Division of Hematology, Department of Medicine, College of Medicine, The Ohio State University, Columbus, USA.
Blood. 2011 Apr 28;117(17):4530-41. doi: 10.1182/blood-2010-08-303354. Epub 2011 Jan 12.
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a median survival of 3 years despite chemoimmunotherapy. Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), has shown only modest activity as single agent in MCL. The humanized mAb milatuzumab targets CD74, an integral membrane protein linked with promotion of B-cell growth and survival, and has shown preclinical activity against B-cell malignancies. Because rituximab and milatuzumab target distinct antigens and potentially signal through different pathways, we explored a preclinical combination strategy in MCL. Treatment of MCL cell lines and primary tumor cells with immobilized milatuzumab and rituximab resulted in rapid cell death, radical oxygen species generation, and loss of mitochondrial membrane potential. Cytoskeletal distrupting agents significantly reduced formation of CD20/CD74 aggregates, cell adhesion, and cell death, highlighting the importance of actin microfilaments in rituximab/milatuzumab-mediated cell death. Cell death was independent of caspase activation, Bcl-2 family proteins or modulation of autophagy. Maximal inhibition of p65 nuclear translocation was observed with combination treatment, indicating disruption of the NF-κB pathway. Significant in vivo therapeutic activity of combination rituximab and milatuzumab was demonstrated in a preclinical model of MCL. These data support clinical evaluation of combination milatuzumab and rituximab therapy in MCL.
套细胞淋巴瘤（MCL）是一种侵袭性 B 细胞恶性肿瘤，尽管采用化疗免疫疗法，其平均生存时间仍只有 3 年。利妥昔单抗，一种嵌合抗 CD20 单克隆抗体（mAb），作为单一药物在 MCL 中的活性仅为中等。人源化 mAb 米妥昔单抗靶向 CD74，这是一种与促进 B 细胞生长和存活相关的完整膜蛋白，并且在针对 B 细胞恶性肿瘤的临床前研究中显示出活性。由于利妥昔单抗和米妥昔单抗针对不同的抗原，并且可能通过不同的途径信号转导，因此我们在 MCL 中探索了一种临床前联合策略。固定化米妥昔单抗和利妥昔单抗处理 MCL 细胞系和原代肿瘤细胞会导致细胞迅速死亡、产生大量活性氧物质以及丧失线粒体膜电位。细胞骨架破坏剂可显著减少 CD20/CD74 聚集、细胞黏附和细胞死亡，这突出了肌动蛋白微丝在利妥昔单抗/米妥昔单抗介导的细胞死亡中的重要性。细胞死亡与 caspase 激活、Bcl-2 家族蛋白或自噬的调节无关。联合治疗观察到 p65 核易位的最大抑制，表明 NF-κB 途径被破坏。在 MCL 的临床前模型中证明了联合利妥昔单抗和米妥昔单抗治疗的显著体内治疗活性。这些数据支持在 MCL 中评估米妥昔单抗和利妥昔单抗联合治疗的临床应用。
