ADCC. Toxicities include pain, fever, capillary
leak, O 2 requirement due to capillary leak,
hypotension, mild reversible increased hepatic
transaminases, and infection. 18
Anti-GD2 antibodies in clinical practice
Targeted immunotherapy using anti-GD2 mAbs is
an important clinical advance in the treatment of
HR neuroblastoma. In a landmark study
published in 2010 by the cooperative American
group COG, the addition of the anti-GD2
monoclonal antibody ch14.18 (dinutuximab)
combined with cytokines and isotretinoin
improved the survival rates compared with
isotretinoin alone in the post-consolidation
phase. 19 As a consequence of this and subsequent
studies, in 2015, dinutuximab was approved in
Europe and the US for the treatment of HR
neuroblastoma, and is now considered part of the
standard of care. 20
There are two anti-GD2 antibodies approved by
the European Medicines Agency (EMA):
dinutuximab (Unituxin ® ) and dinutuximab beta
(Qarziba ® ). Other anti-GD2 antibodies are
currently being tested in clinical trials.
Dinutuximab (Unituxin)
Dinutuximab is a chimeric monoclonal antibody
composed of the variable heavy and light-chain
region of the murine anti GD2 mAb14.18 and the
constant region of human IgG1 heavy-chain and k
light-chain. It was initially produced in the
murine myeloma cell line SP2/O. On 10 March
2015 and 14 August 2015, the US FDA and the
EMA, respectively, approved IV dinutuximab, in
Anti-GD2 monoclonal antibodies
have undergone a very long journey
from discovery to clinical practice
combination with GM-CSF, IL-2 and cis-Retinoic
acid (CRA), for the treatment of paediatric
patients with HR-NB who achieved at least partial
response with prior first-line multi agent,
multimodality therapy. 20 Dinutuximab is now
Unitux in ® , a registered trademark from United
Therapeutics Company (UTC).
Because of the pain side effects, dosing is
limited. The recommended dosage of
dinutuximab is 17.5 mg/m 2 /day administered IV
over 10–20 hours for four consecutive days for
maximum of five cycles. The infusion of
dinutuximab initiated at a rate of 0.875mg/m 2 /
hour over 30 minutes and the rate can be
increased gradually, as tolerated, to the maximum
rate of 1.75 mg/m 2 /hour. Dinutuximab should be
diluted with 0.9% sodium chloride for injection
prior to infusion. The supplied dinutuximab does
not require filtration during preparation and does
not need protection from the light during
administration. Vials should be stored in the
original container tightly closed at 2–8ºC. The
solution is stable at room temperature for at least
24 hours when diluted to a concentration
between 0.044 and 0.56mg/ml.
Dinutuximab, similar to all the anti-GD2
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immunotherapies tested, is associated with
potentially serious side effects. The most common
include neuropathic pain, tachycardia,
hypertension, hypotension, fever, and urticaria. In
the COG Phase III trial, grade 3 or 4 pain was
observed in 52% of patients, more frequent during
cycle 1 (37%) and decreasing to 14% during cycle
5. 19 The most common site of pain was the
abdomen. Grade 3 or 4 hypersensitivity reactions
were reported in 25% of patients. Consequently,
the US label for dinutuximab contains a warning
for the risk of infusion-related reactions and
neuropathy. 21 Other secondary described effects of
dinutuximab include fever, hypokalaemia,
hyponatraemia, liver dysfunction, hypotension,
diarrhoea, and hypoxia. Recently acute-onset
transverse myelitis as a novel infusion-related
toxicity of dinutuximab was described. 22 Myelitis
rapidly improved when the infusion was stopped
and corticosteroids were administered resulting
in functional recovery. Importantly, this serious
but reversible complication has not been
observed or reported with other anti-GD2
antibodies.
Overall, the pain side effects remain the major
drawback of all anti-GD2 antibodies. Although
these side effects are not lethal, the emotional
burden to the patients, their parents and the
health care professionals, is important.
Furthermore, in rare occasions, analgesics and
sedatives used to treat the pain side effects can
become life threatening. For such reasons,
anti-GD2 immunotherapy should be performed
in highly specialised centres. It has been shown
that pain control (and safety) becomes more
proficient with practice and improvement over
the years.
The cost for one 17.5mg single-use vial is $7500
approximated wholesaler acquisition cost (WAC)
or manufacturer’s published price to wholesalers.
In 2016, the market price was being negotiated in
Europe, country by country, when dinutuximab
beta (Qarziba ® ) came into play. The European
marketing authorisation of Unituxin was
withdrawn in early 2017 and it is no longer
licensed in Europe.
Since approval, Unituxin ® has been widely
used in the USA. Since then, a remarkable
advance in the use of dinutuximab has occurred.
The COG reported the ANBL1221 study whereby
they randomised relapsed neuroblastoma patients
to receive irinotecan–temozolomide with either
temsirolimus or dinutuximab. Between 22 Feb
2013 and 23 March 2015, 35 patients were
randomised. Eighteen patients were assigned to
irinotecan–temozolomide–temsirolimus and 17 to
irinotecan–temozolomide–dinutuximab. Of the 18
patients assigned to irinotecan–temozolomide–
temsirolimus, one patient achieved a partial
response. Of the 17 patients assigned to
irinotecan–temozolomide–dinutuximab, nine had
objective responses, including four partial
responses and five complete responses. 23 This
study has opened the door for further
chemoimmunotherapeutic regimens and the
potential use of dinutuximab earlier in the
treatment schema of HR neuroblastoma.
Dinutuximab beta (Qarziba ® )
Dinutuximab beta (also called ch14.18/CHO or
APN311) is a mAb directed against GD2