肿瘤细胞治疗研究
英文原题：A glycoengineered anti-ROR1 antibody, GE-zilovertamab, selectively enhances antibody-dependent cellular cytotoxicity against chronic lymphocytic leukemia.
受体酪氨酸激酶样孤儿受体1（ROR1）选择性表达于慢性淋巴细胞白血病（CLL）B细胞及某些癌症中，但在正常B细胞和健康成人组织中不表达。
受体酪氨酸激酶样孤儿受体1（ROR1）选择性表达于慢性淋巴细胞白血病（CLL）B细胞及某些癌症中，但在正常B细胞和健康成人组织中不表达。GE-zilovertamab是一种去岩藻糖基化抗ROR1 IgG1抗体，经工程改造以增强FcγRIIIA结合，从而增强抗体依赖性细胞介导的细胞毒性（ADCC）。使用CLL细胞系（MEC1、MEC1-ROR1）和原代CLL细胞与Jurkat-Lucia™ NFAT-CD16、NK或外周血单个核细胞效应细胞进行共培养实验。处理包括抗CD20单克隆抗体利妥昔单抗、抗ROR1单克隆抗体（GE-zilovertamab、zilovertamab）以及内吞抑制剂丙氯拉嗪，并对ADCC进行定量。GE-zilovertamab显示出显著高于其亲本抗体的ADCC，且活性与利妥昔单抗相当。我们发现内吞抑制剂丙氯拉嗪进一步增强了这一效应。GE-zilovertamab是一种有前景的下一代CLL免疫治疗药物，将ROR1的选择性靶向与相比抗CD20抗体可能减少治疗诱导的免疫缺陷相结合。
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is selectively expressed on chronic lymphocytic leukemia (CLL) B cells and certain cancers, but is absent from normal B cells and healthy adult tissues. GE-zilovertamab, an afucosylated anti-ROR1 IgG1 antibody, is engineered to increase FcγRIIIA binding and thereby enhance antibody-dependent cellular cytotoxicity (ADCC). Co-culture assays were performed using CLL cell lines (MEC1, MEC1-ROR1) and primary CLL cells with Jurkat-Lucia™ NFAT-CD16, NK, or peripheral blood mononuclear cell effectors. Treatments included the anti-CD20 mAb rituximab, anti-ROR1 mAbs (GE-zilovertamab, zilovertamab), and the endocytosis inhibitor prochlorperazine, and ADCC was quantified. GE-zilovertamab showed significantly higher ADCC than its parental antibody and activity that was comparable to that of rituximab. We find that the endocytosis inhibitor prochlorperazine further increased this effect. GE-zilovertamab is a promising next-generation immunotherapeutic for CLL, combining selective targeting of ROR1 with the potential to reduce therapy-induced immunodeficiency compared with anti-CD20 antibodies.
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