公开(公告)号：US20050054607A1

公开(公告)日：2005-03-10

申请号：US10659501

申请日：2003-09-10

申请人： Ned Weinshenker ,  Frederick West ,  Barbara Araneo ,  Weiping Li

发明人： Ned Weinshenker ,  Frederick West ,  Barbara Araneo ,  Weiping Li

IPC分类号： A01N43/04 ,  A61K20060101 ,  A61K31/70 ,  A61K31/714 ,  A61K47/48

CPC分类号： A61K47/551

摘要： The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.

摘要翻译： 本发明提供了一种适用于治疗肿瘤相关疾病的钴胺素药物缀合物。 钴胺素通过可裂解连接体和一个或多个任选的间隔物间接共价结合抗肿瘤药物。 钴胺素通过钴胺核糖环的5'-OH共价结合到第一间隔物或可切割的接头。 药物通过药物上现有或添加的官能团与可切割接头的第二间隔物结合。 给药后，缀合物与转钴胺素（其任何同种型）形成复合物。 然后，该复合物与细胞膜上的受体结合，并被吸收到细胞中。 一旦在细胞中，细胞内酶切割缀合物从而释放药物。 根据缀合物的结构，细胞内酶的特定类别或类型影响切割。 由于对生长细胞中钴胺素的高需求，肿瘤细胞通常占有比正常非生长细胞更高的缀合物百分比。 与相应的游离药物相比，本发明的缀合物有利地提供降低的全身毒性和增强的功效。