Research and Innovation: Development of a new PEG conjugated asparaginase for the neoplasias treatment
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Development of a new PEG conjugated asparaginase for the neoplasias treatment

Grant number: 17/08591-9
Support Opportunities:Research Grants - Innovative Research in Small Business - PIPE
Start date: May 01, 2018
End date: January 31, 2019
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Carlos Alexandre Breyer
Grantee:Carlos Alexandre Breyer
Company:Biobreyer Pesquisa e Desenvolvimento Científico Ltda
CNAE: Pesquisa e desenvolvimento experimental em ciências físicas e naturais
City: Santos
Associated research grant(s):19/12401-6 - Development of a new PEG conjugated asparaginase for treatment of neoplasias, AP.PIPE
Associated scholarship(s):18/11863-3 - Development of a new PEG conjugated asparaginase for the neoplasias treatment, BP.TT
18/11328-0 - Development of a new PEG conjugated asparaginase for the Neoplasias Treatment, BP.PIPE

Abstract

Biopharmaceuticals are biological drugs used in the cancer, diabetes, cardiovascular diseases treatment. In Brazil, there is a great deficiency of biopharmaceuticals production. According to the Brazilian Pharmochemical Industry Association Index of 2016, about 4% of the medicines purchased by the Ministry of Health are biopharmaceuticals, however this drugs represents about 51% of expenses causing a deficit of 2 billion of reais in the trade balance of the pharmaceutical sector. Among the biopharmaceuticals, the Asparaginase (ASNase) enzyme is used in the treatment of lymphatic system cancers, especially Acute Lymphoid Leukemia (ALL) since the 1970s. Currently there are three different ASNase formulations on the world market, produced by Escherichia coli in native form and conjugated with polyethylene glycol (PEG-EcA) and produced by Erwinia chrysanthemi (ErA). The ASNase administration can be promote many side effects, including immune responses and allergic reactions that can lead to anaphylactic shock. Among side effects, the anti-ASNase antibodies production is directly associated with ASNase activity decrease. In addition, the proteases and peptidases activity can lead to additional epitopes exposure, which further increases the immune response. In these cases the change of EcA by pegylated EcA or ErA represents an alternative, however there are still adverse responses in some patients. Therefore, search for new ASNases sources and new variants of the enzymes used as medicines are researched around the world. In this PIPE project, we are proposing the pegylation of the EcAP40S/S206C enzyme, which has proteolytic degradation resistance. The enzyme EcAP40S/S206C was developed in the Fapesp thematic project "Production of extracellular L-asparaginase: from bioprospecting to the engineering of an antileukemic biopharmaceutic". The proof of concept will be based on the development of an efficient pegylation process of EcAP40S/S206C. For this, they will be performed pegylation experiments of thiols and N-terminal regions. Kinetic and cytotoxicity assays will be performed to determine the therapies potential of PEG-EcAP40S/S206C. We believe that development PEG-EcAP40S/S206C has great potential for a biopharmaceutical, since proteolysis resistance and the pegylation can be promote the increase of the enzyme half-life in the bloodstream and decrease the immunogenicity. (AU)

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