Ghose Jayeeta, Viola Domenico, Terrazas Cesar, Caserta Enrico, Troadec Estelle, Khalife Jihane, Gunes Emine Gulsen, Sanchez James, McDonald Tinisha, Marcucci Guido, Kaur Balveen, Rosenzweig Michael, Keats Jonathan, Rosen Steven, Krishnan Amrita, Satoskar Abhay R, Hofmeister Craig C, Pichiorri Flavia
Department of Radiation Oncology, The Ohio State University, Columbus, OH, USA.
Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, CA, USA.
Oncoimmunology. 2018 Jul 23;7(10):e1486948. doi: 10.1080/2162402X.2018.1486948. eCollection 2018.
Daratumumab (Dara), a human immunoglobulin G1 kappa (IgG1κ) monoclonal anti-CD38 antibody, has been approved by the U.S. Food and Drug Administration for the treatment of relapsed multiple myeloma (MM) as a single agent as well as in combination with immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI). Although the scientific rationale behind the use of Dara in combination with IMiDs has been extensively explored, the molecular mechanisms underlying Dara-PI regimens have not yet been investigated. Here, we demonstrate that CD38 on the surface of MM cells is rapidly internalized after Dara treatment; we also show that Dara treatment impairs MM cell adhesion, an effect that can be rescued by using the endocytosis inhibitor Dynasore. Finally, we show that Dara potentiates bortezomib (BTZ) killing of MM cells and , independent of its function as an immune activator. In conclusion, our data show that Dara impairs MM cell adhesion, which results in an increased sensitivity of MM to proteasome inhibition.
达雷妥尤单抗（Dara）是一种人免疫球蛋白G1κ（IgG1κ）单克隆抗CD38抗体，已获美国食品药品监督管理局批准，可作为单一药物以及与免疫调节药物（IMiDs）和蛋白酶体抑制剂（PI）联合用于治疗复发多发性骨髓瘤（MM）。尽管已广泛探讨了Dara与IMiDs联合使用的科学依据，但Dara-PI治疗方案的分子机制尚未得到研究。在此，我们证明Dara治疗后MM细胞表面的CD38会迅速内化；我们还表明Dara治疗会损害MM细胞黏附，使用内吞作用抑制剂dynasore可挽救这一效应。最后，我们表明Dara增强硼替佐米（BTZ）对MM细胞的杀伤作用，且与其作为免疫激活剂的功能无关。总之，我们的数据表明Dara会损害MM细胞黏附，这导致MM对蛋白酶体抑制的敏感性增加。
