Exhaustion of cytotoxic effector systems may limit monoclonal antibody-based immunotherapy in cancer patients.
Exhaustion of cytotoxic effector systems may limit monoclonal antibody-based immunotherapy in cancer patients.
复制标题
DOI：
10.4049/jimmunol.1103693
复制
发表时间：
2012-04-01
期刊：
影响因子：
--
通讯作者：
Taylor RP
中科院分区：
文献类型：
--
作者：
Beurskens FJ;Lindorfer MA;Farooqui M;Beum PV;Engelberts P;Mackus WJ;Parren PW;Wiestner A;Taylor RP
CD20 mAb奥法木单抗（OFA）诱导补体介导的B细胞裂解。在一项OFA联合化疗治疗慢性淋巴细胞白血病（CLL）的II期临床试验中，OFA治疗促进了部分CLL B细胞耗竭，这与补体滴度降低一致。剩余的CLL B细胞与结合的OFA和共价结合的补体分解产物C3 d一起循环，指示正在进行的补体活化。据推测，基于补体或效应细胞的机制都不足以清除这些剩余的B细胞。相反，几乎所有结合的OFA以及CD 20都从细胞中除去，这与先前的临床研究一致，该临床研究证明了在用利妥昔单抗治疗CLL患者后，来自B细胞的CD 20的相当损失。用OFA和利妥昔单抗进行的体外实验表明，支持mAb介导的裂解和肿瘤细胞清除的宿主效应机制是有限的，并且在高B细胞负荷下，特别是在高mAb浓度下，它们可能饱和或耗尽。有趣的是，用CD20 mAb杀死细胞只需要一部分可用的补体，并且可以通过滴定mAb浓度来调节杀死。因此，在中等mAb浓度下实现了初始和二次B细胞攻击的最大B细胞杀伤，而高浓度促进了较低的总体杀伤。因此，基本上依赖于受耗竭影响的效应器机制（包括补体）的mAb疗法可受益于优化的更低、更频繁的给药方案，以维持和最大化细胞毒性免疫效应器系统的杀伤。
The CD20 mAb ofatumumab (OFA) induces complement-mediated lysis of B cells. In an investigator-initiated phase II trial of OFA plus chemotherapy for chronic lymphocytic leukemia (CLL), OFA treatment promoted partial CLL B cell depletion which coincided with reduced complement titers. Remaining CLL B cells circulated with bound OFA and covalently bound complement breakdown product C3d, indicative of ongoing complement activation. Presumably neither complement- nor effector cell-based mechanisms were sufficiently robust to clear these remaining B cells. Instead, almost all of the bound OFA as well as CD20 was removed from the cells, in accordance with previous clinical studies which demonstrated comparable loss of CD20 from B cells after treatment of CLL patients with rituximab. In vitro experiments with OFA and rituximab addressing these observations suggest that host effector mechanisms which support mAb-mediated lysis and tumor cell clearance are finite, and they can be saturated or exhausted at high B cell burdens, particularly at high mAb concentrations. Interestingly, only a fraction of available complement was required to kill cells with CD20 mAbs, and killing could be tuned by titrating the mAb concentration. Consequently, maximal B cell killing of an initial and secondary B cell challenge was achieved with intermediate mAb concentrations, whereas high concentrations promoted lower overall killing. Therefore mAb therapies that rely substantially on effector mechanisms subject to exhaustion, including complement, may benefit from lower, more frequent dosing schemes optimized to sustain and maximize killing by cytotoxic immune effector systems.
登录
查看更多内容
影响因子：
4.4
作者：
Beum, Paul V.;Lindorfer, Margaret A.;Taylor, Ronald P.
通讯作者：
Taylor, Ronald P.
影响因子：
45.3
作者：
Byrd, JC;Murphy, T;Flinn, IW
通讯作者：
Flinn, IW
影响因子：
3.6
作者：
Glennie, Martin J.;French, Ruth R.;Taylor, Ronald P.
通讯作者：
Taylor, Ronald P.
影响因子：
20.3
作者：
Beers, Stephen A.;French, Ruth R.;Cragg, Mark S.
通讯作者：
Cragg, Mark S.
影响因子：
4.4
作者：
Beum, PV;Kennedy, AD;Taylor, RP
通讯作者：
Taylor, RP