模式系统有几个优点 艾滋病相关机会性感染的放射免疫治疗，包括 优秀动物模型的存在和几个井的可用性 特定化的免疫试剂。此外，单抗治疗 已经在临床上使用这种单抗对新生葡萄球菌进行检测。 (Mab)1887年。我们有放射性标记的单抗18B7和治疗性放射性同位素 188-Re(1.88-Re)和21.3-铋(21.3-Bi)，并表明这些 放射性标记抗体在体外可有效杀灭新生葡萄球菌细胞 以及显著延长补体缺乏动物的存活时间 感染致死性新生葡萄球菌。我们推测18B7抗体可能 作为一种有效的递送载体来递送杀菌剂剂量的 体内新生弧菌感染部位的治疗性放射性同位素研究 对周围组织和主要器官无辐射损伤。我们也 假设在诱导C。 通过放射性标记抗体治疗的新生细胞，没有显著意义 会对免疫系统的某些组成部分造成损害，例如 巨噬细胞。这项建议的具体目标是：1.产生 抗新生弧菌抗体的放射性标记衍生物及其片段。2. 鉴定免疫球蛋白的结构和功能特性 决定了它们是否适合作为抗感染放射免疫疗法 体外和体内的药物。3.阐明相互作用的机制 放射性标记抗体与新生隐球菌体外细胞的相互作用。这项研究 这里提出的建议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的或 耐多药艾滋病相关机会性感染。它还将 提供对相互作用的基本原理的一些了解 放射性微粒标记的微生物和抗体 体外和体内的放射性同位素。

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.