Department of Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Ave., Vancouver BC, V5Z 1L3, Canada.
Nanomedicine (Lond). 2011 Nov;6(9):1575-91. doi: 10.2217/nnm.11.50. Epub 2011 Oct 20.
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.
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.
Although indirect and direct mechanisms of multivalent Ritux are enhanced, its further development requires methods to improve its circulation lifetime.
通过构建多价构建体（如抗体脂质纳米粒（LNP））可以增强治疗性抗体的活性。在这里，我们研究了利妥昔单抗（Ritux）和利妥昔单抗-LNP 在其间接作用机制方面的差异：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）。
我们使用了两种套细胞淋巴瘤细胞系，Z138 和 JVM2，它们对 Ritux 的体内敏感性不同，同时细胞表面蛋白的表达水平也不同，这些蛋白调节 ADCC 和 CDC。
在这两种细胞系中，与 Ritux 相比，用 Ritux-LNP 处理后发现 CDC 和 ADCC 显著增强。然而，体内疗效研究表明，Ritux 和 Ritux-LNP 的治疗活性相当，随后的药代动力学研究表明，LNP 的快速消除部分解释了这一点。
尽管多价 Ritux 的间接和直接作用机制得到了增强，但要进一步开发，需要提高其循环寿命的方法。
