Novel immunoconjugates comprised of streptonigrin and 17-amino-geldanamycin attached via a dipeptide-p-aminobenzyl-amine linker system
Novel immunoconjugates comprised of streptonigrin and 17-amino-geldanamycin attached via a dipeptide-p-aminobenzyl-amine linker system
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DOI：
10.1016/j.bmcl.2009.03.145
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发表时间：
2009-05-15
影响因子：
2.7
通讯作者：
Jeffrey, Scott C.
中科院分区：
文献类型：
--
作者：
Burke, Patrick J.;Toki, Brian E.;Jeffrey, Scott C.
将细胞毒剂链球菌素和17-氨基-格尔达那霉素与单抗(MAbs)偶联，形成抗体-药物结合物(ADC)，用于抗原介导的靶向癌细胞。这些药物与一个对溶酶体酶不稳定的连接体结构连接，并结合一个Valine-丙氨酸-对氨基(PAB)-氨基连接，以直接连接到两种药物中存在的电子缺陷胺官能团。由此产生的ADC在内化到抗原阳性的癌细胞后释放药物。通过还原链间二硫键的烷基化反应，将药物连接物与单抗cAC10(抗CD30)和h1F6(抗CD70)偶联，得到4种药物/单抗。在体外和霍奇金淋巴瘤异种移植模型中，链球蛋白ADC在一组癌细胞株上具有强大的免疫学特异性。我们的结论是，链球蛋白ADC是进一步研究的候选者，并且用来制作它们的新型连接系统非常适合于含有电子缺陷胺官能团的细胞毒剂的偶联。(C)2009爱思唯尔有限公司。保留所有权利。
Cytotoxic agents streptonigrin and 17-amino-geldanamycin were linked to monoclonal antibodies (mAbs), forming antibody-drug conjugates (ADCs) for antigen-mediated targeting to cancer cells. The drugs were conjugated with a linker construct that is labile to lysosomal proteases and incorporates a valine-alanine-p-aminobenzyl (PAB)-amino linkage for direct attachment to the electron-deficient amine functional groups present in both drugs. The resulting ADCs release drug following internalization into antigen-positive cancer cells. The drug linkers were conjugated to mAbs cAC10 (anti-CD30) and h1F6 (anti-CD70) via alkylation of reduced interchain disulfides to give ADCs loaded with 4 drugs/mAb. The streptonigrin ADCs were potent and immunologically specific on a panel of cancer cell lines in vitro and in a Hodgkin lymphoma xenograft model. We conclude that streptonigrin ADCs are candidates for further research, and that the novel linker system used to make them is well-suited for the conjugation of cytotoxic agents containing electron-deficient amine functional groups. (C) 2009 Elsevier Ltd. All rights reserved.