Department of Cell Biology and Pharmacology, Medarex, 1324 Chesapeake Terrace, Sunnyvale, CA 94089, USA.
Cancer Immunol Immunother. 2010 Feb;59(2):257-65. doi: 10.1007/s00262-009-0746-z.
A human anti-CD19 antibody was expressed in fucosyltransferase-deficient CHO cells to generate nonfucosylated MDX-1342. Binding of MDX-1342 to human CD19-expressing cells was similar to its fucosylated parental antibody. However, MDX-1342 exhibited increased affinity for FcγRIIIa-Phe158 and FcγRIIIa-Val158 receptors as well as enhanced effector cell function, as demonstrated by increased potency and efficacy in antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis assays. MDX-1342 showed dose-dependent improvement in survival using a murine B-cell lymphoma model in which Ramos cells were administered systemically. In addition, low nanomolar binding to cynomolgus monkey CD19 and increased affinity for cynomolgus monkey FcγRIIIa was observed. In vivo administration of MDX-1342 in cynomolgus monkeys revealed potent B-cell depletion, suggesting its potential utility as a B-lymphocyte depletive therapy for malignancies and autoimmune indications.
一种人源抗 CD19 抗体在岩藻糖基转移酶缺陷型 CHO 细胞中表达，生成非岩藻糖基化的 MDX-1342。MDX-1342 与人 CD19 表达细胞的结合与其糖基化亲本抗体相似。然而，MDX-1342 对 FcγRIIIa-Phe158 和 FcγRIIIa-Val158 受体的亲和力增加，同时增强了效应细胞功能，这在抗体依赖性细胞毒性（ADCC）和吞噬作用测定中表现为效力和功效增加。在使用全身性给予 Ramos 细胞的小鼠 B 细胞淋巴瘤模型中，MDX-1342 显示出剂量依赖性的生存改善。此外，观察到对食蟹猴 CD19 的低纳摩尔结合和对食蟹猴 FcγRIIIa 的亲和力增加。在食蟹猴体内给予 MDX-1342 可导致强烈的 B 细胞耗竭，这表明其可能作为用于恶性肿瘤和自身免疫性疾病的 B 淋巴细胞耗竭疗法具有潜在的应用价值。
