Emerging advancements to improve L-asparaginase-based therapy: New insight into old paradigm, a review

Abstract

Over the past decades, remarkable advancements have been made since the discovery of Escherichia coli-derived L-asparaginase (L-asp), revolutionizing the treatment of acute lymphoblastic leukemia. Undoubtedly, L-asp has improved overall survival rates in both children and adolescents, but its clinical use is limited by the side effects, including hypersensitivity reactions, pancreatitis, hepatotoxicity, thromboembolism, and immunogenicity. Additionally, its short in vivo half-life presents a significant bottleneck, leading to poor clinical outcomes. To overcome the aforementioned shortcomings, various efforts are being made, including protein engineering, PEGylation, chemical modification, nano-encapsulation, and immobilization. Recently, immobilization of L-asp has emerged as a promising strategy to combat its side effects by attenuating the immune responses, while encapsulation in biocompatible nanocarriers preserves its structure and enables targeted delivery. Selecting an appropriate approach is crucial to enhance its stability, clinical efficacy, and reduce side effects. The central focus of this review is to delve into the new challenges, limitations, opportunities, and future directions for the advancements in L-asp formulations aimed at minimizing the risk of adverse effects, enhancing safety, and improving the overall clinical efficacy. We also discuss the associated adverse effects of L-asp, current efforts made through various clinical trials, and important pre-clinical findings to improve its clinical effectiveness. © 2025 Elsevier B.V.