Preclinical validation of a less toxic variant for paediatric leukemia

L-asparaginase is an important drug in the treatment of acute lymphoblastic leukaemia in children. Currently, three enzyme preparations are available in the clinic, all derived from a bacterial source. Unfortunately, allergy is observed in ~15% of patients, resulting in a complete loss of enzyme and thus anticancer activity. In addition, other short-term asparaginase-related toxicities (such as pancreatic or hepatic problems) sometimes occur and further administration of the drug should be limited. It has been shown that early discontinuation (due to toxicity) or loss of enzyme activity is significantly associated with an increased risk of relapse and poorer survival. Moreover, asparaginase-associated toxicities have serious short- and long-term consequences for the quality of life of these sick children.
 
For all the above reasons, there is thus a great need for less toxic and less immunogenic alternative enzyme preparations. Recently, we generated a mammalian-derived asparaginase formulation. Our unpublished results in mouse models (manuscript in preparation) showed that this alternative asparaginase variant has an equivalent anticancer effect, but with significantly reduced toxic side effects compared to the formulation currently used in primary care.
 
The aim of this translational research project is to validate the safety/tolerability and efficacy of our alternative asparaginase formulation in a canine model, which is the final step to initiate clinical trials in humans. We believe that the clinical application of this newly designed asparaginase variant will contribute to a better quality of life for children with blood cancer.