Development of L-Asparaginase biobetters: Current research status and review of the desirable quality profiles
journal contributionposted on 2019-01-15, 15:59 authored by Larissa P. Brumano, Francisco Vitor S. da Silva, Tales Alexandre Costa-Silva, Alexsandra C. Apolinario, Joao Henrique P. Santos, Eduardo K. Kleingesinds, Gisele Monteiro, Carlota D. Rangel-Yagui, Brahim BenyahiaBrahim Benyahia, Adalberto P. Junior
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 pharmaceuticals.
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 support.
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