Targeting cell surface β2 -microglobulin by pentameric IgM antibodies.
Targeting cell surface β2 -microglobulin by pentameric IgM antibodies.
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DOI：
10.1111/j.1365-2141.2011.08714.x
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发表时间：
2011-07
影响因子：
6.5
通讯作者：
Yi Q
中科院分区：
文献类型：
--
作者：
Cao Y;Lan Y;Qian J;Zheng Y;Hong S;Li H;Wang M;Kwak LW;Lin D;Yang J;Yi Q
针对人β2-微球蛋白（β 2 M）的特异性单克隆抗体（mAb）已被证明可通过将主要组织相容性复合物（MHC）I类分子募集到脂筏中并从脂筏中排除细胞因子受体来诱导血液肿瘤和实体瘤中的肿瘤细胞凋亡。基于这些发现，我们假设IgM抗β 2 M mAb可能由于其五聚体结构而具有更强的凋亡作用。我们的研究结果表明，与IgG mAb相比，IgM抗β 2 M mAb在体外对不同的肿瘤细胞（包括骨髓瘤、套细胞淋巴瘤和前列腺癌）以及在体内对类人异种移植骨髓瘤小鼠模型显示出更强的杀肿瘤活性，而不损伤正常组织。IgM mAb诱导的细胞凋亡依赖于mAb的五聚体结构。将五聚体IgM破坏成单体IgM显著降低了它们诱导细胞凋亡的能力。单体IgM单克隆抗体在招募MHC I类分子进入脂筏和排除细胞因子受体以及激活内在凋亡级联方面效率较低。因此，我们开发并验证了可用于临床的抗β 2 M IgM mAb的疗效，并表明IgM抗β 2 M mAb在诱导肿瘤细胞凋亡方面可能比IgG mAb更有效。
Monoclonal antibodies (mAbs) specific for human β2-microglobulin (β2M) have been shown to induce tumour cell apoptosis in haematological and solid tumours via recruiting major histocompatibility complex (MHC) class I molecules into and excluding cytokine receptors from the lipid rafts. Based on these findings, we hypothesized that IgM anti-β2M mAbs might have stronger apoptotic effects because of their pentameric structure. Our results showed that, compared with IgG mAbs, IgM anti-β2M mAbs exhibited stronger tumouricidal activity in vitro against different tumour cells, including myeloma, mantle cell lymphoma, and prostate cancer, and in vivo in a human-like xenografted myeloma mouse model without damaging normal tissues. IgM mAb-induced apoptosis is dependent on the pentameric structure of the mAbs. Disrupting pentameric IgM into monomeric IgM significantly reduced their ability to induce cell apoptosis. Monomeric IgM mAbs were less efficient at recruiting MHC class I molecules into and exclusion of cytokine receptors from lipid rafts, and at activating the intrinsic apoptosis cascade. Thus, we developed and validated the efficacy of anti-β2M IgM mAbs that may be utilized in the clinical setting and showed that IgM anti-β2M mAbs may be more potent than IgG mAbs at inducing tumour apoptosis.
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