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A novel L-asparaginase with low L-glutaminase coactivity is highly efficacious against both T- and B-cell acute lymphoblastic leukemias in vivo

Tijdschriftbijdrage - Tijdschriftartikel

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
Tijdschrift: Cancer Research
ISSN: 0008-5472
Issue: 6
Volume: 78
Pagina's: 1549 - 1560
Jaar van publicatie:2018