A nonfucosylated human antibody to CD19 with potent B-cell depletive activity for therapy of B-cell malignancies
A nonfucosylated human antibody to CD19 with potent B-cell depletive activity for therapy of B-cell malignancies
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DOI：
10.1007/s00262-009-0746-z
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发表时间：
2010-02-01
影响因子：
5.8
通讯作者：
King, David J.
中科院分区：
文献类型：
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作者：
Cardarelli, Pina M.;Rao-Naik, Chetana;King, David J.
人抗CD19抗体在岩藻糖基转移酶缺陷的CHO细胞中表达，产生非岩藻糖基化的MDX-1342。MDX-1342与人CD19表达细胞的结合类似于其岩藻糖化亲本抗体。然而，MDX-1342表现出对Fc-Gamma RIIIa-Phe158和Fc Gamma RIIIa-Val158受体的亲和力增加，并增强了效应细胞功能，在抗体依赖的细胞毒性(ADCC)和吞噬试验中显示出更高的效力和效率。MDX-1342在小鼠B细胞淋巴瘤模型中显示出剂量依赖性的生存改善，在该模型中，拉莫斯细胞被全身注射。此外，还观察到与食蟹猴CD19的低纳米分子结合率和与食蟹猴Fc-Gamma RIIIa的亲和力增加。在食蟹猴体内给予MDX-1342显示出有效的B细胞耗竭，这表明它作为恶性肿瘤和自身免疫适应症的B淋巴细胞耗竭治疗的潜在用途。
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 Fc gamma RIIIa-Phe158 and Fc gamma RIIIa-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 Fc gamma RIIIa 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.