| 摘要 |
The present invention relates to novel conjugates, methods for their production, pharmaceutical compositions and methods for delivering cytotoxic anthracyclines to a selected population of cells desired to be eliminated. More particularly, the invention relates to anthracycline conjugates comprising at least one anthracycline molecule linked to a molecule that is reactive with a cell population to be eliminated. According to one embodiment of the invention, the conjugate is comprised of an antibody reactive with a selected cell population, the antibody having a number of anthracycline molecules linked to its structure. Each anthracycline molecule, having a keto group at the C-13 position, is conjugated to the antibody via a linker arm and is bound to that linker arm via an acid-sensitive acylhydrazone bond at the 13-keto position of the anthracycline. A preferred embodiment of the invention relates to an adriamycin immunoconjugate wherein a 13-keto acylhydrazone bond is the site of the adriamycin attachment to the linker arm, the linker additionally containing a disulfide or thioether linkage as part of the antibody attachment to the immunoconjugate. According to another embodiment of the invention, the conjugate is comprised of at least one anthracycline molecule conjugated via a linker arm to a ligand such as bombesin, epidermal growth factor or transferrin, the anthracycline being bound to the linker via an acid-sensitive acylhydrazone bond at the 13-keto position of the anthracycline. In addition, novel anthracycline acylhydrazone derivatives are disclosed that are useful in the preparation of the conjugates of this invention. The acid-sensitive hydrazone bond of the conjugates of this invention allows the release of free anthracycline from the conjugates in the acidic external or internal environment of the target cell. The conjugates and methods of the invention are therefore useful in antibody- or ligand-mediated drug delivery systems for the preferential killing of a selected cell population in the treatment of diseases such as cancers and other tumors, non-cytocidal viral or other pathogenic infections, and autoimmune disorders.
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