A Novel L-Asparaginase with low L-Glutaminase Coactivity Is Highly Efficacious against Both T- and B-cell Acute Lymphoblastic Leukemias In Vivo

作者：Hien Anh Nguyen; Su Ying; Zhang Jenny Y; Antanasijevic Aleksandar; Caffrey Michael; Schalk Amanda M; Liu Li; Rondelli Damiano; Oh Annie; Mahmud Dolores L; Bosland Maarten C; Kajdacsy Balla Andre; Peirs Sofie; Lammens Tim; Mondelaers Veerle; De Moerloose Barbara; Goossens Steven; Schlicht Michael J; Kabirov Kasim K; Lyubimov Alexander V; Merrill Bradley J; Saunthararajah Yogen; Van Vlierberghe Pieter^*; Lavie Arnon^*

来源：Cancer Research, 2018, 78(6): 1549-1560.

DOI：10.1158/0008-5472.CAN-17-2106

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 antileukemic 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.
Significance: A newL-asparaginase-based therapy is less toxic compared with FDA-approved high L-glutaminase enzymes

• 出版日期2018-3-15