公开(公告)号：US20080188421A1

公开(公告)日：2008-08-07

申请号：US11795703

申请日：2005-03-31

申请人： Dale E. Bredesen ,  Michael Ellerby ,  Lisa Ellerby

发明人： Dale E. Bredesen ,  Michael Ellerby ,  Lisa Ellerby

IPC分类号： A61K38/10 ,  C07K7/00 ,  A61K38/08 ,  A61P35/00

CPC分类号： A61K38/16 ,  A61K47/64

摘要： The present invention provides homing conjugates containing an antimicrobial peptide and a tumor homing molecule, wherein the tumor homing molecule comprises a dimer of two endothelium-homing peptide monomers, wherein the conjugate homes to and is internalized by a tumor cell type or tissue comprising angiogenic endothelial cells and exhibits high toxicity thereto, wherein the high toxicity is due to disruption of mitochondrial membranes, and wherein the antimicrobial peptide has low mammalian cell toxicity when not linked to said tumor homing molecule. The present invention is based, in part, on the discovery that dimerization of endothelium-homing peptide monomer confers greatly increased cytotoxic activity on the conjugate. Based on this discovery, the invention further provides methods of inducing selective toxicity in vivo in an angiogenic endothelial tissue or cell type as well as methods of treating an individual having cancer by administering an effective amount of a homing conjugate of the invention also are provided.

摘要翻译： 本发明提供了含有抗微生物肽和肿瘤归巢分子的归巢缀合物，其中所述肿瘤归巢分子包含两个内皮归巢肽单体的二聚体，其中所述缀合物归因于包含血管生成内皮的肿瘤细胞类型或组织 细胞并且对其呈现高毒性，其中高毒性是由于线粒体膜的破坏，并且其中当不与所述肿瘤归巢分子连接时，所述抗微生物肽具有低的哺乳动物细胞毒性。 本发明部分地基于发现内皮归巢肽单体的二聚化大大提高了缀合物的细胞毒活性。 基于该发现，本发明还提供了在血管生成内皮组织或细胞类型中诱导体内选择性毒性的方法以及通过施用有效量的本发明的归巢缀合物治疗患有癌症的个体的方法。