CD38 is highly and uniformly expressed on multiple myeloma (MM) cells, and at relatively low levels on normal lymphoid and myeloid cells, and in some tissues of nonhematopoietic origin. CD38 is a transmembrane glycoprotein with ectoenzymatic activity, and also functions as a receptor and adhesion molecule. Altogether, this has triggered the development of several CD38 antibodies including daratumumab (fully human), isatuximab (chimeric), and MOR202 (fully human). CD38 antibodies have pleiotropic mechanisms of action including Fc-dependent immune-effector mechanisms, direct apoptotic activity, and immunomodulatory effects by the elimination of CD38+ immune-suppressor cells. CD38-targeting antibodies are generally well tolerated and induce partial response or better in ∼30% of heavily pretreated MM patients as monotherapy. Based on their distinct mechanisms of action, favorable toxicity profile, and single-agent activity, CD38 antibodies are attractive partners in combination regimens. Indeed, deep responses and prolonged progression-free survival can be achieved in relapsed/refractory MM patients when CD38 antibodies are combined with immunomodulatory agents or proteasome inhibitors. Infusion-related reactions, which typically occur during the first infusion, are the most frequent adverse events. Attention should also be paid to the interference of CD38 antibodies with certain laboratory assays, which may complicate response evaluation and blood compatibility testing. Several studies are currently examining the role of CD38-based therapies in newly diagnosed and high-risk smoldering MM. Furthermore, CD38 antibodies are currently also under investigation in other hematologic malignancies, including acute lymphoblastic leukemia, natural killer/T-cell lymphoma, and acute myeloid leukemia, as well as in solid tumors.

中文翻译：

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多发性骨髓瘤中的 CD38 抗体：回到未来

CD38 在多发性骨髓瘤 (MM) 细胞上高度一致地表达，而在正常淋巴和骨髓细胞以及一些非造血来源的组织中表达水平相对较低。CD38 是一种具有胞外酶活性的跨膜糖蛋白，还具有受体和粘附分子的功能。总之，这引发了几种 CD38 抗体的开发，包括 daratumumab（全人源）、isatuximab（嵌合）和 MOR202（全人源）。CD38 抗体具有多效性作用机制，包括 Fc 依赖性免疫效应机制、直接凋亡活性和通过消除 CD38+ 免疫抑制细胞产生的免疫调节作用。CD38 靶向抗体通常具有良好的耐受性，并在约 30% 的严重预处理的 MM 患者中作为单一疗法诱导部分反应或更好。基于其独特的作用机制、有利的毒性特征和单药活性，CD38 抗体是联合方案中有吸引力的合作伙伴。事实上，当 CD38 抗体与免疫调节剂或蛋白酶体抑制剂联合使用时，复发/难治性 MM 患者可以实现深度缓解和延长无进展生存期。输液相关反应通常发生在第一次输液期间，是最常见的不良事件。还应注意 CD38 抗体对某些实验室检测的干扰，这可能会使反应评估和血液相容性测试复杂化。目前有几项研究正在研究基于 CD38 的疗法在新诊断和高危冒烟型 MM 中的作用。此外，