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Preclinical assays of glycoprotein asparaginase proteoforms or resistant to serum proteases.

Grant number: 18/15104-0
Support type:Regular Research Grants
Duration: April 01, 2019 - March 31, 2022
Field of knowledge:Health Sciences - Pharmacy
Principal researcher:Gisele Monteiro
Grantee:Gisele Monteiro
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Acute Lymphoblastic Leukemia (ALL) is the cancer with the highest incidence in the age group of 3 to 5 years. Therapy for the treatment of ALL utilizes, among other drugs, the bacterial L-asparaginase enzyme of Escherichia coli (Ec_ASNase) and as a second option that of D. chrysanthemi (Er_ASNase). Immunogenic reactions are the major side effects related to ASNase use, and the formation of anti-ASNase antibodies makes treatment difficult. Two lysosomal cysteine proteases are involved to the degradation of Ec_ASNase in the bloodstream: Cathepsin B (CTSB) and asparaginyl endopeptidase (AEP). In previous studies in our laboratory, we obtained three Ec_ASNase mutants resistant to degradation by AEP and / or CTSB. In another front, we obtained asparaginases of E. coli and D. chrysanthemi expressed in Pichia pastoris, resulting in glycosylated proteoforms. All these recombinant proteins were the result of the thematic project FAPESP 2013 / 08617-7 (CIBio authorization attached), as well as of the Regular Project FAPESP 2015 / 07749-2. In this work, we propose to assess the cytotoxicity profile of these proteoforms by thiazolyl blue tetrazolium (MTT) and perform in vivo assays (CEUA authorization - FCF 560 attached) in Balb / C mice for evaluation of antibody formation and half-life of proteoforms in comparison with the wild-type enzymes expressed in E. coli bacteria (conventional system for obtaining L_ASNases). (AU)

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Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LIMA, GUILHERME M.; ATRAZHEV, ALEXEY; SARKAR, SUSMITA; SOJITRA, MIRAT; REDDY, REVATHI; TORRES-OBREQUE, KARIN; RANGEL-YAGUI, CARLOTA DE OLIVEIRA; MACAULEY, MATTHEW S.; MONTEIRO, GISELE; DERDA, RATMIR. DNA-Encoded Multivalent Display of Chemically Modified Protein Tetramers on Phage: Synthesis and in Vivo Applications. ACS Chemical Biology, DEC 2021. Web of Science Citations: 0.
COSTA, IRIS MUNHOZ; MOURA, DEBORA CUSTODIO; LIMA, GUILHERME MEIRA; PESSOA, ADALBERTO; DOS SANTOS, CAMILA ORESCO; DE OLIVEIRA, MARCOS A.; MONTEIRO, GISELE. Engineered asparaginase from Erwinia chrysanthemi enhances asparagine hydrolase activity and diminishes enzyme immunoreactivity - a new promise to treat acute lymphoblastic leukemia. JOURNAL OF CHEMICAL TECHNOLOGY AND BIOTECHNOLOGY, v. 97, n. 1 OCT 2021. Web of Science Citations: 0.
LIMA, GUILHERME M.; MENEZES, MILENE C.; COSTA, IRIS M.; SERRANO, SOLANGE M. T.; MONTEIRO, GISELE. Development of a cell-free protein synthesis protocol to rapidly screen L-asparaginase proteoforms by enzymatic activity. JOURNAL OF CHEMICAL TECHNOLOGY AND BIOTECHNOLOGY, v. 96, n. 9, p. 2659-2666, SEP 2021. Web of Science Citations: 0.
RODRIGUES, MARIANE A. D.; PIMENTA, MARCELA V.; COSTA, IRIS M.; ZENATTI, PRISCILA P.; MIGITA, NATACHA A.; YUNES, JOSE A.; RANGEL-YAGUI, CARLOTA O.; DE SA, MATHEUS M.; PESSOA, ADALBERTO; COSTA-SILVA, TALES A.; TOYAMA, MARCOS H.; BREYER, CARLOS A.; DE OLIVEIRA, MARCOS A.; SANTIAGO, VERONICA F.; PALMISANO, GIUSEPPE; BARBOSA, CHRISTIANO M. V.; HEBEDA, CRISTINA B.; FARSKY, SANDRA H. P.; MONTEIRO, GISELE. Influence of lysosomal protease sensitivity in the immunogenicity of the antitumor biopharmaceutical asparaginase. Biochemical Pharmacology, v. 182, DEC 2020. Web of Science Citations: 0.
CAVALCANTE, LUCAS DE SOUSA; COSTA-SILVA, TALES A.; SOUZA, TIAGO ANTONIO; IENNE, SUSAN; MONTEIRO, GISELE. Chemogenomic study of gemcitabine using Saccharomyces cerevisiae as model cell-molecular insights about chemoresistance. Brazilian Journal of Microbiology, v. 51, n. 2, p. 489-496, JUN 2020. Web of Science Citations: 0.
MAGRI, AGNES; PIMENTA, MARCELA V.; SANTOS, JOAO H. P. M.; COUTINHO, JOAO A. P.; VENTURA, SONIA P. M.; MONTEIRO, GISELE; RANGEL-YAGUI, CARLOTA O.; PEREIRA, JORGE F. B. Controlling the l-asparaginase extraction and purification by the appropriate selection of polymer/salt-based aqueous biphasic systems. JOURNAL OF CHEMICAL TECHNOLOGY AND BIOTECHNOLOGY, v. 95, n. 4, p. 1016-1027, APR 2020. Web of Science Citations: 3.

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