-
Applied Biochemistry and Biotechnology Mar 2016L-asparaginase (LA) catalyzes the degradation of asparagine, an essential amino acid for leukemic cells, into ammonia and aspartate. Owing to its ability to inhibit... (Review)
Review
L-asparaginase (LA) catalyzes the degradation of asparagine, an essential amino acid for leukemic cells, into ammonia and aspartate. Owing to its ability to inhibit protein biosynthesis in lymphoblasts, LA is used to treat acute lymphoblastic leukemia (ALL). Different isozymes of this enzyme have been isolated from a wide range of organisms, including plants and terrestrial and marine microorganisms. Pieces of information about the three-dimensional structure of L-asparaginase from Escherichia coli and Erwinia sp. have identified residues that are essential for catalytic activity. This review catalogues the major sources of L-asparaginase, the methods of its production through the solid state (SSF) and submerged (SmF) fermentation, purification, and characterization as well as its biological roles. In the same breath, this article explores both the past and present applications of this important enzyme and discusses its future prospects.
Topics: Amino Acids; Asparaginase; Bacteria; Chlorophyta; Food Industry; Fungi; Protein Conformation
PubMed: 26547852
DOI: 10.1007/s12010-015-1917-3 -
Future Oncology (London, England) Mar 2022Asparaginase is commonly used in combination therapy of acute lymphoblastic leukemia. However, as an immunogenic protein, hypersensitivity reactions (HSRs) during... (Review)
Review
Asparaginase is commonly used in combination therapy of acute lymphoblastic leukemia. However, as an immunogenic protein, hypersensitivity reactions (HSRs) during asparaginase therapy are frequent, indicating the development of anti-asparaginase antibodies. These can be associated with diminished clinical effectiveness, including poorer survival. Therapeutic drug monitoring of serum asparaginase activity to confirm complete asparagine depletion is therefore crucial during asparaginase therapy. Switching to alternative types of asparaginase is recommended for patients experiencing HSRs or silent inactivation; those with HSRs or silent inactivation on derived asparaginases should switch to another preparation. However, prior global shortages of asparaginase highlight the importance of alternative non- derived asparaginase, including recombinant asparaginase.
Topics: Adolescent; Antineoplastic Agents; Asparaginase; B-Lymphocytes; Child; Drug Hypersensitivity; Drug Monitoring; Female; Humans; Immunoglobulin M; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes, Helper-Inducer
PubMed: 35107320
DOI: 10.2217/fon-2021-1288 -
Leukemia & Lymphoma Feb 2011Asparaginase is one of the main drugs used to treat acute lymphoblastic leukemia and certain non-Hodgkin lymphomas. The drug is a bacterial product, and this results in... (Review)
Review
Asparaginase is one of the main drugs used to treat acute lymphoblastic leukemia and certain non-Hodgkin lymphomas. The drug is a bacterial product, and this results in differences in activity, efficacy, and side effects among the various marketed products. Native products originate from either Escherichia coli or Erwinia chrysanthemi. Currently a new product, PEG-asparaginase, is on the market. Recombinant asparaginases will be entering the market in a few years, and development of the incorporation of asparaginase in erythrocytes is progressing. This article reviews the available data on the various asparaginases and current developments. Differences between the various preparations are discussed in relation to pharmacokinetics, i.e. the short half-life of Erwinia preparations and prolonged activity of PEG-asparaginase. Uncertainties in relation to antibody formation and batch related differences of the newer products are discussed. The adverse effects related to origin of a product, mode of action, and antibody formation are also discussed.
Topics: Asparaginase; Clinical Trials as Topic; Humans; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 21281233
DOI: 10.3109/10428194.2010.537796 -
Anti-cancer Agents in Medicinal... 2022Microbial L-asparaginase is the most effective first-line therapy used in the treatment protocols of paediatric and adult leukemia. Leukemic cells' auxotrophy for... (Review)
Review
Microbial L-asparaginase is the most effective first-line therapy used in the treatment protocols of paediatric and adult leukemia. Leukemic cells' auxotrophy for L-asparagine is exploited as a therapeutic strategy to mediate cell death through metabolic blockade of L-asparagine using L-asparaginase. Escherichia coli and Erwinia chrysanthemi serve as the major enzyme deriving sources accepted in clinical practice, and the enzyme has bestowed improvements in patient outcomes over the last 40 years. However, an array of side effects generated by the native enzymes due to glutamine co-catalysis and short serum stays augmenting frequent dosages intended a therapeutic switch towards developing bio better alternatives for the enzyme, including the formulations resulting in sustained local depletion of Lasparagine. In addition, the treatment with L-asparaginase in a few cancer types has proven to elicit drug-induced cytoprotective autophagy mechanisms and therefore warrants concern. Although the off-target glutamine hydrolysis has been viewed as contributing to the drug-induced secondary responses in cells deficient with asparagine synthetase machinery, the beneficial role of glutaminase-asparaginase in proliferative regulation of asparagine prototrophic cells has been looked forward. The current review provides an overview of the enzyme's clinical applications in leukemia and possible therapeutic implications in other solid tumours, recent advancements in drug formulations, and discusses the aspects of two-sided roles of glutaminase-asparaginases and drug-induced cytoprotective autophagy mechanisms.
Topics: Asparaginase; Asparagine; Child; Escherichia coli; Glutaminase; Glutamine; Humans; Leukemia
PubMed: 34994334
DOI: 10.2174/1871520622666220106103336 -
Expert Opinion on Pharmacotherapy Aug 2007L-asparaginases have been established components in the treatment of acute leukemias for nearly 40 years. Their antitumor effect results from the depletion of... (Review)
Review
L-asparaginases have been established components in the treatment of acute leukemias for nearly 40 years. Their antitumor effect results from the depletion of asparagine, an amino acid essential to leukemic cells, and subsequent inhibition of protein synthesis leading to considerable cytotoxicity. The efficacy of L-asparaginases has been limited by a high rate of hypersensitivity reactions and development of anti-asparaginase antibodies, which neutralize their activity. PEG-asparaginase, a form of Escherichia coli L-asparaginase covalently linked to polyethylene glycol, was rationally synthesized to decrease immunogenicity of the enzyme and prolong its half-life. In recent years, clinical trials have established the importance of intramuscular PEG-asparaginase in frontline pediatric and adult acute lymphoblastic leukemia therapy. Present studies are evaluating the feasibility of intravenous PEG-asparaginase administration.
Topics: Adult; Antineoplastic Agents; Asparaginase; Child; Controlled Clinical Trials as Topic; Drug Approval; Humans; Injections, Intramuscular; Injections, Intravenous; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 17696798
DOI: 10.1517/14656566.8.12.1977 -
Blood Feb 2023AALL1931, a phase 2/3 study conducted in collaboration with the Children's Oncology Group, investigated the efficacy and safety of JZP458 (asparaginase erwinia...
AALL1931, a phase 2/3 study conducted in collaboration with the Children's Oncology Group, investigated the efficacy and safety of JZP458 (asparaginase erwinia chrysanthemi [recombinant]-rywn), a recombinant Erwinia asparaginase derived from a novel expression platform, in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma who developed hypersensitivity/silent inactivation to Escherichia coli-derived asparaginases. Each dose of a pegylated E coli-derived asparaginase remaining in patients' treatment plan was substituted by 6 doses of intramuscular (IM) JZP458 on Monday/Wednesday/Friday (MWF). Three regimens were evaluated: cohort 1a, 25 mg/m2 MWF; cohort 1b, 37.5 mg/m2 MWF; and cohort 1c, 25/25/50 mg/m2 MWF. Efficacy was evaluated by the proportion of patients maintaining adequate nadir serum asparaginase activity (NSAA ≥0.1 IU/mL) at 72 hours and at 48 hours during the first treatment course. A total of 167 patients were enrolled: cohort 1a (n = 33), cohort 1b (n = 83), and cohort 1c (n = 51). Mean serum asparaginase activity levels (IU/mL) at 72 hours were cohort 1a, 0.16, cohort 1b, 0.33, and cohort 1c, 0.47, and at 48 hours were 0.45, 0.88, and 0.66, respectively. The proportion of patients achieving NSAA ≥0.1 IU/mL at 72 and 48 hours in cohort 1c was 90% (44/49) and 96% (47/49), respectively. Simulated data from a population pharmacokinetic model matched the observed data well. Grade 3/4 treatment-related adverse events occurred in 86 of 167 (51%) patients; those leading to discontinuation included pancreatitis (6%), allergic reactions (5%), increased alanine aminotransferase (1%), and hyperammonemia (1%). Results demonstrate that IM JZP458 at 25/25/50 mg/m2 MWF is efficacious and has a safety profile consistent with other asparaginases. This trial was registered at www.clinicaltrials.gov as #NCT04145531.
Topics: Child; Humans; Asparaginase; Escherichia coli; Drug Hypersensitivity; Antineoplastic Agents; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hypersensitivity; Erwinia
PubMed: 36108304
DOI: 10.1182/blood.2022016923 -
Pediatric Blood & Cancer Oct 2021Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Bacterial L-asparaginase has played an important role in ALL treatment for several decades;... (Review)
Review
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Bacterial L-asparaginase has played an important role in ALL treatment for several decades; however, hypersensitivity reactions to Escherichia coli-derived asparaginases often preclude their use. Inability to receive asparaginase due to hypersensitivities is associated with poor patient outcomes. Erwinia chrysanthemi-derived asparaginase (ERW) is an effective, non-cross-reactive treatment option, but is limited in supply. Consequently, alternative asparaginase preparations are needed to ensure asparaginase availability for patients with hypersensitivities. Recombinant technology can potentially address this unmet need by programming cells to produce recombinant asparaginase. JZP-458, a recombinant Erwinia asparaginase derived from a novel Pseudomonas fluorescens expression platform with no immunologic cross-reactivity to E. coli-derived asparaginases, has the same primary amino acid sequence as ERW, with comparable activity based on in vitro measurements. The efficient manufacturing of JZP-458 would provide an additional asparaginase preparation for patients with hypersensitivities.
Topics: Antineoplastic Agents; Asparaginase; Child; Dickeya chrysanthemi; Drug Hypersensitivity; Escherichia coli; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pseudomonas fluorescens; Technology
PubMed: 34105243
DOI: 10.1002/pbc.29169 -
Leukemia & Lymphoma 1993
Review
Topics: Animals; Asparaginase; Dogs; Humans; Leukemia; Lymphoma; Polyethylene Glycols
PubMed: 8481663
DOI: 10.3109/10428199309149127 -
Biomedicine & Pharmacotherapy =... Jul 2021L-asparaginase is an enzyme that catalyzes the degradation of asparagine and successfully used in the treatment of acute lymphoblastic leukemia. L-asparaginase toxicity... (Review)
Review
L-asparaginase is an enzyme that catalyzes the degradation of asparagine and successfully used in the treatment of acute lymphoblastic leukemia. L-asparaginase toxicity is either related to hypersensitivity to the foreign protein or to a secondary L-glutaminase activity that causes inhibition of protein synthesis. PEGylated versions have been incorporated into the treatment protocols to reduce immunogenicity and an alternative L-asparaginase derived from Dickeya chrysanthemi is used in patients with anaphylactic reactions to the E. coli L-asparaginase. Alternative approaches commonly explore new sources of the enzyme as well as the use of protein engineering techniques to create less immunogenic, more stable variants with lower L-glutaminase activity. This article reviews the main strategies used to overcome L-asparaginase shortcomings and introduces recent tools that can be used to create therapeutic enzymes with improved features.
Topics: Animals; Antineoplastic Agents; Asparaginase; Glutaminase; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Engineering
PubMed: 33932739
DOI: 10.1016/j.biopha.2021.111616 -
Advances in Colloid and Interface... Jun 2023L-asparaginase (L-ASP) is one of the key enzymes used in therapeutic applications, particularly to treat Acute Lymphocytic Leukemia (ALL). L-asparagine is a... (Review)
Review
L-asparaginase (L-ASP) is one of the key enzymes used in therapeutic applications, particularly to treat Acute Lymphocytic Leukemia (ALL). L-asparagine is a non-essential amino acid, which means that it can be synthesized by the body and is not required to be obtained through the diet. The synthesis of L-asparagine occurs primarily in the liver, but it also takes place in other tissues throughout the body. In contrast, leukemic cells cannot synthesize L-asparagine due the absence of L-asparagine synthetase and should obtain it from circulating sources for protein synthesis and cell division processes to ensure their vital functions. L-ASP catalyzes the deamination process of L-asparagine amino-acid into aspartic acid and ammonia, depriving leukemic cells of asparagine. This leads to decreased protein synthesis and cell division in tumor cells. However, using L-ASP has side effects, such as hypersensitivity or allergic reaction, antigenicity, short half-life, temporary blood clearance, and toxicity. L-ASP immobilization can minimize the side effects of L-ASP by stopping the immune system from attacking non-human enzymes and improving the enzyme's performance. The first strategy includes modification of enzyme structure, such as covalent binding (conjugation), adsorption to the support material and cross-linking of the enzyme. The chemical modification of residues, often nonspecific, changes the enzyme's hydrophobicity and surface charge, lowering the enzyme's activity. Also, the first strategy exposes the enzyme's surface to the environment. This eliminates its performance and does not allow targeted delivery of the enzyme. The second strategy is based on the entrapment of the enzyme inside the protecting structure or encapsulation. This strategy offers the same benefits as the first. Still, it also enables reducing toxicity, prolonging in vivo half-life, enhancing stability and activity, enables a targeted delivery and controlled release of the enzyme. Compared to the first strategy, encapsulation does not modify the chemical structure of the enzyme since L-ASP is only effective against leukemia in its native tetrameric form. This review aims to present state of the art in L-ASP formulations developed for reducing the side effects of L-ASP, focusing on describing improvements in their safety. The primary focus in the field remains to be improving the overall performance of the L-ASP formulations. Almost all encapsulation systems allow reducing immune response due to screening the enzyme from antibodies and prolonging its half-life. However, the enzyme's activity and stability depend on the encapsulation system type. Therefore, the selection of the right encapsulation system is crucial in therapy due to its effect on the performance parameters of the L-ASP. Biodegradable and biocompatible materials, such as chitosan, alginate and liposomes, mainly attract the researcher's interest in enzyme encapsulation. The research trends are also moving towards developing formulations with targeted delivery and increased selectivity.
Topics: Humans; Asparaginase; Antineoplastic Agents; Asparagine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Aspartate-Ammonia Ligase
PubMed: 37159987
DOI: 10.1016/j.cis.2023.102915