天然免疫球蛋白M(IgM)抗体是五聚体或六聚体的宏免疫球蛋白,并且在进化过程中高度保守。IgM最初在B细胞个体发育期间表达,并且是在暴露于外来抗原后分泌的第一抗体。IgM多聚体具有10个(五聚体)或12个(六聚体)抗原结合域,由成对的µ重链与四个恒定域组成,每个都有一个单一的可变域,与相应的轻链配对。尽管天然IgM抗体的抗原结合亲和力通常低于IgG,它们的多价允许补体的高亲合力结合和有效接合以诱导补体依赖性细胞裂解。IgM抗体的高亲和力使它们在结合低水平存在的抗原时特别有效。和非蛋白质抗原,例如,碳水化合物或脂质存在于微生物表面。五聚体IgM抗体还含有连接(J)链,其稳定五聚体结构并能够与几种受体结合。一个这样的受体,聚合免疫球蛋白受体(pIgR),负责从脉管系统到肺和胃肠道的粘膜表面的胞吞作用。已经在临床试验中探索了几种天然存在的IgM抗体作为治疗剂,和一类新的分子,具有增强的结合和/或其他功能特性的工程IgM抗体正在人类中进行评估。这里,我们回顾了在理解生物学方面取得的重大进展,结构,函数,制造,和IgM抗体的治疗潜力,因为他们发现超过80年前。
Natural immunoglobulin M (IgM) antibodies are pentameric or hexameric macro-immunoglobulins and have been highly conserved during evolution. IgMs are initially expressed during B cell ontogeny and are the first antibodies secreted following exposure to foreign antigens. The IgM multimer has either 10 (pentamer) or 12 (hexamer) antigen binding domains consisting of paired µ heavy chains with four constant domains, each with a single variable domain, paired with a corresponding light chain. Although the antigen binding affinities of natural IgM antibodies are typically lower than IgG, their
polyvalency allows for high avidity binding and efficient engagement of complement to induce complement-dependent cell lysis. The high avidity of IgM antibodies renders them particularly efficient at binding antigens present at low levels, and non-protein antigens, for example, carbohydrates or lipids present on microbial surfaces. Pentameric IgM antibodies also contain a joining (J) chain that stabilizes the pentameric structure and enables binding to several receptors. One such receptor, the polymeric immunoglobulin receptor (pIgR), is responsible for transcytosis from the vasculature to the mucosal surfaces of the lung and gastrointestinal tract. Several naturally occurring IgM antibodies have been explored as therapeutics in clinical trials, and a new class of molecules, engineered IgM antibodies with enhanced binding and/or additional functional properties are being evaluated in humans. Here, we review the considerable progress that has been made regarding the understanding of biology, structure, function, manufacturing, and therapeutic potential of IgM antibodies since their discovery more than 80 years ago.