Influence of lysosomal protease sensitivity in the immunogenicity of the antitumor biopharmaceutical asparaginase

Autor: Iris Munhoz Costa, Carlos Alexandre Breyer, Priscila Pini Zenatti, Adalberto Pessoa, Natacha Azussa Migita, Gisele Monteiro, Christiano Marcello Vaz Barbosa, Marcos H. Toyama, T. A. Costa-Silva, Carlota de Oliveira Rangel-Yagui, Sandra Helena Poliselli Farsky, Cristina Bichels Hebeda, Giuseppe Palmisano, Matheus Malta de Sá, José Andrés Yunes, Marcela V. Pimenta, Mariane Augusta Domingues Rodrigues, Veronica Feijoli Santiago, Marcos Antonio de Oliveira
Přispěvatelé: Universidade de São Paulo (USP), Centro Infantil Boldrini, Universidade Estadual de Campinas (UNICAMP), Universidade Estadual Paulista (Unesp)
Rok vydání: 2020
Předmět:
0301 basic medicine
Proteases
Cell Survival
Antineoplastic Agents
Human proteases
Biochemistry
Epitope
Cathepsin B
Protein Structure
Secondary
Error-prone polymerase chain reaction
03 medical and health sciences
Jurkat Cells
Mice
0302 clinical medicine
Immune system
In vivo
Protein stability
Escherichia coli
Animals
Asparaginase
Humans
Amino Acid Sequence
Horses
Immunogenetic Phenomena
Pharmacology
chemistry.chemical_classification
Biological Products
Mice
Inbred BALB C
Dose-Response Relationship
Drug
Immunogenicity
Acute lymphoblastic leukaemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
L-asparaginase
Endopeptidase
Biopharmaceutical
030104 developmental biology
Enzyme
chemistry
CITOTOXICIDADE IMUNOLÓGICA
030220 oncology & carcinogenesis
Cattle
Female
Lysosomes
Chickens
Peptide Hydrolases
Zdroj: Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual)
Universidade de São Paulo (USP)
instacron:USP
Scopus
Repositório Institucional da UNESP
Universidade Estadual Paulista (UNESP)
instacron:UNESP
ISSN: 1873-2968
Popis: Made available in DSpace on 2021-06-25T10:35:17Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-12-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Ministério da Ciência, Tecnologia, Inovações e Comunicações Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) L-asparaginase (ASNase) from Escherichia coli (EcAII) is used in the treatment of acute lymphoblastic leukaemia (ALL). EcAII activity in vivo has been described to be influenced by the human lysosomal proteases asparaginyl endopeptidase (AEP) and cathepsin B (CTSB); these hydrolases cleave and could expose epitopes associated with the immune response against EcAII. In this work, we show that ASNase resistance to CTSB and/or AEP influences the formation of anti-ASNase antibodies, one of the main causes of hypersensitivity reactions in patients. Error-prone polymerase chain reaction was used to produce variants of EcAII more resistant to proteolytic cleavage by AEP and CTSB. The variants with enzymatic activity and cytotoxicity levels equivalent to or better than EcAII WT were submitted to in vivo assays. Only one of the mutants presented increased serum half-life, so resistance to these proteases is not the only feature involved in EcAII stability in vivo. Our results showed alteration of the phenotypic profile of B cells isolated after animal treatment with different protease-resistant proteoforms. Furthermore, mice that were exposed to the protease-resistant proteoforms presented lower anti-asparaginase antibodies production in vivo. Our data suggest that modulating resistance to lysosomal proteases can result in less immunogenic protein drugs. Departamento de Tecnologia Bioquímico-Farmacêutica Faculdade de Ciências Farmacêuticas Universidade de São Paulo Centro Infantil Boldrini, Campinas Department of Medical Genetics Faculty of Medical Sciences State University of Campinas, Campinas Heart Institute (InCor) Medical School University of São Paulo Biosciences Institute UNESP – São Paulo State University Coastal Campus, São Vicente Department of Parasitology Biomedical Sciences Institute University of São Paulo Department of Clinical and Toxicological Analysis Faculdade de Ciências Farmacêuticas Universidade de São Paulo Biosciences Institute UNESP – São Paulo State University Coastal Campus, São Vicente FAPESP: 2013/08139-8 FAPESP: 2013/08617-7 FAPESP: 2014/06863-3 FAPESP: 2015/07749-2 FAPESP: 2016/25896-5 FAPESP: 2018/15104-0 FAPESP: 2018/15549-1 FAPESP: 2018/18257-1 CNPq: 28/2018 CNPq: 301596/2017-4 CAPES: 309595/2016-9 CNPq: 423532/2018-9
Databáze: OpenAIRE
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