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 in vitro and in vivo, 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.

中文翻译：

---

Daratumumab诱导CD38内化并损害骨髓瘤细胞粘附。

Daratumumab（Dara）是一种人类免疫球蛋白G1κ（IgG1κ）单克隆抗CD38抗体，已被美国食品药品监督管理局批准用于治疗复发性多发性骨髓瘤（MM），作为单一药物以及与免疫调节剂联用药物（IMiDs）和蛋白酶体抑制剂（PI）。尽管已经广泛探索了将Dara与IMiD结合使用的科学原理，但尚未研究Dara-PI疗法基础的分子机制。在这里，我们证明了Dara处理后，MM细胞表面的CD38迅速被内在化。我们还表明，Dara治疗会损害MM细胞的粘附力，这种作用可以通过使用胞吞抑制剂Dynasore挽救。最后，我们证明了Dara在体外和体内均增强了硼替佐米（BTZ）对MM细胞的杀伤作用，与其作为免疫激活剂的功能无关。总之，我们的数据表明Dara损害MM细胞粘附，从而导致MM对蛋白酶体抑制作用的敏感性增加。