Cardarelli Pina M, Moldovan-Loomis Maria-Cristina, Preston Ben, Black Amelia, Passmore David, Chen Tseng-Hui, Chen Sharline, Liu Jie, Kuhne Michelle R, Srinivasan Mohan, Assad Albert, Witte Alison, Graziano Robert F, King David J
Department of Cell Biology and Pharmacology, Medarex, Sunnyvale, CA 94089, USA.
Clin Cancer Res. 2009 May 15;15(10):3376-83. doi: 10.1158/1078-0432.CCR-08-3222. Epub 2009 Apr 28.
This study was undertaken to evaluate the effects of MDX-1401, a nonfucosylated fully human monoclonal antibody that binds to human CD30, and to determine whether it exhibits greater in vitro and in vivo activity than its parental antibody.
Assays measuring antibody binding to CD30-expressing cells and FcgammaRIIIa (CD16) transfectants as well as antibody-dependent cellular cytotoxicity (ADCC) were conducted. Antitumor activity was determined using a Karpas-299 systemic model.
The binding of MDX-1401 to CD30 antigen was identical to fucose-containing parental anti-CD30 antibody (MDX-060). In contrast, MDX-1401 showed increased binding affinity to FcgammaRIIIa-transfected cells resulting in increased effector function. MDX-1401 greatly improved ADCC activity as evidenced by a decrease in half-maximal effective concentration (EC(50)) and an increase in maximum cell lysis when compared with MDX-060. Increased ADCC activity was observed among a panel of cell lines, including one with very low CD30 antigen expression in which parental antibody failed to induce any detectable ADCC. MDX-1401 activity with all FcgammaRIIIa polymorphic variants, including less active Phe/Phe158 and Phe/Val158 effector cells, was shown. Furthermore, MDX-1401 was efficacious in inhibiting tumor growth in CD30(+) lymphoma xenografts.
The low doses of antibody required for ADCC activity irrespective of donor genotype, the ability to mediate ADCC in target cells expressing low levels of CD30, and increased in vivo efficacy support the development of MDX-1401 for treatment of malignant lymphoma.
本研究旨在评估MDX - 1401（一种与人类CD30结合的非岩藻糖基化全人单克隆抗体）的作用，并确定其在体外和体内是否比其亲本抗体表现出更强的活性。
进行了检测抗体与表达CD30的细胞及FcγRIIIa（CD16）转染子结合的试验以及抗体依赖性细胞毒性（ADCC）试验。使用Karpas - 299全身模型确定抗肿瘤活性。
MDX - 1401与CD30抗原的结合与含岩藻糖的亲本抗CD30抗体（MDX - 060）相同。相比之下，MDX - 1401对FcγRIIIa转染细胞的结合亲和力增加，导致效应子功能增强。与MDX - 060相比，MDX - 1401的半数最大有效浓度（EC(50)）降低，最大细胞裂解增加，这证明其显著提高了ADCC活性。在一组细胞系中观察到ADCC活性增加，包括一个CD30抗原表达极低的细胞系，亲本抗体在该细胞系中未能诱导任何可检测到的ADCC。MDX - 1401对所有FcγRIIIa多态变体均有活性，包括活性较低的Phe/Phe158和Phe/Val158效应细胞。此外，MDX - 1401在抑制CD30(+)淋巴瘤异种移植瘤的肿瘤生长方面有效。
无论供体基因型如何，ADCC活性所需的抗体剂量较低，能够在低水平表达CD30的靶细胞中介导ADCC，以及体内疗效增强，这些都支持开发MDX - 1401用于治疗恶性淋巴瘤。
