A human-like glutaminase-free asparaginase is highly efficacious in ASNSlow leukemia and solid cancer mouse xenograft models

Maaike Van Trimpont; Amanda M Schalk; Kenneth Hofkens; Evelien Peeters; Sara T'Sas; Katrien Vandemeulebroecke; Ying Su; Ashley De Loera; Alyssa Garcia; Hui Chen; Tim Lammens; Pieter Van Vlierberghe; Steven Goossens; Arnon Lavie

doi:10.1016/j.canlet.2024.217404

A human-like glutaminase-free asparaginase is highly efficacious in ASNS^low leukemia and solid cancer mouse xenograft models

Cancer Lett. 2024 Dec 19:217404. doi: 10.1016/j.canlet.2024.217404. Online ahead of print.

Authors

Affiliations

¹ Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
² Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, USA; Enzyme by Design Inc., Chicago, USA.
³ Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
⁴ Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, USA.
⁵ Director, Mass Spectrometry Core, Research Resources Center, University of Illinois at Chicago, Chicago, USA.
⁶ Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
⁷ Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, USA; Enzyme by Design Inc., Chicago, USA; Research Biologist, Biological Science Research and Development, Department of Veterans Affairs Medical Center, Chicago, Illinois, USA. Electronic address: Lavie@uic.edu.

PMID: 39709177
DOI: 10.1016/j.canlet.2024.217404

Abstract

L-asparaginase (L-ASNase) is crucial in treating pediatric acute lymphoblastic leukemia (ALL), but its use is hampered by side effects from the immunogenicity and L-glutaminase (L-GLNase) co-activity of FDA-approved bacterial L-ASNases, often leading to treatment discontinuation and poor outcomes. The toxicity of these L-ASNases makes them especially challenging to use in adult cancer patients. To overcome these issues, we developed EBD-200, a humanized guinea pig L-ASNase with low Km and no L-GLNase activity, eliminating glutamine-related toxicity. EBD-200 showed comparable anti-cancer effects to PEGylated L-ASNase in ASNS^low ALL, melanoma and liver cancer models, with improved tolerability. Its potent anti-cancer efficacy and enhanced safety profile suggest that EBD-200 could benefit ALL patients and broaden treatment options for ASNS^low solid cancers.

Keywords: (max 7); ASNS(low) solid tumors; Asparagine synthetase; acute lymphoblastic leukemia; liver cancer; melanoma.