cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity
cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity
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DOI：
10.1182/blood-2003-01-0039
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发表时间：
2003-08-15
期刊：
影响因子：
20.3
通讯作者：
Wahl, AF
中科院分区：
文献类型：
--
作者：
Francisco, JA;Cerveny, CG;Wahl, AF
针对CD 30的嵌合单克隆抗体cAC 10在体外诱导CD 30（+）细胞系的生长停滞，并在霍奇金病的重度联合免疫缺陷（SCID）小鼠异种移植模型中具有显著的抗肿瘤活性。我们通过将细胞毒性剂单甲基澳瑞他汀E（MMAE）缀合至cAC 10以产生抗体-药物缀合物cAC 10-vcMMAE来显著增强这些活性。MMAE是细胞毒性微管蛋白修饰剂奥瑞他汀E的衍生物，通过缬氨酸-瓜氨酸肽接头与cAC 10共价偶联。药物与抗体稳定连接，在人血浆中孵育10天后仅显示2%的MMAE释放，但在受体介导的内化后容易被溶酶体蛋白酶裂解。MMAE释放到胞质溶胶中通过诱导细胞凋亡诱导G（2）/M期生长停滞和细胞死亡。在体外，cAC 10-vcMMAE对CD 30（+）肿瘤细胞系具有高度效力和选择性（IC 50小于10 ng/mL），但对抗原阴性细胞的活性低300倍以上。在间变性大细胞淋巴瘤或霍奇金病的SCID小鼠异种移植模型中，cAC 10-vcMMAE在低至1 mg/kg的剂量下有效。以30 mg/kg cAC 10-vcMMAE给药的小鼠未显示毒性体征。这些数据表明，cAC 10-vcMMAE可能是治疗CD 30（+）肿瘤的一种高效和选择性疗法。(C)2003年，美国血液学会。
The chimeric monoclonal antibody cAC10, directed against CD30, induces growth arrest of CD30(+) cell lines in vitro and has pronounced antitumor activity in severe combined immunodeficiency (SCID) mouse xenograft models of Hodgkin disease. We have significantly enhanced these activities by conjugating to cAC10 the cytotoxic agent monomethyl auristatin E (MMAE) to create the antibody-drug conjugate cAC10-vcMMAE. MMAE, a derivative of the cytotoxic tubulin modifier auristatin E, was covalently coupled to cAC10 through a valine-citrulline peptide linker. The drug was stably attached to the antibody, showing only a 2% release of MMAE following 10-day incubation in human plasma, but it was readily cleaved by lysosomal proteases after receptor-mediated internalization. Release of MMAE into the cytosol induced G(2)/M-phase growth arrest and cell death through the induction of apoptosis. in vitro, cAC10-vcMMAE was highly potent and selective against CD30(+) tumor lines (IC50 less than 10 ng/mL) but was more than 300-fold less active on antigen-negative cells. In SCID mouse xenograft models of anaplastic large cell lymphoma or Hodgkin disease, cAC10-vcMMAE was efficacious at doses as low as 1 mg/kg. Mice treated at 30 mg/kg cAC10-vcMMAE showed no signs of toxicity. These data indicate that cAC10-vcMMAE may be a highly effective and selective therapy for the treatment of CD30(+) neoplasias. (C) 2003 by The American Society of Hematology.