Van Trimpont Maaike, Schalk Amanda M, Hofkens Kenneth, Peeters Evelien, T'Sas Sara, Vandemeulebroecke Katrien, Su Ying, De Loera Ashley, Garcia Alyssa, Chen Hui, Lammens Tim, Van Vlierberghe Pieter, Goossens Steven, Lavie Arnon
Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, USA; Enzyme By Design Inc., Chicago, USA.
Cancer Lett. 2024 Dec 19;611:217404. doi: 10.1016/j.canlet.2024.217404.
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 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 solid cancers.
L-天冬酰胺酶（L-ASNase）在治疗儿童急性淋巴细胞白血病（ALL）中至关重要，但其应用受到FDA批准的细菌L-ASNases免疫原性和L-谷氨酰胺酶（L-GLNase）共活性所产生副作用的阻碍，这常常导致治疗中断和不良预后。这些L-ASNases的毒性使其在成年癌症患者中的应用尤其具有挑战性。为克服这些问题，我们研发了EBD-200，一种具有低Km且无L-GLNase活性的人源化豚鼠L-ASNase，消除了谷氨酰胺相关毒性。在ASNS ALL、黑色素瘤和肝癌模型中，EBD-200显示出与聚乙二醇化L-ASNase相当的抗癌效果，且耐受性有所改善。其强大的抗癌功效和更高的安全性表明，EBD-200可能使ALL患者受益，并拓宽ASNS实体癌的治疗选择。
