文章：

VIS832，一种新型靶向CD138的单克隆抗体，可有效杀伤人多发性骨髓瘤细胞，并在体外和体内与IMiDs或硼替佐米产生协同作用

VIS832, a novel CD138-targeting monoclonal antibody, potently induces killing of human multiple myeloma and further synergizes with IMiDs or bortezomib in vitro and in vivo

原文发布日期：2020-11-02

DOI: 10.1038/s41408-020-00378-z

类型: Article

开放获取: 是

英文摘要：

Therapeutically targeting CD138, a define multiple myeloma (MM) antigen, is not yet approved for patients. We here developed and determined the preclinical efficacy of VIS832, a novel therapeutic monoclonal antibody (MoAb) with differentiated CD138 target binding to BB4 that is anti-CD138 MoAb scaffold for indatuximab ravtansine (BT062). VIS832 demonstrated enhanced CD138-binding avidity and significantly improved potency to kill MM cell lines and autologous patient MM cells regardless of resistance to current standard-of-care therapies, via robust antibody-dependent cellular cytotoxicity and phagocytosis mediated by NK and macrophage effector cells, respectively. Specifically, CD38-targeting daratumumab-resistant MM cells were highly susceptible to VIS832 which, unlike daratumumab, spares NK cells. Superior maximal cytolysis of VIS832 vs. daratumumab corresponded to higher CD138 vs. CD38 levels in MM cells. Furthermore, VIS832 acted synergistically with lenalidomide or bortezomib to deplete MM cells. Importantly, VIS832 at a sub-optimal dose inhibited disseminated MM1S tumors in vivo as monotherapy (P < 0.0001), and rapidly eradicated myeloma burden in all mice concomitantly receiving bortezomib, with 100% host survival. Taken together, these data strongly support clinical development of VIS832, alone and in combination, for the therapeutic treatment of MM in relapsed and refractory patients while pointing to its potential therapeutic use earlier in disease intervention.
 

摘要翻译： 

靶向CD138（明确的多发性骨髓瘤抗原）的治疗方法尚未获批用于患者。本研究开发并评估了VIS832的临床前疗效，这是一种新型治疗性单克隆抗体，其CD138靶点结合方式与用于indatuximab ravtansine（BT062）的抗CD138单克隆抗体支架BB4不同。VIS832通过增强的CD138结合亲和力，分别经NK细胞和巨噬细胞效应子介导的强效抗体依赖性细胞毒作用及吞噬作用，显著提升了对多发性骨髓瘤细胞系和自体患者骨髓瘤细胞的杀伤效力，且不受当前标准治疗方案耐药性的影响。特别值得注意的是，针对CD38的达雷木单抗耐药骨髓瘤细胞对VIS832高度敏感，且与达雷木单抗不同，VIS832不会损伤NK细胞。相较于达雷木单抗，VIS832更卓越的最大细胞溶解效应与骨髓瘤细胞中CD138高于CD38的表达水平相对应。此外，VIS832与来那度胺或硼替佐米联用可协同清除骨髓瘤细胞。重要的是，次优剂量的VIS832单药即可抑制体内播散性MM1S肿瘤（P < 0.0001），并在联合硼替佐米治疗时迅速清除所有小鼠的骨髓瘤负荷，实现100%宿主存活率。综上所述，这些数据强有力支持VIS832单药及联合疗法的临床开发，用于复发难治性多发性骨髓瘤患者的治疗，同时提示其在疾病干预早期阶段的应用潜力。

原文链接：

VIS832, a novel CD138-targeting monoclonal antibody, potently induces killing of human multiple myeloma and further synergizes with IMiDs or bortezomib in vitro and in vivo