Perentesis J P, Gunther R, Waurzyniak B, Yanishevski Y, Myers D E, Ek O, Messinger Y, Shao Y, Chelstrom L M, Schneider E, Evans W E, Uckun F M
Departments of Pediatrics and Biochemistry, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Clin Cancer Res. 1997 Dec;3(12 Pt 1):2217-27.
Acute myeloid leukemia (AML) is the most common form of acute leukemia. Contemporary chemotherapy regimens fail to cure most patients with AML. We have genetically engineered a recombinant diphtheria toxin human granulocyte macrophage colony-stimulating factor (GMCSF) chimeric fusion protein (DTctGMCSF) that specifically targets the GMCSF receptor on fresh human AML cells and myeloid leukemia cell lines. At a nontoxic dose level, DTctGMCSF therapy was superior to the standard chemotherapeutic agents 1-beta-D-arabinofuranosylcytosine and Adriamycin, resulting in 60% long-term event-free survival of severe combined immunodeficient mice challenged with an otherwise invariably fatal cell dose of the human HL-60 myeloid leukemia. Notably, systemic exposure levels of DTctGMCSF, which were found to be therapeutic in the severe combined immunodeficient mouse xenograft model of human HL-60 myeloid leukemia, could be achieved in cynomolgus monkeys without any significant nonhematological toxicities. The recombinant DTctGMCSF fusion toxin might be useful in the treatment of AML patients whose leukemias have recurred and developed resistance to contemporary chemotherapy programs.
急性髓系白血病（AML）是急性白血病最常见的形式。当代化疗方案无法治愈大多数AML患者。我们通过基因工程构建了一种重组白喉毒素-人粒细胞巨噬细胞集落刺激因子（GMCSF）嵌合融合蛋白（DTctGMCSF），它能特异性靶向新鲜人AML细胞和髓系白血病细胞系上的GMCSF受体。在无毒剂量水平下，DTctGMCSF疗法优于标准化疗药物1-β-D-阿拉伯呋喃糖基胞嘧啶和阿霉素，在用否则必然致命剂量的人HL-60髓系白血病细胞攻击的严重联合免疫缺陷小鼠中，实现了60%的长期无事件生存率。值得注意的是，在食蟹猴中可以达到在人HL-60髓系白血病的严重联合免疫缺陷小鼠异种移植模型中具有治疗效果的DTctGMCSF全身暴露水平，且无任何明显的非血液学毒性。重组DTctGMCSF融合毒素可能对白血病复发且对当代化疗方案产生耐药性的AML患者的治疗有用。
