Protective Human Anti-Candida Antibodies

描述（由申请方提供）：白色念珠菌是一种酵母样真菌病原体，可引起危及生命的血源性播散性念珠菌病。C.白色念珠菌富含甘露寡糖和多糖，称为甘露聚糖，其在真菌-人相互作用中起重要作用。我们已经开发了第一个全长人IgG 1抗甘露聚糖抗体，M1 G1，并发现它是在小鼠模型的血源性播散性念珠菌病的保护。这项研究沿着鼠抗甘露聚糖抗体的结果表明，抗甘露聚糖抗体在宿主对念珠菌病的抗性中发挥作用。我们的长期目标是开发用于预防和治疗应用的保护性人抗念珠菌抗体。 最近的研究表明，M1 g1启动调理素C3片段在C.在一些实施方案中，本发明的抗体以Fc依赖性方式通过经典途径或以新的Fc非依赖性Fab依赖性方式通过替代途径感染白色念珠菌。然而，M1 g4，M1 g1的IgG 4变体，仅激活旁路途径。M1 g1或M1 g4单独促进人嗜中性粒细胞对酵母细胞的吞噬作用。然而，补体增强M1 g4调理酵母细胞的吞噬作用，而不是M1 g1调理酵母。其他研究显示M1 g4在抵抗播散性念珠菌病中具有保护作用。 这些观察结果表明，补体片段和抗甘露聚糖IgG之间的相互作用，当沉积在细胞上作为吞噬细胞的调理素时，可能是协同的，拮抗的，或无关紧要的，因此可能影响抗甘露聚糖抗体的保护功效。将使用一整套人IgG亚类变体M1 g1、M1 g2、M1 g3和M1 g4（含有相同Fab、M1，但Fc区和Fc介导的效应子功能不同）来检验这一假设。具体目标是：1）分析IgG亚类特异性对抗甘露聚糖抗体介导的C. 2）测定人抗甘露聚糖抗体IgG亚类变体激活小鼠补体系统的能力; 3）观察补体对IgG亚类介导的白念珠菌吞噬和吞噬杀伤作用的影响。4）确定补体系统对抗甘露聚糖抗体的IgG亚类变体的保护效力的影响，和5）评价补体和IgG作为调理素对于与Fc介导的效应子功能不同的遗传改变的M1抗体的吞噬作用的相对贡献。 本研究的结果将为深入了解抗甘露聚糖抗体介导的对血源性播散性念珠菌病的耐药机制提供依据。这些见解对于开发用于免疫预防和免疫抑制应用的人保护性抗甘露聚糖抗体具有价值。 公共卫生相关性：白色念珠菌是一种酵母样真菌病原体，是住院患者感染的最常见原因。本项目将研究人类抗念珠菌抗体的保护机制。

DESCRIPTION (provided by applicant): Candida albicans is a yeast-like fungal pathogen and can cause life-threatening hematogenously disseminated candidiasis. The cell surface of C. albicans is enriched with manose oligosaccharides and polysaccharides known as mannan that plays an important role in Candida-human interactions. We have developed the first full length human IgG1 antimannan antibody, M1g1, and found it to be protective in a mouse model of hematogenously disseminated candidiasis. This study along with results from murine antimannan antibodies indicate a role for antimannan antibody in host resistance to candidiasis. Our long term goal is to develop protective human anti-Candida antibodies for prophylactic and therapeutic applications. Recent studies have demonstrated that M1g1 initiates deposition of opsonic C3 fragments on C. albicans through the classical pathway in an Fc-dependent manner or through the alternative pathway in a novel Fc- independent Fab-dependent manner. However, M1g4, an IgG4 variant of M1g1, activates the alternative pathway only. M1g1 or M1g4 alone promotes phagocytosis of yeast cells by human neutrophils. However, complement enhanced phagocytosis of M1g4-opsonized yeast cells, not M1g1-opsonized yeast. Additional studies revealed a protective role for M1g4 in resistance to disseminated candidiasis. These observations suggest that the interplay between complement fragments and antimannan IgG, when deposited on cells as opsonins for phagocytes, may be synergistic, antagonistic, or indifferent and thus may influence the protective efficacy of an antimannan antibody. This hypothesis will be examined using a complete set of human IgG subclass variants, M1g1, M1g2, M1g3, and M1g4, that contain the same Fab, M1, but differ in the Fc region and Fc-mediated effector functions. The specific aims are: 1) To analyze the influence of IgG subclass specificity on antimannan antibody-mediated phagocytosis and phagocytic killing of C. albicans, 2) To determine the ability of IgG subclass variants of human antimannan antibody to activate the murine complement system, 3) To assess the effect of complement on IgG subclass-mediated phagocytosis and phagocytic killing of C. albicans, 4) To determine the influence of the complement system on the protective efficacy of IgG subclass variants of antimannan antibody, and 5) To evaluate the relative contribution of complement and IgG as opsonins for phagocytosis with genetically altered M1 antibodies that differ in Fc- mediated effector functions. Results from this study will provide insights into the mechanisms of antimannan antibody-mediated resistance to hematogenously disseminated candidiasis. These insights are valuable to the development of human protective antimannan antibodies for immunoprophylactic and immunotherapeutic applications. PUBLIC HEALTH RELEVANCE: Candida albicans is a yeast-like fungal pathogen and is among the most common causes of infections in hospitalized patients. This project will study the protective mechanisms of human anti-Candida antibodies.