抗β2微球蛋白单克隆抗体治疗多发性骨髓瘤的机制研究

Multiple myeloma (MM) still remains fatal for most of the patients. Elevated levels of β2-microglobulin (β2M) are present in MM cells and serum, and correlate with a poor prognosis. We have observed monoclonal antibody against human β2M (Anti-β2M mAb) have a remarkably strong apoptotic effect on myeloma cells without damaging osteoclasts or blood mononuclear cells in their cocultures with myeloma cells. More importantly, Anti-β2M mAb is therapeutic in vivo in xenograft SCID and SCID-hu mouse models, and in the HLA-A2-transgenic NOD-SCID (A2-NOD-SCID) model of myeloma in which every mouse tissue expresses human MHC class I/β2M molecules and circulating human β2M could reach the levels seen in most myeloma patients without causing damage to normal human hematopoiesis or murine organs. In the proposed project, we will first elucidate the mechanisms of Anti-β2M mAb-induced apoptosis in MM cells both in vitro and in vivo models, and establish the extracellular-to-intracellular signal pathways triggered by Anti-β2M mAb. Second, we will investigate the enhanced efficacy of Anti-β2M mAb by combinational therapy with novel anti-MM agents such as bortezomib and lenalidomide, and the potential mechanisms in vitro and in vivo models. Third, we will explore whether immune effector cells or molecules enhance the efficacy of Anti-β2M mAb, and whether and how Anti-β2M mAb affects the viability, differentiation, proliferation and function of normal human hematopoietic and immune cells in vitro and in vivo models. When the work described in this proposal has been completed, we will clarify the mechanisms responsible for Anti-β2M mAb mediated MM treatment and safety of its application, and provide a theoretical basis for the development of Anti-β2M mAb as clinically useful and effective therapeutic mAb for the treatment of MM.

研究表明β2微球蛋白（β2M）在多发性骨髓瘤（MM）细胞的表达和患者血清中的含量明显升高，且与MM的发生发展及预后密切相关。本课题组前期获得了抗β2M单克隆抗体（Anti-β2M mAb），并在细胞水平及SCID、人源化SCID-hu与人HLA-A2转基因NOD-SCID (A2-NOD-SCID)动物模型均证实Anti-β2M mAb能诱导MM细胞凋亡且抑制MM进展，而对正常细胞、组织及器官无损害。本课题拟首先进一步探讨Anti-β2M mAb单独或联合化疗药物的体内外抗MM作用及分子机制；其次将从肿瘤微环境角度出发，探讨免疫效应细胞或效应因子与Anti-β2M mAb的相互影响，及其在抗MM中的作用和可能机制。这些研究将全面阐明Anti-β2M mAb抗MM的分子和免疫机制及其应用的安全性，为其应用于临床以提高MM治疗效果奠定坚实的理论基础。

本项目进一步研究发现Anti-β2M mAb 与硼替佐米BTZ联合可以增强药物敏感性，这种增敏效应依赖于MM细胞的β2M表达；其次我们发现Anti-β2M mAbs介导抗体依赖的细胞毒作用（即ADCC）来对抗骨髓瘤细胞，Anti-β2M mAbs还可以介导补体依赖性细胞毒性作用（即CDC）来抵抗骨髓瘤细胞。这些研究全面阐明了 Anti-β2M mAb 抗 MM 的分子和免疫机制及其应用的安全性，为其应用于临床以提高 MM 治疗效果奠定坚实的理论基础。