Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection
Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection
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DOI：
10.1182/blood-2010-01-263533
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发表时间：
2010-06-24
期刊：
影响因子：
20.3
通讯作者：
Cragg, Mark S.
中科院分区：
文献类型：
--
作者：
Beers, Stephen A.;French, Ruth R.;Cragg, Mark S.
利妥昔单抗是一种靶向B细胞上的CD 20的单克隆抗体，现在是治疗各种恶性和自身免疫性疾病的核心。尽管取得了这一成功，但相当大比例的B细胞淋巴瘤是无反应的或产生耐药性，因此正在不断寻求更有效的抗CD 20单克隆抗体（mAb）。在此，我们证明了II型（托西莫单抗样）抗CD 20 mAb在消耗人CD 20 Tg B细胞方面的效力是I型（利妥昔单抗样）试剂的5倍，尽管两者都仅通过表达活化Fc γ受体的巨噬细胞起作用。这种性能上的差异大部分归因于I型mAb介导的B细胞对CD 20的内化，导致巨噬细胞募集减少和CD 20/mAb复合物降解，缩短mAb半衰期。重要的是，来自健康供体的人B细胞和大多数慢性淋巴性白血病和套细胞淋巴瘤病例显示出快速的CD 20内化，这与在Tg小鼠B细胞中观察到的相反，而大多数滤泡性淋巴瘤和弥漫性大B细胞淋巴瘤细胞对CD 20损失的抵抗力要大得多。我们推测，CD 20调节的差异可能在确定利妥昔单抗治疗这些疾病的相对疗效方面发挥核心作用，并加强了在临床上关注II型抗CD 20 mAb的情况。（血。2010;115（25）：5191-5201）
Rituximab, a monoclonal antibody that targets CD20 on B cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success, a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 monoclonal antibodies (mAbs) are continuously being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAbs are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B cells, despite both operating exclusively via activatory Fc gamma receptor-expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B cells, leading to reduced macrophage recruitment and the degradation of CD20/mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors and most cases of chronic lymphatic leukemia and mantle cell lymphoma, showed rapid CD20 internalization that paralleled that seen in the Tg mouse B cells, whereas most follicular lymphoma and diffuse large B-cell lymphoma cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic. (Blood. 2010;115(25):5191-5201)