Lambert John M
ImmunoGen Inc, Cambridge, MA 02139, USA.
Curr Opin Pharmacol. 2005 Oct;5(5):543-9. doi: 10.1016/j.coph.2005.04.017.
Early clinical development in the field of targeted delivery of cytotoxic drugs to tumors was not successful because the limitations imposed by the pharmacokinetic and pharmacodynamic properties of monoclonal antibodies were not fully appreciated. Recently, development of this concept has been reinvigorated by the approval of gemtuzumab ozogamicin for treatment of acute myeloid leukemia. Other conjugates of calicheamicin and conjugates of potent tubulin poisons (maytansinoids auristatins and taxoids) are undergoing clinical evaluation or are in preclinical development. What all of these drugs have in common is that their cytotoxic potencies are in the picomolar range. Thirty years after the discovery of monoclonal antibodies, this new generation of highly potent compounds could yield targeted cytotoxic agents that are effective treatments for many cancers.
在将细胞毒性药物靶向递送至肿瘤领域的早期临床开发并不成功，因为单克隆抗体的药代动力学和药效学特性所带来的局限性尚未得到充分认识。最近，吉妥珠单抗奥唑米星获批用于治疗急性髓系白血病，这一概念的开发得以重振。其他加利车霉素缀合物以及强效微管蛋白毒物（美登素、澳瑞他汀和紫杉烷类）的缀合物正在进行临床评估或处于临床前开发阶段。所有这些药物的共同之处在于它们的细胞毒性效力处于皮摩尔范围内。在发现单克隆抗体30年后，这新一代高效化合物有望产生对多种癌症有效的靶向细胞毒性药物。
