Liu Xiufen, Müller Fabian, Wayne Alan S, Pastan Ira
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Division of Hematology, Oncology and Blood and Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
Mol Cancer Ther. 2016 May;15(5):1053-62. doi: 10.1158/1535-7163.MCT-15-0828. Epub 2016 Mar 3.
HA22 (Moxetumomab pasudotox) is a recombinant immunotoxin (RIT), composed of an anti-CD22 Fv fused to a truncated portion of Pseudomonas exotoxin A. HA22 is in clinical trials to treat patients with hairy cell leukemia and acute lymphoblastic leukemia (ALL). LMB-11 is an improved variant of HA22 with reduced immunogenicity, has a longer half-life in the blood and high activity in vitro and in a Burkitt lymphoma model in vivo Searching for RIT enhancing combination therapies, we found the protein kinase A inhibitor H89 to enhance LMB-11 and HA22 activity 5- to 10-fold on ALL cell lines and on patient-derived ALL samples. In addition, H89 increased the activity of mesothelin-targeting RITs SS1P (38-fold) and RG7787 (7-fold) against the cervical cancer cell line KB31. Unexpectedly we found that the enhancement by H89 was not because of inhibition of protein kinase A; it was partially recapitulated by inhibition of S6K1, which led to inactivation of its downstream targets rpS6 and GSK3β, resulting in a fall in MCL1 levels. H89 increased the rate of ADP-ribosylation of eukaryotic elongation factor 2, enhancing the arrest of protein synthesis and the reduction of MCL1 in synergy with the RIT. In summary, H89 increased RIT activity by enhancing the two key events: ADP-ribosylation of eEF2 and reduction of MCL1 levels. Significant enhancement was seen with both CD22- and mesothelin-targeting RITs, indicating that H89 might be a potent addition to RIT treatment of CD22-positive ALL and mesothelin-expressing solid tumors. Mol Cancer Ther; 15(5); 1053-62. ©2016 AACR.
HA22（莫克妥珠单抗）是一种重组免疫毒素（RIT），由与铜绿假单胞菌外毒素A截短部分融合的抗CD22 Fv组成。HA22正在进行治疗毛细胞白血病和急性淋巴细胞白血病（ALL）患者的临床试验。LMB - 11是HA22的一种免疫原性降低的改进变体，在血液中的半衰期更长，在体外和体内伯基特淋巴瘤模型中具有高活性。在寻找增强RIT的联合疗法时，我们发现蛋白激酶A抑制剂H89可使LMB - 11和HA22在ALL细胞系和患者来源的ALL样本上的活性提高5至10倍。此外，H89使靶向间皮素的RITs SS1P（38倍）和RG7787（7倍）对宫颈癌细胞系KB31的活性增加。出乎意料的是，我们发现H89的增强作用并非由于抑制蛋白激酶A；部分作用可通过抑制S6K1来重现，这导致其下游靶点rpS6和GSK3β失活，从而使MCL1水平下降。H89提高了真核延伸因子2的ADP核糖基化速率，增强了蛋白质合成的阻滞，并与RIT协同降低了MCL1。总之，H89通过增强两个关键事件来提高RIT活性：eEF2的ADP核糖基化和MCL1水平的降低。在靶向CD22和间皮素的RITs中均观察到显著增强，表明H89可能是RIT治疗CD22阳性ALL和间皮素表达实体瘤的有效辅助药物。《分子癌症治疗》；15(5)；1053 - 62。©2016美国癌症研究协会。
