Development of L-Asparaginase Biobetters: Current Research Status and Review of the Desirable Quality Profiles

Author(s)

Brumano, Larissa Pereira ^[1] ; Santos da Silva, Francisco Vitor ^[1] ; Costa-Silva, Tales Alexandre ^[1] ; Apolinario, Alexsandra Conceicao ^[1] ; Picado Madalena Santos, Joao Henrique ^{[1, 2]} ; Kleingesinds, Eduardo Krebs ^[1] ; Monteiro, Gisele ^[1] ; Rangel-Yagui, Carlota de Oliveira ^[1] ; Benyahia, Brahim ^[3] ; Pessoa Junior, Adalberto ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Biochem & Pharmaceut Technol, Sao Paulo - Brazil

^[2] Univ Aveiro, Aveiro Inst Mat, CICECO, Dept Chem, Aveiro - Portugal

^[3] Loughborough Univ, Dept Chem Engn, Loughborough, Leics - England

• Document type: Review article
• Source: FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY; v. 6, JAN 10 2019.
• Web of Science Citations: 3

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 preventingmetastasis 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. (AU)

• FAPESP's process: 17/21819-9 - Optimization and economic feasibility study of recombinant L-asparaginase production process for pharmaceutical application
• Grantee: Larissa Pereira Brumano
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 15/07749-2 - Protein engineering and comparison of microbial expression systems of the biopharmaceutical L-asparaginase
• Grantee: Gisele Monteiro
• Support type: Regular Research Grants
• FAPESP's process: 18/03734-9 - Implementation of quality by design to the development of the production process of the chemotherapeutical enzyme L- asparaginase
• Grantee: Francisco Vitor Santos da Silva
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 13/08617-7 - Production of extracellular L-asparaginase: from bioprospecting to the engineering of an antileukemic biopharmaceutical
• Grantee: Adalberto Pessoa Junior
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 14/10456-4 - Development and characterization of poly(ethylene glycol) methyl ether-Block-Poly (D,L-Lactide) (PEG-PLA) Polymersomes for the release of recombinant L-asparaginase
• Grantee: Alexsandra Conceição Apolinário
• Support type: Scholarships in Brazil - Doctorate