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IgG 协同性——存在别构效应吗？对抗体功能和治疗性抗体开发的影响。

IgG cooperativity - Is there allostery? Implications for antibody functions and therapeutic antibody development.

机构信息

a Biotherapeutics Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc. , Ridgefield , Connecticut , USA.

b Janssen BioTherapeutics, Janssen Research & Development, LLC, Spring House , Pennsylvania , USA.

出版信息

MAbs. 2017 Nov/Dec;9(8):1231-1252. doi: 10.1080/19420862.2017.1367074. Epub 2017 Aug 16.

DOI:10.1080/19420862.2017.1367074
PMID:28812955
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5680800/
Abstract

A central dogma in immunology is that an antibody's in vivo functionality is mediated by 2 independent events: antigen binding by the variable (V) region, followed by effector activation by the constant (C) region. However, this view has recently been challenged by reports suggesting allostery exists between the 2 regions, triggered by conformational changes or configurational differences. The possibility of allosteric signals propagating through the IgG domains complicates our understanding of the antibody structure-function relationship, and challenges the current subclass selection process in therapeutic antibody design. Here we review the types of cooperativity in IgG molecules by examining evidence for and against allosteric cooperativity in both Fab and Fc domains and the characteristics of associative cooperativity in effector system activation. We investigate the origin and the mechanism of allostery with an emphasis on the C-region-mediated effects on both V and C region interactions, and discuss its implications in biological functions. While available research does not support the existence of antigen-induced conformational allosteric cooperativity in IgGs, there is substantial evidence for configurational allostery due to glycosylation and sequence variations.

摘要

免疫学的一个中心法则是，抗体的体内功能是由两个独立的事件介导的：可变（V）区与抗原结合，然后由恒定（C）区激活效应器。然而，最近有报道称，2 个区域之间存在变构，这一观点挑战了这一观点，其由构象变化或构象差异引发。IgG 结构域之间的变构信号传播的可能性使我们对抗体结构-功能关系的理解变得复杂，并对治疗性抗体设计中的当前亚类选择过程提出了挑战。通过检查 Fab 和 Fc 结构域中变构协同作用的证据和反证，以及效应子系统激活中的缔合协同作用的特征，我们研究了 IgG 分子中的协同作用类型。我们研究了变构的起源和机制，并重点讨论了 C 区对 V 和 C 区相互作用的介导效应，以及其在生物学功能中的意义。虽然现有研究不支持 IgG 中存在抗原诱导的构象变构协同作用，但由于糖基化和序列变异，存在大量构象变构的证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/5bbca70c2d6f/kmab-09-08-1367074-g011.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/d9c1965475bb/kmab-09-08-1367074-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/6ba420c774c9/kmab-09-08-1367074-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/5bbca70c2d6f/kmab-09-08-1367074-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/2eea0eb85b48/kmab-09-08-1367074-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/437e68adc283/kmab-09-08-1367074-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/24ec12b63574/kmab-09-08-1367074-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/e9ca325fd44f/kmab-09-08-1367074-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/12db59789085/kmab-09-08-1367074-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/e8bcdb3d762e/kmab-09-08-1367074-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/f680cf40c027/kmab-09-08-1367074-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/027a2d013ba9/kmab-09-08-1367074-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/d9c1965475bb/kmab-09-08-1367074-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/6ba420c774c9/kmab-09-08-1367074-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4611/5680800/5bbca70c2d6f/kmab-09-08-1367074-g011.jpg

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