Correspondence
Monitoring
asparaginase activity
The findings of Daiane Cecconello
and colleagues, 1 published in
The Lancet Oncology, show differ­
ences in the in-vivo activity of
two dissimilar brands of Escherichia
coli L-asparaginase (ASNase) used for
the treatment of acute lymphoblastic
leukaemia. Despite their similarities
in sequence and in-vitro activity,
a previous study showed that
two ASNase products (aginasa [Medac,
Kyowa, Japan] and leuginase [Beijing
SL Pharmaceutical, Beijing, China])
had key differences, with leuginase
having increased immunogenicity,
product-related impurities, and
the presence of β-lactamase. 2
Using nuclear magnetic resonance,
we also identified approximately
0·3 mM L-aspartate (L-ASP) in the
formulation of aginasa, which is not
disclosed in its composition and which
we did not detect in leuginase. We also
identified L-ASP bound to the catalytic
site in crystal structures that we solved
from aginasa, which resembled the
previously reported structure of
ASNase3 in a catalytic-site closed state,
whereas the catalytic site from the
crystal structure of leuginase was open
in multiple conformers and free from
ligand in the active site.
Although equivalent in sequence,
such dissimilarities in formulation
and pharmacology in these
two ASNase bioproducts could result
in distinct pharmacokinetic, stability,
activity, and inactivation profiles. To
avoid such disparities, it is desirable
that all drugs and pharmaceutical
preparations should be subjected to
physicochemical characterisation and
a comprehensive appraisal of their in-
vivo safety, potency, and efficacy trial
data. Although such data are required
upon registration by regulatory
agencies such as the Brazilian Health
Regulatory Agency (ANVISA),4 the
US Food and Drug Administration,
and the European Medicines Agency,
the requirements are looser for
www.thelancet.com/oncology Vol 19 November 2018 e574
the direct import of drugs and
pharmaceutical preparations that
are not registered in Brazil and thus,
no a priori association with clinical
outcomes can be fully inferred from
a limited dataset. For cases in which
the product quality and full clinical
data are unknown, the adequacy of
the treatment has no support and
any eventual failure in treatment or
adverse effects cannot be understood
in terms of effectiveness or otherwise.
The international trade of drugs
and drug products is a contemporary
reality. It is time for full transparency
and public availability of clinical and
physicochemical properties for drugs
and drug products, and standard­
ised assessment of registration by
the International Conference on
Harmonization, WHO, 5 regulatory
agencies, or third-party organisations,
to provide global biopharmaceutical
health security and efficacy.
We declare no competing interests.
*Luís Maurício T R Lima,
Talita S Araujo, Fábio C L Almeida,
Marcius S Almeida
Mauricio@pharma.ufrj.br
Faculty of Pharmacy (LMTRL) and National Center
for Bioimaging, Institute of Medical Biochemistry
(TSA, FCLA, MSA), Federal University of
Rio de Janeiro—UFRJ, Brazil; and National Institute
of Metrology, Quality and Technology—
INMETRO/DIMAV, Brazil (LMTRL)
1 Cecconello DK, Werlang ICR, Alegretti AP, et al.
Monitoring asparaginase activity in
middle-income countries. Lancet Oncol 2018;
19: 1149–50.
2 Zenatti PP, Migita NA, Cury NM, et al.
Low bioavailability and high immunogenicity
of a new brand of E coli L-asparaginase with
active host contaminating proteins.
EBioMedicine 2018; 30: 158–66.
3 Swain AL, Jaskólski M, Housset D, Rao JK,
Wlodawer A. Crystal structure of Escherichia coli
L-asparaginase, an enzyme used in cancer
therapy. Proc Natl Acad Sci USA 1993;
90: 1474–78.
4 Lima LMTR. Pharmacopeia and ANVISA:
a necessary symbiosis.
Rev Bras Farmácia Hosp E Serviços Saúde 2017;
8: 4.
5 WHO. WHO calls for increased transparency in
medical research. April 14, 2015. http://www.
who.int/news-room/detail/14-04-2015-who-
calls-for-increased-transparency-in-medical-
research (accessed Aug 7, 2018).