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be approved by the FDA for pediatric solid tumor and high-risk neuroblastoma[87].
Anti-GD2mAbs work by binding to the end-terminal penta-oligosaccharide of GD2
and following the ADCC or CDC pathways to kill neuroblastoma tumor cells.
Besides ADCC and CMC pathways, mAbs can enhance nonimmune-mediated
effects, such as survival signal blockade and anoikis. Anoikis is the induction of
apoptosis in cells. It occurs when abnormal cells detach from the extracellular
matrix (ECM) and neighboring cells. In a healthy system, anoikis would remove the
unhealthy or abnormal cells, but tumor cells have the ability to escape anoikis by
constitutive activation of focal adhesion kinase (FAK). However, anti-GD2mAbs
will dephosphorylate FAK and inhibit activation of PI3K/Akt pathways, which
allows the drug to induce apoptosis and cause cancer cell death[87].
7.7.3 Challenges with Unituxin
Unituxin can cause serious adverse side reactions because it binds to GD2 expressed in
both benign and malignant tissues. This means neural tissues in the central nervous
system, peripheral nerves, and neuroblastoma can be affected by the drug [79].
Dinutuximab is a toxic regimen that must be infused into patients over a 20-hour
period in a hospital because there is serious risk of intense pain, serious infusion reactions, capillary leak syndrome, and hypotension[41]. This drug can give patients an
increased risk of infection, neurological eye disorders, suppression of bone marrow,
electrolyte abnormalities, and atypical hemolytic uremic syndrome. It is limited for use
in pediatric patients because adults with melanoma who participated in dose-finding,
safety, and tolerability studies experienced severe and possibly irreversible motor neuropathy[41, 79]. However, Unituxin was still approved because of the seriousness of
the disease and the lack of alternative treatment options for high-risk neuroblastoma[79]. Murine anti-GD2mAbs are tolerated in patients and do show antineuroblastoma activity, but the development of HAMA response and hypersensitive reactions
to injections limit how often the drug can be administered[74, 77]. Some patients had
to wait months for the next round of antibody injections to be administered, which
decreased the efficiency and effectiveness of the treatment. HAMA’s increase the clearance of murine mAbs and often cause unwanted allergic reactions and tumor penetration[75]. Murine mAbs have a shorter half-life than human mAbs, and the Fc region
of murine antibodies is less effective at eliciting ADCC and CDC than human antibodies[73, 77]. These limitations have led to advances in genetic engineering that have
allowed for the development of chimeric and humanized anti-GD2mAbs[87].
211
7.7.4 mAbs Binding to Neuroblastoma
The anti-GD2murine antibodies include murine IgG3 (m3F8) and murine IgG2a
(14G2a). Murine 3F8 was the first anti-GD2monoclonal antibody to be tested in
patients with neuroblastoma, and it is the murine IgG3with the highest reported
affinity for GD2with a K
value of 5 nM. Murine 3F8has been shown to kill neuro-
D
blastoma cells by CDC and by lymphocytes, cultured monocytes, and granulocytes.
Murine 3F8 binds to Fc-receptors FcyRII and FcyRIII for neutrophil- and
7 Carbohydrate-Specific Monoclonal Antibody Therapeutics
212
NK-mediated ADCC. The CR3 receptor also plays an important role in cytotoxicity[83, 87]. CDC can be enhanced by naturally occurring complex polysaccharide
β-glucan (BG)[36]. This enhancement increases the adhesion of complement receptors on myeloid cells to natural ligands like iC3b. When m3F8 is combined with the
cytokine GM-CSF, there is a greater than 60% long-term survival rate among pediatric patients with stage-4 high-risk neuroblastoma.
Other murine anti-GD2 antibodies include ME36.1 and 14.G2a, which have lower
affinities to GD2 with K
values of 19 and 77 nM, respectively[83, 89]. While
D
ME36.1was originally obtained as a mouse IgG3, it can be class-switched to IgG2a
and IgG1 variants. Also, ME36.1mostly binds to GD2, but it does have some crossreactivity to GD3, which means that ME36.1 can be a useful antibody for targeting
other tumors, such as melanoma[83]. Preclinical studies showed ME36.1-inhibiting
tumor growth at the inoculation site and in the lymph nodes and lungs.
7.7.5 Chimeric and Humanized Anti-GD2 Antibodies
When creating chimeric versions of the anti-GD2mAbs, the VH and VL domains of
the murine antibody are grafted onto human IgG constant domains. When creating
humanized versions of the anti-GD2mAbs, a fully human monoclonal antibody is
grafted with murine CDR loops and a few structurally significant residues, or a fully
human monoclonal antibody with no murine residues is used[77, 83]. L72, which
is a fully human IgM, was the first nonmurine anti-GD2 antibody. It was produced
using the Epstein–Barr virus (EBV) to transform B lymphocytes from the peripheral
blood lymphocytes of melanoma patients into lymphoblastoid cell lines[83]. L72’s
clinical studies showed injections caused regression in melanoma tumor cells,
except for patients who had tumors with low antigenicity. After that, no further
studies were reported.
ch14.18 is the chimeric form of m14.G2a, and hu14.18 is the human form. The
names were derived from the original mouse isotype 14.18 IgG3. Phase 1 studies
concluded the safety of both forms, with a warning about severe pain during administration and other possible side effects. Phase 3 studies showed that combining
ch14.18with GM-CSF and interleukin-2 can greatly increase the two-year survival
rate of patients with high-risk neuroblastoma in comparison to the standard therapy options.
Murine 3F8 was also humanized (hu3F8) through grafting on the CDR, and it is
currently in Phase 1 trials. Initial test results show a reduction in the production of
HAHA and complement activation in comparison to murine 3F8[83].
7.7.6 Naxitamab asa Potential Alternative forHigh-Risk Patients
In 2020, the ongoing research efforts to reduce the toxicity and development of
human anti-mouse antibodies (HAMA) in anti-GD2 antibodies like dinutuximab
were a success, and naxitamab, marketed as Danyelza®, was approved by the
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
FDA[90]. Naxitamab is a humanized anti-GD2monoclonal antibody developed by
Memorial Sloan Kettering Cancer Center and Y-mAbs Therapeutics Inc.[41, 91].
Structurally speaking, naxitamab is very similar to dinutuximab, except some
mouse components have been substituted with human ones[64]. Naxitamab is a
treatment for high-risk neuroblastoma, osteosarcoma, and many other GD2positive cancers. This drug is injected intravenously in combination with GM-CSF
to treat patients with relapsed or refractory high-risk neuroblastoma in the bone or
bone marrow[41, 92]. This drug regimen is an improvement over Unituxin because
it has a shorter infusion time (naxitamab infuses in 30–60
hours needed for Unituxin), and it can be used in a greater age range of
10–20
minutes compared to the
patients, from 1-year-olds to adults[41, 91]. As mentioned above, Unituxin is too
risky for most adults to use because of the high probability of side effects. Also,
because of the toxicity profiles, dinutuximab is for inpatient administration only,
while naxitamab allows for outpatient administration and a better quality of life
−1
during treatment[41]. Naxitamab’s recommended dosage is 3 mg kg
day−1[41].
This treatment cycle is administered on days 1, 3, and 5 of a four-week-long treatment. The treatment cycle is repeated every four weeks until a complete or partial
response is noted[41, 91, 92]. Once a response is noted, the studies recommend at
least five more treatment cycles. However, be warned that this treatment still has
risks because it may cause severe infusion-related reactions and neurotoxicity[41].
During testing, the drug showed promising binding via surface plasmon resonance
to GD2 coated onto CM5 chips. Naxitamab had a k
1.03E, a K
value of 11 nM, and low reactivity with gangliosides other than
D
GD2[91]. In fact, naxitamab’s affinity for GD2 is 10
value of 9.19, a k
on
times higher than dinutuxi-
value of
off
mab’s affinity [41]. These results, along with the drug’s cytotoxicity against the
LAN-1neuroblastoma cell line with an EC
of 5.1 μg ml−1, allow naxitamab to be
50
a treatment option for patients with high-risk neuroblastoma[91]. When naxitamab is used as a treatment in conjunction with GM-CSF, the three-year EFS is
74.3% and the OS is 91.6%, which is an increase in survival rates compared to
dinutuximab[41].
213
7.7.7 Chimeric Antigen Receptors (CARs) Targeting GD2
Therefore, alternative cancer cell targets are necessary for treatment options. This
idea led to the discovery of T-cell-independent carbohydrate differentiation antigens, such as GD2, GD3, O-acetylated GD2 and GD3, and polysialic acid (PSA)[68].
mAbs can be used as chimeric antigen receptors (CARs) or bispecific antibodies,
such as anti-GD2 and anti-CD3, to allow polyclonal T cells to target tumors. CARs
are single-chain Fv fragments that can fuse through the transmembrane domain of
T-cell-activating motifs, such as CD3ζ and CD28 or 41BB, to allow the T cells to
target a specific protein[68]. All of these possible neuroblastoma-killing pathways
are illustrated in Figure7.4. There are several CARs that have gone through clinical
trials; here is an example of an anti-GD2 CAR that utilized an scFv based on
7 Carbohydrate-Specific Monoclonal Antibody Therapeutics
CMC
(anti-GD2 and anti-CD3)
n)
214
Phagocytosis
Macrophage
Anti-GD2 antibody
(e.g. 3F8 or ch14.18)
Bispecific antibody
KEY
GD2 Peptide
Other targets
(e.g. GD3, PSA, or ALK)
CAR
Immune
inactivators
Fc receptor
Neuroblastoma
Rare or
absent
C1q
MAC
HLA
T cell
Granulocyte-ADCC
Activation
Granulocyte
Cytotoxin
(e.g. granzyme or perfori
NK cell
NK-ADCC
Dendritic cell
Figure7.4 Illustration of potential immune responses to neuroblastoma tumor cells.
Source: Adapted from Cheyung and Dyer[68].
humanized murine antibody KM8138 that is fused to CD28 [93]. This trial took
children with relapsed or refractory neuroblastoma; out of 34 patients, only 15%
reported a partial response. In this study, two patients showed significant tumor
regression; one had two large tumors and the other patient had one retroperitoneal
tumor. Both patients had greater than 90% regression after two months of CAR
T-cell therapy[94]. There are drawbacks to CARs; in a different phase 1 clinical trial,
anti-GD2 CAR was administered to 11 patients with relapsed or refractory neuroblastoma. The patients were treated with either anti-GD2 CAR T cells alone or in
conjunction with lymphodepleting chemotherapy. This trial saw minimal activity
with no measurable responses in all patients. CAR T cells aggregated and caused
tonic signaling of 14g2a anti-GD2 scFv; this led to T-cell exhaustion and limited
antitumor efficacy[95].
7.8 Summary
Overall, carbohydrate-specific mAbs that target carbohydrate antigens have proven
to be effective as therapies against cancer, and what waits in the wings is further
development against bacterial infections and viruses. Unituxin and naxitamab have
paved the path for using immunotherapeutics against carbohydrates a reality. The
research community will need to take advantage of carbohydrate antigens further to
develop other important therapies in the quest to combat disease more effectively.
List ofAbbreviations
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tumor-associated carbohydrate antigens TACAs
antibody-dependent cell-mediated cytotoxicity
complement-dependent cytotoxicity
monoclonal antibodies
natural killer
gra
nulocyte–macrophage colony-stimulating
factor
interleukin 2
isotretinoin
Biopharmaceutical Development Program
United Therapeutics Corporation
Food and Drug Administration
European Commission
event-free survival
overall survival
human anti-mouse antibodies
human leukocyte antigen
cytotoxic T lymphocyte
FAS ligand
polysialic acid
NK
cell-mediated antibody-dependent
cell-mediated cytotoxicity
granulocyte-mediated ADCC
complement-mediated cytotoxicity
membrane attack complex
chimeric antigen receptors
single-chain Fv fragments
anaplastic lymphoma receptor tyrosine kinase ALK
central nervous system CNS
lactosylceramide LacCer
asialo-GM2 GA2
cerebrospinal fluid CSF
extracellular matrix ECM
focal adhesion kinase FAK
m3F8 murine IgG3
14G2a murine IgG2a
β-glucan BG
Epstein–Barr virus EBV
humanized m3F8 hu3F8
complementarity-determining region CDR
NK
GM-CSF
IL-2
13-cis-retinoic acid- RA
OS
FASL
PSA
mAbs
EC
EFS
HLA
CTL
MAC
CARs
scFvs
CDC
UTC
FDA
HAMA
NK-ADCC
granulocyte ADCC
CMC
ADCC
BDP
215
7 Carbohydrate-Specific Monoclonal Antibody Therapeutics
216
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