文章：

DuoHexaBody-CD37®，一种新型双表位CD37抗体，通过增强Fc介导的六聚化，作为B细胞恶性肿瘤的潜在治疗手段

DuoHexaBody-CD37®, a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies

原文发布日期：2020-04-28

DOI: 10.1038/s41408-020-0292-7

类型: Article

开放获取: 是

英文摘要：

Tetraspanin CD37 has recently received renewed interest as a therapeutic target for B-cell malignancies. Although complement-dependent cytotoxicity (CDC) is a powerful Fc-mediated effector function for killing hematological cancer cells, CD37-specific antibodies are generally poor inducers of CDC. To enhance CDC, the E430G mutation was introduced into humanized CD37 monoclonal IgG1 antibodies to drive more efficient IgG hexamer formation through intermolecular Fc-Fc interactions after cell surface antigen binding. DuoHexaBody-CD37, a bispecific CD37 antibody with the E430G hexamerization-enhancing mutation targeting two non-overlapping epitopes on CD37 (biparatopic), demonstrated potent and superior CDC activity compared to other CD37 antibody variants evaluated, in particular ex vivo in patient-derived chronic lymphocytic leukemia cells. The superior CDC potency was attributed to enhanced IgG hexamerization mediated by the E430G mutation in combination with dual epitope targeting. The mechanism of action of DuoHexaBody-CD37 was shown to be multifaceted, as it was additionally capable of inducing efficient antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vitro. Finally, potent anti-tumor activity in vivo was observed in cell line- and patient-derived xenograft models from different B-cell malignancy subtypes. These encouraging preclinical results suggest that DuoHexaBody-CD37 (GEN3009) may serve as a potential therapeutic antibody for the treatment of human B-cell malignancies.
 

摘要翻译： 

四跨膜蛋白CD37作为B细胞恶性肿瘤的治疗靶点近期重新引起关注。尽管补体依赖性细胞毒性（CDC）是杀伤血液癌细胞的一种强大Fc介导效应功能，但CD37特异性抗体通常诱导CDC的能力较弱。为增强CDC，研究人员在人源化CD37单克隆IgG1抗体中引入E430G突变，通过细胞表面抗原结合后的分子间Fc-Fc相互作用驱动更有效的IgG六聚体形成。DuoHexaBody-CD37是一种双特异性CD37抗体，具有E430G六聚化增强突变，靶向CD37上两个非重叠表位（双互补位）。与评估的其他CD37抗体变体相比，该抗体在患者来源的慢性淋巴细胞白血病细胞中（尤其在离体条件下）展现出强效且更优越的CDC活性。这种卓越的CDC效力归因于E430G突变介导的增强型IgG六聚化与双表位靶向的协同作用。DuoHexaBody-CD37的作用机制具有多面性，在体外还能有效诱导抗体依赖性细胞介导的细胞毒性和抗体依赖性细胞吞噬作用。最后，在不同B细胞恶性肿瘤亚型的细胞系来源和患者来源的异种移植模型中，均观察到显著的体内抗肿瘤活性。这些令人鼓舞的临床前结果表明，DuoHexaBody-CD37（GEN3009）可能成为治疗人类B细胞恶性肿瘤的潜在治疗性抗体。

原文链接：

DuoHexaBody-CD37®, a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies