Department of Pre-Clinical Research, Seattle Genetics, Inc., Bothell, Washington 98021, USA.
Clin Cancer Res. 2011 Jul 15;17(14):4672-81. doi: 10.1158/1078-0432.CCR-11-0479. Epub 2011 May 24.
Individually targeting B-cell antigens with monoclonal antibody therapeutics has improved the treatment of non-Hodgkin lymphoma (NHL). We examined if the antitumor activity of rituximab, CD20-specific antibody, could be improved by simultaneously targeting CD40 with the humanized monoclonal antibody dacetuzumab (SGN-40).
Dacetuzumab was dosed with rituximab to determine the in vivo activity of this combination in a subcutaneous Ramos xenograft model of non-Hodgkin lymphoma (NHL). The effect of dacetuzumab on rituximab antibody-dependent cell mediated-cytotoxicity (ADCC), antiproliferative, and apoptotic activities were evaluated in vitro using NHL cell lines. Western blotting and flow cytometry were used to contrast the signaling pathways activated by dacetuzumab and rituximab in NHL cells.
The dacetuzumab-rituximab combination had significantly improved antitumor activity over the equivalent dose of rituximab in the Ramos xenograft model (P = 0.0021). Dacetuzumab did not augment rituximab-mediated ADCC activity; however, these antibodies were additive to synergistic in cell-proliferation assays and produced increased apoptosis in combination. Rituximab signaling downregulated BCL-6 oncoprotein in a cell line-specific manner, whereas dacetuzumab strongly downregulated BCL-6 in each cell line. Dacetuzumab induced expression of the proapoptotic proteins TAp63 and Fas, whereas rituximab did not affect basal expression of either protein. Finally, rituximab partially blocked dacetuzumab-mediated upregulation of the prosurvival protein BCL-x(L).
Targeting CD40 with dacetuzumab enhanced the antitumor activity of rituximab in cell line and xenograft NHL models. The distinct but complementary apoptotic signal transduction profiles of dacetuzumab and rituximab are an important mechanism behind the improved activity of this combination.
用单克隆抗体治疗药物针对 B 细胞抗原进行个体化靶向治疗已经改善了非霍奇金淋巴瘤（NHL）的治疗效果。我们研究了用靶向 CD40 的人源化单克隆抗体达妥昔单抗（SGN-40）与利妥昔单抗联合使用是否能提高利妥昔单抗（CD20 特异性抗体）的抗肿瘤活性。
在非霍奇金淋巴瘤（NHL）的皮下 Ramos 异种移植模型中，用达妥昔单抗与利妥昔单抗联合用药，以确定该联合用药的体内活性。用 NHL 细胞系在体外评估达妥昔单抗对利妥昔单抗抗体依赖细胞介导的细胞毒性（ADCC）、抗增殖和凋亡活性的影响。用 Western blot 和流式细胞术来对比达妥昔单抗和利妥昔单抗在 NHL 细胞中激活的信号通路。
在 Ramos 异种移植模型中，与等效剂量的利妥昔单抗相比，达妥昔单抗-利妥昔单抗联合用药具有显著提高的抗肿瘤活性（P=0.0021）。达妥昔单抗没有增强利妥昔单抗介导的 ADCC 活性；然而，这些抗体在细胞增殖测定中是相加的，联合用药产生了更多的凋亡。利妥昔单抗信号以细胞系特异性的方式下调 BCL-6 癌蛋白，而达妥昔单抗则在每个细胞系中强烈下调 BCL-6。达妥昔单抗诱导促凋亡蛋白 TAp63 和 Fas 的表达，而利妥昔单抗则不影响这两种蛋白的基础表达。最后，利妥昔单抗部分阻断了达妥昔单抗介导的生存蛋白 BCL-x(L)的上调。
用达妥昔单抗靶向 CD40 增强了利妥昔单抗在细胞系和异种移植 NHL 模型中的抗肿瘤活性。达妥昔单抗和利妥昔单抗的独特但互补的凋亡信号转导谱是该联合用药活性提高的一个重要机制。
