以FcγR为靶标治疗炎症及癌症的药物状况论述.doc

以FcγR为靶标治疗炎症及癌症的研究概况 2012- 目 录 第一章 概述FcγR与IgG的结构与功能 1 第三章 可溶性FcγR 7 第四章 抗FcγR的单抗 11 第五章 小分子肽和类肽物 13 第六章 免疫球蛋白类似物 17 第七章 小分子化合物 19 第八章 静脉注射免疫球蛋白 22 第九章 修饰Ig的Fc段 28 第十章 修饰IgG的半衰期 36 附件1 Fc/FcR的化学计量学问题 45 附件2 FcγR与IgG结合的空间构象 47 第一章 概述FcγR与IgG的结构与功能 一、FcγR在体内不同细胞上的分布与表达水平[1, 2] FcγRs are the most diverse family of FcRs and include three distinct classes of receptor encoded by six genes: FCGR1A (which encodes FcγRI; also known as CD64), FCGR2A (which encodes FcγRIIa; also known as CD32A), FCGR2B (which encodes FcγRIIb; also known as CD32B), FCGR2C (which encodes FcγRIIc; also known as CD32C), FCGR3A (which encodes FcγRIIIa; also known as CD16A) and FCGR3B (which encodes FcγRIIIb; also known as CD16B). FCGR2C is the product of a crossover between FCGR2A and FCGR2B, which share a high degree of homology. 二、FcγR的分型与结构[1-3] The Fc receptors (FcRs) consist of an immunoglobulin-binding polypeptide chain containing two immunoglobulin-like domains that form the extracellular region. FcγRI is an exception as it has three such domains, the first two of which are related to those of the other FcγRs and FcεRI, the third domain is unique. FcαR, which also has two extracellular domains, is more closely related to the leukocyte immunoglobulin-like receptors. Signal transduction by the activating FcRs occurs via immunoreceptor tyrosine-based activation motif (ITAM)-dependent mechanisms, usually via a non-covalent association of the immunoglobulin-binding chain with a dimeric, ITAM-containing subunit, typically the ‘common’ FcR γ-chain. In mast cells, FcεRI also associates with a multimembrane-spanning and signal-amplifying β-subunit (the same applies to FcγRIIIa; not shown). FcγRIIa, FcγRIIb and FcγRIIc are unusual as their signalling motifs are contained in the cytoplasmic tail of the ligand-binding chain. This comprises an ITAM for the activating FcγRIIa or FcγRIIc, and an immunoreceptor tyrosine-based inhibition motif (ITIM) for the inhibitory F