Development of L-Asparaginase biobetters: Current research status and review of the desirable quality profiles
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 Benyahia
Adalberto P. Junior
2134/36598
https://repository.lboro.ac.uk/articles/journal_contribution/Development_of_L-Asparaginase_biobetters_Current_research_status_and_review_of_the_desirable_quality_profiles/9244724
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.
2019-01-15 15:59:36
L-asparaginase
Quality-by-design
Biobetters
Protein engineering
PEGylation
Nanobiotechnology
Acute lymphoblastic leukemia
Site-directed mutagenesis
Chemical Engineering not elsewhere classified