The shaving reaction: Rituximab/CD20 complexes are removed from mantle cell lymphoma and chronic lymphocytic leukemia cells by THP-1 monocytes
The shaving reaction: Rituximab/CD20 complexes are removed from mantle cell lymphoma and chronic lymphocytic leukemia cells by THP-1 monocytes
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DOI：
10.4049/jimmunol.176.4.2600
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发表时间：
2006-02-15
影响因子：
4.4
通讯作者：
Taylor, RP
中科院分区：
文献类型：
--
作者：
Beum, PV;Kennedy, AD;Taylor, RP
临床研究表明，输注针对正常细胞或肿瘤细胞的免疫治疗性单克隆抗体可导致靶向表位的丢失，这种现象称为抗原调节。最近，我们报道了利妥昔单抗治疗慢性淋巴细胞白血病患者，当利妥昔单抗血浆浓度高时，在输注利妥昔单抗后循环中发现B细胞上CD20的大量丢失。这种抗原调节可能严重影响治疗效果，我们假设在Fc γ r介导的反应中，B细胞被单核细胞或巨噬细胞剥离（剃光）了利妥昔单抗/CD20复合物。我们建立了一个体外模型，基于利妥昔单抗调理的CD20（+）细胞与受体THP-1单核细胞的反应，来复制这种体内剃光过程。在37℃下45分钟后，利妥昔单抗和CD20从调理细胞中去除，两者在受体THP-1细胞上均可见。在正常人血清存在和不存在的情况下，该反应同样发生，并且从外周血中分离的单核细胞也能促进利妥昔单抗调理细胞中CD20的去除。使用利妥昔单抗的抑制剂和F(ab')2的试验表明，利妥昔单抗/CD20复合物向THP-1细胞的转移是由Fc γ r介导的，以前的报道中描述的抗原调节可能是由这种剪切介导的，我们的发现可能对单克隆单抗在癌症免疫治疗中的应用具有深远的意义。
Clinical investigations have revealed that infusion of immunotherapeutic mAbs directed to normal or tumor cells can lead to loss of targeted epitopes, a phenomenon called antigenic modulation. Recently, we reported that rituximab treatment of chronic lymphocytic leukemia patients induced substantial loss of CD20 on B cells found in the circulation after rituximab infusion, when rituximab plasma concentrations were high. Such antigenic modulation can severely compromise therapeutic efficacy, and we postulated that B cells had been stripped (shaved) of the rituximab/CD20 complex by monocytes or macrophages in a reaction mediated by Fc gamma R. We developed an in vitro model to replicate this in vivo shaving process, based on reacting rituximab-opsonized CD20(+) cells with acceptor THP-1 monocytes. After 45 min at 37 degrees C, rituximab and CD20 are removed from opsonized cells, and both are demonstrable on acceptor THP-1 cells. The reaction occurs equally well in the presence and absence of normal human serum, and monocytes isolated from peripheral blood also promote shaving of CD20 from rituximab-opsonized cells. Tests with inhibitors and use of F(ab')2 of rituximab indicate transfer of rituximab/CD20 complexes to THP-1 cells is mediated by Fc gamma R. Antigenic modulation described in previous reports may have been mediated by such shaving, and our findings may have profound implications for the use of mAbs in the immunotherapy of cancer.