Suppression of Rituximab-resistant B-cell lymphoma with a novel multi-component anti-CD20 mAb nanocluster.
Suppression of Rituximab-resistant B-cell lymphoma with a novel multi-component anti-CD20 mAb nanocluster.
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用新型多组分抗 CD20 mAb 纳米簇抑制利妥昔单抗耐药 B 细胞淋巴瘤
DOI：
10.18632/oncotarget.4206
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发表时间：
2015-09-15
期刊：
影响因子：
--
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Li H;Zhang G;Jiang C;Zhang F;Ke C;Zhao H;Sun Y;Zhao M;Chen D;Zhu X;Zhang L;Li B;Dai J;Li W
尽管抗CD20抗体利妥昔单抗使非霍奇金淋巴瘤(NHL)的治疗发生了革命性的变化，但对治疗的耐药性仍然存在。因此，迫切需要抑制利妥昔单抗耐药的NHL的策略。在这里，由其I型和II型单抗(利妥昔单抗和11B8)成功地构建了抗CD20纳米簇(ACNC)。这些独特的抗CD20单抗被大量接枝到短链聚合物(聚乙烯亚胺)上。与亲本利妥昔单抗和11B8相比，ACNC的“失败率”较低。重要的是，在播散性和局限性人非霍奇金淋巴瘤异种移植模型中，ACNC有效地抑制了利妥昔单抗耐药淋巴瘤。进一步的结果表明，ACNC在诱导caspase依赖的细胞凋亡和溶酶体介导的程序性细胞死亡(PCD)方面具有显着的效力。这可能有助于解释为什么ACNC在抑制利妥昔单抗耐药的淋巴瘤方面有效，而利妥昔单抗和11B8无效。此外，ACNC患者外周血清除率低，肿瘤内蓄积高。这种药代动力学的改善归因于抗体-抗原反应(主动靶向)和增强的通透性和滞留(ERP)效应(被动靶向)。这项研究表明，ACNC可能是治疗利妥昔单抗耐药淋巴瘤的一种有前途的药物。
Although the anti-CD20 antibody Rituximab has revolutionized the treatment of Non-Hodgkin Lymphoma (NHL), resistance to treatment still existed. Thus, strategies for suppressing Rituximab-resistant NHLs are urgently needed. Here, an anti-CD20 nanocluster (ACNC) is successfully constructed from its type I and type II mAb (Rituximab and 11B8). These distinct anti-CD20 mAbs are mass grafted to a short chain polymer (polyethylenimine). Compared with parental Rituximab and 11B8, the ACNC had a reduced “off-rate”. Importantly, ACNC efficiently inhibited Rituximab-resistant lymphomas in both disseminated and localized human NHL xenograft models. Further results revealed that ACNC is significantly potent in inducing caspase-dependent apoptosis and lysosome-mediated programmed cell death (PCD). This may help explain why ACNC is effective in suppressing rituximab-resistant lymphoma while Rituximab and 11B8 are not. Additionally, ACNC experienced low clearance from peripheral blood and high intratumor accumulation. This improved pharmacokinetics is attributed to the antibody-antigen reaction (active targeting) and enhanced permeability and retention (ERP) effect (passive targeting). This study suggested that ACNC might be a promising therapeutic agent for treatment of rituximab-resistant lymphomas.