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|Title: ||Development of L-Asparaginase biobetters: Current research status and review of the desirable quality profiles|
|Authors: ||Brumano, Larissa P.|
da Silva, Francisco Vitor S.
Costa-Silva, Tales Alexandre
Apolinario, Alexsandra C.
Santos, Joao Henrique P.
Kleingesinds, Eduardo K.
Rangel-Yagui, Carlota D.
Junior, Adalberto P.
Acute lymphoblastic leukemia
|Issue Date: ||2019|
|Publisher: ||© The Authors. Publsihed by Frontiers|
|Citation: ||BRUMANO, L.P. ... et al., 2019. Development of L-Asparaginase biobetters: Current research status and review of the desirable quality profiles. Frontiers in Bioengineering and Biotechnology, 6 :212.|
|Abstract: ||L-Asparaginase (ASNase) is a vital component of the first line treatment of acute
lymphoblastic leukemia (ALL), an aggressive type of blood cancer expected to afflict over
53,000 people worldwide by 2020. More recently, ASNase has also been shown to have
potential for preventing metastasis from solid tumors. The ASNase treatment is, however,
characterized by a plethora of potential side effects, ranging from immune reactions to
severe toxicity. Consequently, in accordance with Quality-by-Design (QbD) principles,
ingenious new products tailored to minimize adverse reactions while increasing patient
survival have been devised. In the following pages, the reader is invited for a brief
discussion on the most recent developments in this field. Firstly, the review presents an
outline of the recent improvements on the manufacturing and formulation processes,
which can severely influence important aspects of the product quality profile, such
as contamination, aggregation and enzymatic activity. Following, the most recent
advances in protein engineering applied to the development of biobetter ASNases
(i.e., with reduced glutaminase activity, proteolysis resistant and less immunogenic)
using techniques such as site-directed mutagenesis, molecular dynamics, PEGylation,
PASylation and bioconjugation are discussed. Afterwards, the attention is shifted toward
nanomedicine including technologies such as encapsulation and immobilization, which
aim at improving ASNase pharmacokinetics. Besides discussing the results of the most
innovative and representative academic research, the review provides an overview of the
products already available on the market or in the latest stages of development. With this,
the review is intended to provide a solid background for the current product development
and underpin the discussions on the target quality profile of future ASNase-based
|Description: ||This is an Open Access Article. It is published by Frontiers under the Creative Commons Attribution 4.0 Unported Licence (CC BY). Full details of this licence are available at: http://creativecommons.org/licenses/by/4.0/|
|Sponsor: ||We would like to thank the São Paulo Research Foundation
(FAPESP) [Award Number 2013/08617-7, 2014/10456-4,
2015/07749-2, 2016-22065-5, 2017/21819-9, and 2018/03734-9],
the Brazilian National Council for Scientific and Technological
Development (CNPq) [Award Number 303334/2014-2],
the National Postdoctoral Program (PNPD/Capes-FCFUSP) [Award Number 1781837], the Coordination
for the Improvement of Higher Education Personnel
(CAPES) [Financial Number 001] and the Portuguese
Foundation for Science and Technology (FCT) for the
doctoral grant SFRH/BD/102915/2014 for the financial
|Publisher Link: ||https://doi.org/10.3389/fbioe.2018.00212|
|Appears in Collections:||Published Articles (Chemical Engineering)|
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