A Novel l-Asparaginase with low l-Glutaminase Coactivity Is Highly Efficacious against Both T- and B-cell Acute Lymphoblastic Leukemias In Vivo.
A Novel l-Asparaginase with low l-Glutaminase Coactivity Is Highly Efficacious against Both T- and B-cell Acute Lymphoblastic Leukemias In Vivo.
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DOI：
10.1158/0008-5472.can-17-2106
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发表时间：
2018-03-15
期刊：
影响因子：
11.2
通讯作者：
Lavie A
中科院分区：
文献类型：
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作者：
Nguyen HA;Su Y;Zhang JY;Antanasijevic A;Caffrey M;Schalk AM;Liu L;Rondelli D;Oh A;Mahmud DL;Bosland MC;Kajdacsy-Balla A;Peirs S;Lammens T;Mondelaers V;De Moerloose B;Goossens S;Schlicht MJ;Kabirov KK;Lyubimov AV;Merrill BJ;Saunthararajah Y;Van Vlierberghe P;Lavie A
急性淋巴细胞白血病（ALL）是最常见的儿科癌症类型，尽管每10例中约有4例发生在成人中。酶药物L-天冬酰胺酶作为ALL治疗的基石，并利用ALL细胞的天冬酰胺依赖性。除了水解氨基酸L-天冬酰胺之外，所有FDA批准的L-天冬酰胺酶还具有显著的L-天冬酰胺酶共活性。由于一些报告表明L-谷氨酰胺耗竭与这些药物的许多副作用相关，如果保留其抗白血病活性，则具有降低的L-谷氨酰胺酶共活性的酶变体可能具有临床益处。在这里，我们表明，在FDA批准的欧文氏菌L-天冬酰胺酶的主链上开发的新型低L-丙氨酸氨基转移酶变体对T细胞和B细胞ALL都非常有效，同时显示出降低的急性毒性特征。这些结果支持开发新一代更安全的无L-天冬酰胺酶活性的L-天冬酰胺酶用于治疗人ALL。
Acute lymphoblastic leukemia (ALL) is the most common type of pediatric cancer, although about 4 of every 10 cases occur in adults. The enzyme drug L-asparaginase serves as a cornerstone of ALL therapy and exploits the asparagine-dependency of ALL cells. In addition to hydrolyzing the amino acid L-asparagine, all FDA-approved L-asparaginases also have significant L-glutaminase coactivity. Since several reports suggest that L-glutamine depletion correlates with many of the side effects of these drugs, enzyme variants with reduced L-glutaminase coactivity might be clinically beneficial if their anti-leukemic activity would be preserved. Here we show that novel low L-glutaminase variants developed on the backbone of the FDA-approved Erwinia chrysanthemi L-asparaginase were highly efficacious against both T and B cell ALL, while displaying reduced acute toxicity features. These results support the development of a new generation of safer L-asparaginases without L-glutaminase activity for the treatment of human ALL.