CONSTANT DOMAIN MODULATION OF ANTIBODY ACTIVITY

这项提议的主要目标是澄清分子基础。 对于依赖于FC区域的，以及其重要性和一般性， 抗体与抗原的协同结合。此外，我们还将 其他功能的免疫球蛋白亚类相关差异的特征 属性。描述了将要采用的实验方法。 下面。 第一，表达不同的免疫球蛋白抗体的功能亲和力 重链恒定结构域将与不同的 (特别是关于表位间距)抗原形式 各种条件(如温度或离子强度)。单克隆 不同免疫球蛋白亚类的抗体(单抗)，但表达相同的， 或者类似的可变域将被用于这些研究。 第二，伽马3 Fc区域中涉及的站点 协同结合将通过血清学和电子显微镜进行定位 方法：研究方法。 第三，将小鼠免疫球蛋白亚类与 链球菌感染小鼠模型的清除和保护作用 肺炎。 四是筛选结合表型新颖的单抗， 特征，以及赋予抗体以 合作绑定的能力将得到评估。 这些研究应该有助于理解功能 免疫球蛋白亚类之间的差异，特别是在抗- 细菌和抗多糖抗体反应。此外，通过 增加我们对抗体之间的关系的理解 恒定的结构域结构和功能，这些研究应该表明 改变抗体结构以增强所需功能的新方法 属性。

The major objectives of this proposal are to clarify the molecular basis for, and the significance and generality of, Fc region-dependent, cooperative binding of antibodies to antigen. In addition, we will characterize IgG subclass-associated difference in other functional properties. The experimental approaches to be employed are delineated below. First, the functional affinities of IgG antibodies expressing different heavy chain constant domains will be compared with respect to different (particularly with regard to epitope spacing) forms of antigen under a variety of conditions (e.g., temperature or ionic strength). Monoclonal antibodies (mAbs) of different IgG subclasses, but expressing identical, or comparable, variable domains will be used for these studies. Second, the sites in the gamma 3 Fc region that are involved in cooperative binding will be mapped by serologic and electron microscopic methods. Third, the murine IgG subclasses will be compared with respect to clearance and protection in a murine model infection with Streptococcus pneumoniae. Forth, mAbs with novel binding phenotypes will be selected and characterized, and new strategies for endowing antibodies with the ability to bind cooperatively will be evaluated. These studies should contribute to an understanding of the functional differences among IgG subclasses, particularly in the contexts of anti- bacterial and anti-polysaccharide antibody responses. Further more, by increasing our understanding of the relationships between antibody constant domain structure and function, these studies should suggest novel ways to alter antibody structure to enhance desired functional properties.