文章：

奥比妥珠单抗和利妥昔单抗在滤泡性淋巴瘤3D模型中的抗肿瘤活性

Anti-tumor activity of obinutuzumab and rituximab in a follicular lymphoma 3D model

原文发布日期：2013-08-09

DOI: 10.1038/bcj.2013.32

类型: Original Article

开放获取: 是

英文摘要：

Follicular lymphomas (FLs) account for 35–40% of all adult lymphomas. Treatment typically involves chemotherapy combined with the anti-CD20 monoclonal antibody (MAb) rituximab (RTX). The development of the type II anti-CD20 MAb obinutuzumab (GA101) aims to further improve treatment. Here, using FL cells we show that RTX and GA101 display a similar activity on RL cells cultured in 2D. However, 2D culture cannot mimic tumor spatial organization and conventional 2D models may not reflect the effects of antibodies as they occur in vivo. Thus, we created a non-Hodgkin’s lymphoma (NHL) 3D culture system, termed multicellular aggregates of lymphoma cells (MALC), and used it to compare RTX and GA101 activity. Our results show that both antibodies display greater activity towards FL cells in 3D culture compared with 2D culture. Moreover, we observed that in the 3D model GA101 was more effective than RTX both in inhibiting MALC growth through induction of (lysosomal) cell death and senescence and in inhibiting intracellular signaling pathways, such as mammalian target of rapamycin, Akt, PLCgamma (Phospholipase C gamma) and Syk. Altogether, our study demonstrates that spatial organization strongly influences the response to antibody treatment, supporting the use of 3D models for the testing of therapeutic agents in NHL.

摘要翻译： 

滤泡性淋巴瘤（FL）占所有成人淋巴瘤的35%-40%。其标准治疗方案通常为化疗联合抗CD20单克隆抗体利妥昔单抗（RTX）。二代抗CD20单克隆抗体奥滨尤妥珠单抗（GA101）的研发旨在进一步提升疗效。本研究采用FL细胞系进行实验，发现在二维培养条件下RTX与GA101对RL细胞的作用活性相近。然而二维培养体系无法模拟肿瘤空间结构，传统二维模型可能无法真实反映抗体在体内的作用机制。为此我们建立了名为淋巴瘤细胞多细胞聚集体（MALC）的非霍奇金淋巴瘤（NHL）三维培养体系，并借此比较RTX与GA101的活性。结果表明：在三维培养环境中，两种抗体对FL细胞的作用活性均显著优于二维培养。更重要的是，在三维模型中GA101通过诱导（溶酶体途径）细胞死亡和细胞衰老来抑制MALC生长的效果优于RTX，同时在抑制哺乳动物雷帕霉素靶蛋白、Akt、PLCγ（磷脂酶Cγ）及Syk等细胞内信号通路方面也更具优势。本研究充分证实空间结构会显著影响抗体治疗应答，支持采用三维模型进行NHL治疗药物的效能评估。

原文链接：

Anti-tumor activity of obinutuzumab and rituximab in a follicular lymphoma 3D model