STRUCTURE STUDIES ON PROTEINS THAT MODULATE IL-10 ACTION

描述：（来自申请人摘要）本研究的总体目标 是确定蛋白质相互作用的结构基础， 通过阐明晶体调节白细胞介素10（IL-10）生物活性 IL-10与其细胞表面受体复合的结构，以及几种Fab 使用X射线衍射技术的中和抗体片段。这些 数据将用于设计IL-10突变体，其增强或阻止IL-10/IL-10 受体相互作用以及改变几何形状和/或 IL-10受体-配体复合物的化学计量。形成复合物 由IL-10、高亲和性受体（IL-10 R α）和信号肽组成。 转导受体（IL-10 R β）是产生IL-10所必需的 抑制TH 1依赖性细胞介导免疫的生物活性 应答由于这些活性，IL-10是非常有前途的蛋白质 用于治疗慢性炎性疾病的治疗剂。IL-10是 目前正在进行克罗恩病的III期临床试验和II期临床试验， 风湿性关节炎影响了4000万人， 每年超过650亿美元的工作残疾。除了其 IL-10具有免疫抑制作用，被认为是一种自分泌生长因子 在几种B细胞恶性肿瘤的发病机制中起作用。因此，在本发明中， IL-10的拮抗剂具有潜在的治疗应用。

Description: (From the applicant's abstract) The overall goal of this research is to identify the structural basis for protein-protein interactions that modulate interleukin 10 (IL-10) biological activities by elucidating crystal structures of IL-10 complexed with its cell surface receptors, and several Fab fragments of neutralizing antibodies using X-ray diffraction techniques. These data will be used to design IL-10 mutants that enhance or prevent IL-10/IL-10 receptor interactions as well as mutants that change the geometry and/or the stoichiometry of the IL-10 receptor-ligand complex. Formation of a complex consisting of IL-10, a high affinity receptor (IL-10Ralpha), and a signal transducing receptor (IL-10Rbeta) is required for the generation of IL-10 biological activities that suppress TH1-dependent, cell-mediated immune responses. As a result of these activities, IL-10 is a very promising protein therapeutic for the treatment of chronic inflammatory diseases. IL-10 is currently in phase III clinical trials for Crohn's disease and phase II trials for rheumatoid arthritis that affects 40 million people and costs the country over 65 billion dollars annually in work disability. In addition to its immunosuppressive role, IL-10 has been implicated as an autocrine growth factor responsible in the pathogenesis of several B-cell malignancies. Thus, antagonists of IL-10 have potential therapeutic applications.