Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan.
Blood Cancer J. 2018 Oct 22;8(11):99. doi: 10.1038/s41408-018-0127-y.
CD26, a 110-kDa transmembrane glycoprotein that is expressed on several tumor cells including malignant lymphoma, has been implicated in tumorigenesis: however, little is known regarding its role in multiple myeloma (MM). Recently, we identified CD26 expression on human osteoclasts (OCs) and demonstrated that humanized IgG monoclonal antibody targeting CD26, huCD26mAb, inhibits human OC differentiation. Herein, we show that CD26 expression was present on plasma cells in the bone marrow tissues of MM patients. In vitro immunostaining studies revealed that although CD26 expression was low or absent on MM cell lines cultured alone, it was intensely and uniformly expressed on MM cell lines co-cultured with OCs. The augmented CD26 expression in MM cells was exploited to enhance anti-MM efficacy of huCD26mAb via a substantial increase in antibody-dependent cytotoxicity (ADCC) but not complement-dependent cytotoxicity (CDC). Moreover, huCD26mAb in combination with novel agents synergistically enhanced huCD26mAb induced ADCC activity against CD26+ MM cells compared with each agent alone. huCD26mAb additionally reduced the ratio of the side population (SP) fraction in CD26+ MM cells by ADCC. Finally, huCD26mAb significantly reduced the MM tumor burden and OC formation in vivo. These results suggest that CD26 is a potential target molecule in MM and that huCD26mAb could act as a therapeutic agent.
CD26 是一种 110kDa 的跨膜糖蛋白，在包括恶性淋巴瘤在内的几种肿瘤细胞中表达，已被认为与肿瘤发生有关：然而，关于其在多发性骨髓瘤（MM）中的作用知之甚少。最近，我们在人破骨细胞（OC）上鉴定出 CD26 的表达，并证明靶向 CD26 的人源化 IgG 单克隆抗体 huCD26mAb 抑制人 OC 分化。在此，我们表明 CD26 在 MM 患者的骨髓组织中的浆细胞上表达。体外免疫染色研究表明，尽管单独培养的 MM 细胞系上 CD26 表达水平低或缺失，但与 OC 共培养的 MM 细胞系上 CD26 表达强烈且均匀。通过实质性增加抗体依赖性细胞毒性（ADCC）而不是补体依赖性细胞毒性（CDC），MM 细胞中增强的 CD26 表达被利用来增强 huCD26mAb 的抗 MM 功效。此外，与新型药物联合使用 huCD26mAb 与每种药物单独使用相比，协同增强了针对 CD26+MM 细胞的 huCD26mAb 诱导的 ADCC 活性。huCD26mAb 还通过 ADCC 降低了 CD26+MM 细胞中侧群（SP）分数的比例。最后，huCD26mAb 显著减少了体内 MM 肿瘤负担和 OC 形成。这些结果表明 CD26 是 MM 的潜在靶分子，huCD26mAb 可作为治疗剂。
