2010 Antibody-drug conjugates Targeted drug delivery for cancer.精品.pdfVIP

Available online at Antibody–drug conjugates: targeted drug delivery for cancer Stephen C Alley, Nicole M Okeley and Peter D Senter The antibody–drug conjugate field has made significant Development of optimized ADCs progress recently owing to careful optimization of several Optimization parameters parameters, including mAb specificity, drug potency, linker Extensive optimization of several ADC parameters has technology, and the stoichiometry and placement of taken place over multiple decades, and clinical develop- conjugated drugs. The underlying reason for this has been ment of ADCs has required attention to these details. obtained in pre-clinical biodistribution and pharmacokinetics Table 1 lists these optimization parameters and different studies showing that targeted delivery leads to high solutions for producing pharmacologically active ADCs. intratumoral free drug concentrations, while non-target tissues There are 3 key components of an ADC: the mAb, the are largely spared from chemotherapeutic exposure. Recent drug, and the linker. Ideally, the mAb will specifically developments in the field have led to an increase in the number bind to an antigen with substantial expression on tumor of ADCs being tested clinically, with 3 in late stage clinical trials: cells but limited expression on normal tissues. Specificity brentuximab vedotin (also referred to as SGN-35) for Hodgkin allows the utilization of drugs that otherwise would be too lymphoma; Trastuzumab-DM1 for breast cancer; and toxic for clinical application. Thus, most of the recent Inotuzumab ozogamicin for non-Hodgkin lymphoma. This work in this field has centered on the use of highly