Yang Jing, Qian Jianfei, Wezeman Michele, Wang Siqing, Lin Pei, Wang Michael, Yaccoby Shmuel, Kwak Larry W, Barlogie Bart, Yi Qing
Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Cell. 2006 Oct;10(4):295-307. doi: 10.1016/j.ccr.2006.08.025.
We discovered that monoclonal antibodies (mAbs) specific to human beta(2)-microglobulin (beta(2)M) induce apoptosis in vitro and were therapeutic in mouse models of myeloma and other hematological tumor cells. Cell death occurred rapidly, without the need for exogenous immunological effector mechanisms. The mAbs induced cell death via recruiting MHC class I molecules to lipid rafts and activating Lyn and PLCgamma2, leading to activated JNK and inhibited PI3K/Akt and ERK, compromised mitochondrial integrity, and caspase-9-dependent cascade activation. Although the expression of beta(2)M on normal hematopoietic cells is a potential safety concern, the mAbs were selective to tumor-transformed cells and did not induce apoptosis of normal cells. Therefore, such mAbs offer the potential for a therapeutic approach to hematological malignancies.
我们发现，特异性针对人β2微球蛋白（β2M）的单克隆抗体（mAb）在体外可诱导细胞凋亡，并且在骨髓瘤及其他血液肿瘤细胞的小鼠模型中具有治疗作用。细胞死亡迅速发生，无需外源性免疫效应机制。这些单克隆抗体通过将MHC I类分子募集到脂筏并激活Lyn和PLCγ2来诱导细胞死亡，导致JNK激活，PI3K/Akt和ERK受到抑制，线粒体完整性受损，以及半胱天冬酶-9依赖性级联激活。尽管β2M在正常造血细胞上的表达是一个潜在的安全问题，但这些单克隆抗体对肿瘤转化细胞具有选择性，不会诱导正常细胞凋亡。因此，此类单克隆抗体为血液系统恶性肿瘤提供了一种潜在的治疗方法。
