Secreted Gal-3BP is a novel promising target for non-internalizing Antibody-Drug Conjugates
Secreted Gal-3BP is a novel promising target for non-internalizing Antibody-Drug Conjugates
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DOI：
10.1016/j.jconrel.2018.12.018
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发表时间：
2019-01-28
影响因子：
10.8
通讯作者：
Iacobelli, Stefano
中科院分区：
文献类型：
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作者：
Giansanti, Francesco;Capone, Emily;Iacobelli, Stefano
半乳糖凝集素 3 结合蛋白 (Gal-3BP) 已被确定为一种与癌症和转移相关的分泌蛋白，大多数癌症都表达该蛋白。本研究描述了一种特殊类型的非内化抗体药物缀合物，专门针对 Gal-3BP。在这里，我们展示了 1959 年人源化抗体，它特异性识别分泌的 Gal-3BP，选择性地定位在肿瘤周围，而不是正常细胞周围。硫醇-美登木素生物碱与 1959 的未配对半胱氨酸残基进行位点特异性二硫键连接，导致药物抗体比为 2，产生了 ADC 产品，该产品治愈了携带 A375m 黑色素瘤的小鼠。基于非内化 1959 抗体的 ADC 产品可能可用于治疗多种人类恶性肿瘤，因为同源抗原被大量表达和分泌 由多种癌症引起，但在大多数正常成人组织中含量较低。
Galectin-3-binding protein (Gal-3BP) has been identified as a cancer and metastasis-associated, secreted protein that is expressed by the large majority of cancers. The present study describes a special type of non-internalizing antibody-drug-conjugates that specifically target Gal-3BP. Here, we show that the humanized 1959 antibody, which specifically recognizes secreted Gal-3BP, selectively localized around tumor but not normal cells. A site specific disulfide linkage with thiol-maytansinoids to unpaired cysteine residues of 1959, resulting in a drug-antibody ratio of 2, yielded an ADC product, which cured A375m melanoma bearing mice.ADC products based on the non-internalizing 1959 antibody may be useful for the treatment of several human malignancies, as the cognate antigen is abundantly expressed and secreted by several cancers, while being present at low levels in most normal adult tissues.