Hematology/Oncology Fellowship Program, University of Washington, Seattle, WA, USA.
Front Biosci (Landmark Ed). 2013 Jun 1;18(4):1311-34. doi: 10.2741/4181.
Antibodies have created high expectations for effective yet tolerated therapeutics in acute myeloid leukemia (AML). Hitherto the most exploited target is CD33, a myeloid differentiation antigen found on AML blasts in most patients and, perhaps, leukemic stem cells in some. Treatment efforts have focused on conjugated antibodies, particularly gemtuzumab ozogamicin (GO), an anti-CD33 antibody carrying a toxic calicheamicin-g 1 derivative that, after intracellular hydrolytic release, induces DNA strand breaks, apoptosis, and cell death. Serving as paradigm for this strategy, GO was the first anti-cancer immunoconjugate to obtain regulatory approval in the U.S. While efficacious as monotherapy in acute promyelocytic leukemia (APL), GO alone induces remissions in less than 25-35% of non-APL AML patients. However, emerging data from well controlled trials now indicate that GO improves survival for many non-APL AML patients, supporting the conclusion that CD33 is a clinically relevant target for some disease subsets. It is thus unfortunate that GO has become unavailable in many parts of the world, and the drug's usefulness should be reconsidered and selected patients granted access to this immunoconjugate.
抗体为急性髓系白血病（AML）带来了有效且可耐受的治疗药物的高度期望。迄今为止，最受关注的靶点是 CD33，它是一种存在于大多数 AML 原始细胞上的髓系分化抗原，在某些情况下可能存在于白血病干细胞上。治疗工作主要集中在缀合抗体上，特别是吉妥珠单抗奥佐米星（GO），这是一种携带有毒 calicheamicin-g1 衍生物的抗 CD33 抗体，在细胞内水解释放后，可诱导 DNA 链断裂、凋亡和细胞死亡。作为该策略的范例，GO 是第一个在美国获得监管批准的抗癌免疫偶联物。虽然作为单药治疗急性早幼粒细胞白血病（APL）有效，但 GO 单独治疗不到 25-35%的非 APL AML 患者可诱导缓解。然而，来自精心控制的试验的新数据现在表明，GO 改善了许多非 APL AML 患者的生存，这支持了 CD33 是一些疾病亚群的临床相关靶点的结论。不幸的是，GO 在世界许多地区已经无法获得，应该重新考虑该药物的用途，并为符合条件的患者提供这种免疫偶联物。
