MECHANISM OF ANTIBODY PROTECTION AGAINST C. NEOFORMANS

在美国，新生隐球菌会导致8%的艾滋病患者发生致命性脑膜脑炎。 目前的治疗是不够的，因为10%-20%的患者死于隐球菌性脑膜炎，尽管具有侵袭性 抗真菌治疗，存活超过最初治疗期的个体必须维持在 终身治疗，防止复发。由于这些治疗的局限性，抗体已经被 被认为是预防和治疗新生葡萄球菌感染的药物。抗囊膜单抗 可延长致死感染小鼠的寿命，增加体内抗真菌药物的效力。 先前的观察表明，由这些抗体的恒定区域介导的功能是至关重要的。 在确定它们的保护潜力方面。与这一想法一致的是我们在 基因缺陷的小鼠表明抗体与某些Fc受体(FCR)的相互作用是重要的 在中介保护中，虽然补体的存在可能不利于抗体效力， 特别是在没有FCR结合的情况下。在过去的几年里，我们开发了一个大型的图书馆 重组抗体具有多种不同的功能特性。我们现在将移植抗隐球菌 这些抗体上的可变区，以单独和联合检测这些抗体的贡献 动物模型的FCR结合、补体激活、亲和力和半衰期等特征 感染新生葡萄球菌的可能性。我们将首先在体外确认这些抗体的功能特性 通过测试FCR结合、抗体依赖细胞介导的细胞毒性(ADCC)和补体激活 并测定其在体内的药代动力学。然后，我们将测试体内对C。 新形态主义者。具体地说，我们将调查抗体的有效性是否取决于：i)在河流中的持久性，ii) 激活补体的能力，iii)FCR的结合，或iv)表面抗原的有效交联。这个 这里提出的实验旨在探索这样一种假设，即不同类型的抗体 星座的功能特性会有不同程度的疗效，小鼠感染C. 新生杆菌是一个特别相关的系统，因为一种鼠类单抗目前正在进行 艾滋病患者隐球菌性脑膜炎治疗的I期评价。如果这场审判证明 提出的实验前景看好，将为选择最佳治疗候选人(S)提供依据 进一步研究。明确定义哪些属性与功效相关，应该会让我们向前迈进 在设计用于治疗人类疾病的有效治疗性抗体方面。

Cryptococcus neoformans causes a lethal meningoencephalitis in 8% of AIDS patients in the US. Current treatment is inadequate as 10-20% of patients die from cryptococcal meningitis despite aggressive antifungal therapy, and individuals who survive beyond the initial treatment period must be maintained on life-long therapy to prevent relapse. Because of these therapeutic limitations, antibodies have been considered as prevention and treatment for C. neoformans infection. Anti-capsular monoclonal antibodies can prolong the life of lethally infected mice and increase the effectiveness of antifungal agents in vivo. Previous observations indicate that functions mediated by the constant regions of these antibodies are crucial in determining their protective potential. Consistent with this idea are preliminary studies we have done in genetically deficient mice showing that antibody interactions with certain Fc receptors (FcRs) are important in mediating protection, while the presence of complement may be detrimental to antibody efficacy, particularly in the absence of FcR binding. Over the past several years, we have developed a large library of recombinant antibodies with a variety of different functional properties. We will now graft anti-cryptococcal variable regions onto these antibodies to examine, both alone and in combination, the contribution of such characteristics as FcR binding, complement activation, avidity and half-life to efficacy in an animal model of infection with C. neoformans. We will first confirm the functional properties of these antibodies in vitro by testing FcR binding, antibody-dependant cell mediated cytotoxicity (ADCC), and complement activation and determine their pharmacokinetics in vivo. We will then test in vivo efficacy against infection with C. neoformans. Specifically, we will investigate whether antibody efficacy depends on: i) in rive persistence, ii) ability to activate complement, iii) engagement of FcRs, or iv) effective cross-linking of surface antigen. The experiments proposed here are designed to explore the hypothesis that antibodies with different constellations of functional properties will have differing degrees of efficacy, Murine infection with C. neoformans is a particularly relevant system because a murine monoclonal antibody is currently undergoing Phase I evaluation for the treatment of cryptococcal meningitis in AIDS patients. If this trial proves promising, the experiments proposed will provide the basis for selecting the best therapeutic candidate(s) for further study. A clear definition of what properties correlate with efficacy should allow us to move forward in designing effective therapeutic antibodies for treatment of disease in humans.