Seattle Genetics, Inc., Bothell, Washington.
Mol Cancer Ther. 2014 Dec;13(12):2991-3000. doi: 10.1158/1535-7163.MCT-13-0896. Epub 2014 Sep 24.
In this article, we describe a novel antibody-drug conjugate (ADC; SGN-LIV1A), targeting the zinc transporter LIV-1 (SLC39A6) for the treatment of metastatic breast cancer. LIV-1 was previously known to be expressed by estrogen receptor-positive breast cancers. In this study, we show that LIV-1 expression is maintained after hormonal therapy in primary and metastatic sites and is also upregulated in triple-negative breast cancers. In addition to breast cancer, other indications showing LIV-1 expression include melanoma, prostate, ovarian, and uterine cancer. SGN-LIV1A consists of a humanized antibody conjugated through a proteolytically cleavable linker to monomethyl auristatin E, a potent microtubule-disrupting agent. When bound to surface-expressed LIV-1 on immortalized cell lines, this ADC is internalized and traffics to the lysozome. SGN-LIV1A displays specific in vitro cytotoxic activity against LIV-1-expressing cancer cells. In vitro results are recapitulated in vivo where antitumor activity is demonstrated in tumor models of breast and cervical cancer lineages. These results support the clinical evaluation of SGN-LIV1A as a novel therapeutic agent for patients with LIV-1-expressing cancer.
在这篇文章中，我们描述了一种新型的抗体药物偶联物（ADC；SGN-LIV1A），该药物针对锌转运蛋白 LIV-1（SLC39A6），用于治疗转移性乳腺癌。先前已知 LIV-1 在雌激素受体阳性的乳腺癌中表达。在这项研究中，我们表明 LIV-1 的表达在原发性和转移性部位的激素治疗后得以维持，并且在三阴性乳腺癌中也上调。除了乳腺癌，其他显示 LIV-1 表达的适应症包括黑色素瘤、前列腺癌、卵巢癌和子宫癌。SGN-LIV1A 由通过可蛋白水解的接头连接到单甲基奥瑞他汀 E 的人源化抗体组成，单甲基奥瑞他汀 E 是一种有效的微管破坏剂。当与永生化细胞系表面表达的 LIV-1 结合时，该 ADC 被内化并运输到溶酶体。SGN-LIV1A 对表达 LIV-1 的癌细胞表现出特异性的体外细胞毒性活性。体内结果重现了体内结果，在乳腺癌和宫颈癌系的肿瘤模型中证明了抗肿瘤活性。这些结果支持将 SGN-LIV1A 作为表达 LIV-1 的癌症患者的新型治疗剂进行临床评估。
