Chemical modifications of L-Asparaginase to improve acute lymphatic leukemia therapy

Abstract

Acute Lymphoblastic Leukemia (ALL) is one of the usual cancers in children below ten years. ALL is characterized by the production of many immature lymphoblasts in the bone marrow. The treatment of ALL majorly includes chemotherapy. Chemotherapeutic treatment is a phased process and involves many drugs, mainly given in concoction with the drug Asparaginase (ASNase). ASNase works by depleting the serum asparagine required by blast cells to form proteins. ASNase-based therapies have shown promising effects in the treatment of ALL. However, the current ASNase enzyme used for the treatment of ALL is of bacterial origin. Owing to its bacterial origin, it has many side effects, including hypersensitivity, pancreatitis, hyperglycemia, thromboembolism, etc. Also, the ASNase enzyme has a presence of secondary glutaminase activity. Due to glutaminase activity, there are several ill effects, including hepatotoxicity and neurotoxicity. There is a significant drawback of the ASNase therapy. The silent inactivation of ASNase is due to the formation of anti-drug antibodies. These ill effects were counter-managed by forming a novel mutant asparaginase drug using protein engineering approaches. This novel mutant has shown better outcomes in terms of stability and lesser toxicity. However, the mutant drug is susceptible to the serum proteases such as endopeptidase and cathepsin. This causes a reduction in the half-life of the mutant drug due to proteolytic degradation. To enhance the pharmacokinetic properties of this drug, further chemical modification using Methoxy Poly-ethylene glycol N-Hydroxysuccinimide esters (mPEG-NHS) is performed. Random chemical modification using mPEG-NHS was performed with the mutant ASNase. Chemical modification maintains the stealth effect and reduces the number of infusions by increasing the enzyme's half-life. Chemically modified ASNase has been tested for its stability, activity, and other parameters. It is also hypothesized that there will be lesser proteolytic degradation of these chemically modified ASNase. The chemically modified ASNase is a subject of testing anti leukemic activities in-vitro and in-vivo leukemic animal models. We are incredibly hopeful for producing an indigenous chemically modified ASNase that can be a better potential candidate for the treatment of ALL.