PreprintArticleVersion 1Preserved in Portico This version is not peer-reviewed
Protein Bioengineering of a Crucial Biopharmaceutical for Acute Lymphoblastic Leukaemia: Improving Toxicogical, Immune and Inflammatory Responses to Asparaginase
Version 1
: Received: 19 April 2024 / Approved: 22 April 2024 / Online: 22 April 2024 (18:07:38 CEST)
How to cite:
Lara, G.V.R.; Costa-Silva, T.A.; Cachumba, J.J.M.; Cevallos-Espinel, J.; Fontes, M.G.; Garcia-Maya, M.; Rahman, K.M.; RANGEL-YAGUI, C.O.; Monteiro, G. Protein Bioengineering of a Crucial Biopharmaceutical for Acute Lymphoblastic Leukaemia: Improving Toxicogical, Immune and Inflammatory Responses to Asparaginase. Preprints2024, 2024041448. https://doi.org/10.20944/preprints202404.1448.v1
Lara, G.V.R.; Costa-Silva, T.A.; Cachumba, J.J.M.; Cevallos-Espinel, J.; Fontes, M.G.; Garcia-Maya, M.; Rahman, K.M.; RANGEL-YAGUI, C.O.; Monteiro, G. Protein Bioengineering of a Crucial Biopharmaceutical for Acute Lymphoblastic Leukaemia: Improving Toxicogical, Immune and Inflammatory Responses to Asparaginase. Preprints 2024, 2024041448. https://doi.org/10.20944/preprints202404.1448.v1
Lara, G.V.R.; Costa-Silva, T.A.; Cachumba, J.J.M.; Cevallos-Espinel, J.; Fontes, M.G.; Garcia-Maya, M.; Rahman, K.M.; RANGEL-YAGUI, C.O.; Monteiro, G. Protein Bioengineering of a Crucial Biopharmaceutical for Acute Lymphoblastic Leukaemia: Improving Toxicogical, Immune and Inflammatory Responses to Asparaginase. Preprints2024, 2024041448. https://doi.org/10.20944/preprints202404.1448.v1
APA Style
Lara, G.V.R., Costa-Silva, T.A., Cachumba, J.J.M., Cevallos-Espinel, J., Fontes, M.G., Garcia-Maya, M., Rahman, K.M., RANGEL-YAGUI, C.O., & Monteiro, G. (2024). Protein Bioengineering of a Crucial Biopharmaceutical for Acute Lymphoblastic Leukaemia: Improving Toxicogical, Immune and Inflammatory Responses to Asparaginase. Preprints. https://doi.org/10.20944/preprints202404.1448.v1
Chicago/Turabian Style
Lara, G.V.R., CARLOTA OLIVEIRA RANGEL-YAGUI and Gisele Monteiro. 2024 "Protein Bioengineering of a Crucial Biopharmaceutical for Acute Lymphoblastic Leukaemia: Improving Toxicogical, Immune and Inflammatory Responses to Asparaginase" Preprints. https://doi.org/10.20944/preprints202404.1448.v1
Abstract
Acute lymphoblastic leukaemia is currently treated with bacterial L-Asparaginase; however, its side effects bring up the special need for improved and efficient novel enzymes development. Previously, we obtained low anti-asparaginase antibody production and high serum enzyme half-life in mice with the P40S/S206C mutant; however, its specific activity was significantly reduced. Thus, our aim was to test single mutants, S206C and P40S, for in vitro and in vivo assays. Our results showed that the drop in specific activity was caused by P40S substitution. Besides, our single mutants were highly stable in biological environment simulation, unlike double mutant P40S/S206C. The in vitro cell viability assay demonstrated that mutant enzymes have higher cytotoxic effect than WT on T-cells derived ALL and on some solid cancer cell lines. The in vivo assays were performed in mice to identify toxicological effects, to evoke immunological response and to study the enzymes pharmacokinetics. From these tests, none of the enzymes was toxic; however, S206C evoked lower physiological changes and immune responses. In relation to pharmacokinetic profile, S206C has two-fold higher activity than WT and P40S two hours after injection. In conclusion, we present bioengineered E. coli asparaginases with high specific enzyme activity and lesser side effects.
Keywords
E. coli asparaginase; bioengineer; leukaemia; nonclinical assays
Subject
Medicine and Pharmacology, Pediatrics, Perinatology and Child Health
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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