Multivalent rituximab lipid nanoparticles as improved lymphoma therapies: indirect mechanisms of action and in vivo activity
Multivalent rituximab lipid nanoparticles as improved lymphoma therapies: indirect mechanisms of action and in vivo activity
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DOI：
10.2217/nnm.11.50
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发表时间：
2011-11-01
期刊：
影响因子：
5.5
通讯作者：
Chikh, Ghania
中科院分区：
文献类型：
--
作者：
Popov, Jesse;Kapanen, Anita I.;Chikh, Ghania
目的：治疗性抗体的活性可以通过产生多价构建体，如抗体脂质纳米颗粒（LNP）来增强。在这里，我们研究利妥昔单抗（Ritux）和Ritux-LNP之间的差异，其间接作用机制：补体依赖性细胞毒性（CDC）和抗体依赖性细胞介导的细胞毒性（ADCC）。材料和方法：我们采用了两个套细胞淋巴瘤细胞系，Z138和JVM 2，这两个细胞系在体内对美罗华表现出不同的敏感性，沿着调节ADCC和CDC的细胞表面蛋白的表达水平不同。结果：在两种细胞系中，发现与Ritux相比，Ritux-LNP处理后CDC和ADCC显著增强。然而，体内功效研究表明Ritux和Ritux-LNP的治疗活性是等效的，这随后部分地通过药代动力学研究来解释，表明Ritux-LNP的快速消除。结论：虽然多价Ritux的间接和直接机制得到了增强，但其进一步发展需要提高其循环寿命的方法。
Aims: The activity of therapeutic antibodies can be enhanced by creating multivalent constructs, such as antibody lipid nanoparticles (LNPs). Here, we examine differences between rituximab (Ritux) and Ritux-LNPs in terms of their indirect mechanisms of action: complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Materials & Methods: We employed two mantle-cell lymphoma cell lines, Z138 and JVM2, which exhibit different in vivo sensitivities to Ritux along with variable expression levels of cell-surface proteins that regulate ADCC and CDC. Results: In both cell lines, CDC and ADCC were found to be significantly enhanced after treatment with Ritux-LNPs compared with Ritux. In vivo efficacy studies, however, suggested that the therapeutic activities of Ritux and Ritux-LNPs were equivalent, which was subsequently explained in part by pharmacokinetic studies indicating rapid elimination of Ritux-LNP. Conclusion: Although indirect and direct mechanisms of multivalent Ritux are enhanced, its further development requires methods to improve its circulation lifetime.