Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate
Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate
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DOI：
10.1158/1078-0432.ccr-04-0789
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发表时间：
2004-10-15
影响因子：
11.5
通讯作者：
Francisco, JA
中科院分区：
文献类型：
--
作者：
Hamblett, KJ;Senter, PD;Francisco, JA
目的：由单甲基澳瑞他汀E（MMAE）与抗CD 30单克隆抗体（mAb）cAC 10偶联组成的抗体-药物偶联物（每个mAb具有8个药物部分）先前已显示对CD 30（+）恶性细胞具有强效细胞毒性活性。为了确定药物负载对抗体-药物缀合物治疗潜力的影响，我们在体外和体内评估了含有不同药物-mAb比率的cAC 10抗体-药物缀合物。将MMAE偶联至包含cAC 10的链间二硫化物的半胱氨酸产生抗体-药物缀合物群体，使用疏水相互作用色谱法纯化该抗体-药物缀合物群体以产生具有两个、四个、每个抗体八种药物（分别为E2、E4和E8）。在体外针对CD 30（+）细胞系测试抗体-药物缀合物效力，随后在体内异种移植物模型中测试抗体-药物缀合物效力。结果：尽管抗体-药物偶联物的体外效力直接依赖于药物负载（IC 50值E8
Purpose: An antibody-drug conjugate consisting of monomethyl auristatin E (MMAE) conjugated to the anti-CD30 monoclonal antibody (mAb) cAC10, with eight drug moieties per mAb, was previously shown to have potent cytotoxic activity against CD30(+) malignant cells. To determine the effect of drug loading on antibody-drug conjugate therapeutic potential, we assessed cAC10 antibody-drug conjugates containing different drug-mAb ratios in vitro and in vivo.Experimental Design: Coupling MMAE to the cysteines that comprise the interchain disulfides of cAC10 created an antibody-drug conjugate population, which was purified using hydrophobic interaction chromatography to yield antibody-drug conjugates with two, four, and eight drugs per antibody (E2, E4, and E8, respectively). Antibody-drug conjugate potency was tested in vitro against CD30(+) lines followed by in vivo xenograft models. The maximum-tolerated dose and pharmacokinetic profiles of the antibody-drug conjugates were investigated in mice.Results: Although antibody-drug conjugate potency in vitro was directly dependent on drug loading (IC50 values E8