Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics, Boston, MA 02115, USA.
Br J Haematol. 2011 Nov;155(4):438-48. doi: 10.1111/j.1365-2141.2011.08864.x. Epub 2011 Sep 19.
Recent advances regarding the introduction of anti-adhesion strategies as a novel therapeutic concept in oncology hold great promise. Here we evaluated the therapeutic potential of the new-in-class-molecule selective-adhesion-molecule (SAM) inhibitor Natalizumab, a recombinant humanized IgG4 monoclonal antibody, which binds integrin-α4, in multiple myeloma (MM). Natalizumab, but not a control antibody, inhibited adhesion of MM cells to non-cellular and cellular components of the microenvironment as well as disrupted the binding of already adherent MM cells. Consequently, Natalizumab blocked both the proliferative effect of MM-bone marrow (BM) stromal cell interaction on tumour cells, and vascular endothelial growth factor (VEGF)-induced angiogenesis in the BM milieu. Moreover, Natalizumab also blocked VEGF- and insulin-like growth factor 1 (IGF-1)-induced signalling sequelae triggering MM cell migration. In agreement with our in vitro results, Natalizumab inhibited tumour growth, VEGF secretion, and angiogenesis in a human severe combined immunodeficiency murine model of human MM in the human BM microenvironment. Importantly, Natalizumab not only blocked tumour cell adhesion, but also chemosensitized MM cells to bortezomib, in an in vitro therapeutically representative human MM-stroma cell co-culture system model. Our data therefore provide the rationale for the clinical evaluation of Natalizumab, preferably in combination with novel agents (e.g. bortezomib) to enhance MM cytotoxicity and improve patient outcome.
关于将抗黏附策略作为肿瘤学中一种新的治疗概念引入的最新进展具有很大的前景。在这里，我们评估了新型选择性黏附分子（SAM）抑制剂那他珠单抗（一种结合整合素-α4 的重组人源化 IgG4 单克隆抗体）在多发性骨髓瘤（MM）中的治疗潜力。那他珠单抗（而不是对照抗体）抑制 MM 细胞与微环境中非细胞和细胞成分的黏附，并且破坏已经黏附的 MM 细胞的结合。因此，那他珠单抗阻断了 MM-骨髓（BM）基质细胞相互作用对肿瘤细胞的增殖作用以及 BM 环境中血管内皮生长因子（VEGF）诱导的血管生成。此外，那他珠单抗还阻断了 VEGF 和胰岛素样生长因子 1（IGF-1）诱导的触发 MM 细胞迁移的信号级联反应。与我们的体外结果一致，那他珠单抗在人类 BM 微环境中的人类 MM 的人类严重联合免疫缺陷小鼠模型中抑制肿瘤生长、VEGF 分泌和血管生成。重要的是，那他珠单抗不仅阻断了肿瘤细胞的黏附，而且在体外治疗代表性的人类 MM-基质细胞共培养系统模型中使 MM 细胞对硼替佐米产生化疗敏感性。因此，我们的数据为那他珠单抗的临床评估提供了依据，最好与新型药物（例如硼替佐米）联合使用，以增强 MM 的细胞毒性并改善患者的预后。
