Monoclonal antibody therapy of B cell lymphoma: signaling activity on tumor cells appears more important than recruitment of effectors.
Monoclonal antibody therapy of B cell lymphoma: signaling activity on tumor cells appears more important than recruitment of effectors.
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B 细胞淋巴瘤的单克隆抗体治疗：肿瘤细胞的信号传导活性似乎比效应细胞的招募更重要。
DOI：
10.4049/jimmunol.161.6.3176
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发表时间：
1998
影响因子：
4.4
通讯作者：
M. Glennie
中科院分区：
文献类型：
--
作者：
A. Tutt;R. French;Timothy M Illidge;J. Honeychurch;H. M. McBride;Christine A. Penfold;Douglas T. Fearon;R. Parkhouse;Gerry G. B. Klaus;M. Glennie
尽管最近mAb在某些恶性肿瘤的治疗中取得了成功，但关于抗癌Ab的作用机制仍存在相当大的不确定性。在此，研究了一组大鼠抗小鼠B细胞mAb（包括针对表面IgM Id、CD 19、CD 22、CD 40、CD 74和MHC II类的Ab）治疗两种同基因小鼠B细胞淋巴瘤BCL 1和A31的情况。只有三种mAb在体内具有治疗活性，即抗Id、抗CD19和抗CD40。尽管在Ag依赖性细胞毒性和补体测定中提供了良好水平的表面结合和活性，并且在某些情况下在体外抑制细胞生长，但针对其他Ag的mAb在任一模型中显示出很少或没有治疗活性。我们得出结论，mAb在体外的活性并不能预测在体内的治疗性能。此外，使用荧光标记细胞的体内追踪实验表明，抗Id和抗CD40 mAb可能通过不同的机制起作用：抗Id mAb几乎立即引起生长停滞，并且在5或6天内不会消除细胞，而抗CD40 mAb具有延迟效应，允许肿瘤正常生长3天，但随后突然根除淋巴瘤细胞。这项工作支持这样的信念，即mAb特异性对于淋巴瘤的治疗成功至关重要，并且除了它们可能具有的任何效应子募集活性之外，体内mAb通过涉及关键细胞受体的交联和信号传导的机制来操作。
Despite the recent success of mAb in the treatment of certain malignancies, there is still considerable uncertainty about the mechanism of action of anti-cancer Abs. Here, a panel of rat anti-mouse B cell mAb, including Ab directed at surface IgM Id, CD19, CD22, CD40, CD74, and MHC class II, has been investigated in the treatment of two syngeneic mouse B cell lymphomas, BCL1 and A31. Only three mAb were therapeutically active in vivo, anti-Id, anti-CD19, and anti-CD40. mAb to the other Ags showed little or no therapeutic activity in either model despite giving good levels of surface binding and activity in Ag-dependent cellular cytotoxicity and complement assays, and in some cases inhibiting cell growth in vitro. We conclude that the activity of mAb in vitro does not predict therapeutic performance in vivo. Furthermore, in vivo tracking experiments using fluorescently tagged cells showed that anti-Id and anti-CD40 mAb probably operate via different mechanisms: the anti-Id mAb cause growth arrest that is almost immediate and does not eliminate cells over a period of 5 or 6 days, and the anti-CD40 mAb have a delayed effect that allows tumor to grow normally for 3 days, but then abruptly eradicates lymphoma cells. This work supports the belief that mAb specificity is critical to therapeutic success in lymphoma and that, in addition to any effector-recruiting activity they may possess, in vivo mAb operate via mechanisms that involve cross-linking and signaling of key cellular receptors.