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7 Carbohydrate-Specific Monoclonal Antibody Therapeutics
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in an attempt to overcome the pitfalls of previously developed mAbs. PS A1 is a zwitterionic polysaccharide (ZPS) capable of triggering a T-cell immune response in the
absence of peptides, proteins, or other nonsugar-based material. When compared to
commercially available anti-Tn IgM monoclonal Tn-218, using a glycan array,
KT-IgM-8 showed a dramatic difference in being able to bind to monovalent Tn at
varying concentrations, while commercially available Tn-218 showed virtually no
binding to monovalent Tn invitro and induced protection through complementmediated cytotoxicity in invivo tumor mouse models[43]. MCF-7, a human breast
cancer cell line, was xenographed into SCID mice, and KT-IgM-8 showed 40% tumor
reduction compared to the control[43].
7.5 mAbs from Preclinical to Clinical Studies
Over the recent years, several mAbs targeting a variety of different types of TACAs
have given promising results in preclinical studies and are progressing to clinical
trials[44]. Among the TACAs that are being studied here, we will discuss the globo
series, blood group, and mucin-attached glycans in more detail. As Unituxin is an
anti-GD2mAb and is part of the gangliosides, we will discuss this section later with
Unituxin[45].
7.6 Globo Series
This group is made up of stage-specific embryonic antigen 3 (SSEA), SSEA-4, and
Globo-H and is found in several types of cancers, such as breast, gastric, lung, ovarian, endometrial, pancreatic, and prostate[46, 47]. Globo-H is the most common
antigen in the series[48]. Anti-Globo-H mAb OBI-888 is currently in phase II clinical trials and has shown promising results toward more than five types of cancer.
OBI-888 has shown excellent tumor growth inhibition, which tested for 85%
toward breast cancer being the highest and the lowest being 43% for lung cancer[49, 50]. This study showed inhibition of tumor growth in over 150 patients
tested[51].
7.6.1 Blood Group
Type I and Type II Lewis antigens are terminal fucosylated carbohydrate structures
belonging to the human histoblood group system. LewisA (LeA), LewisB (LeB),
LewisX (LeX), and LewisY (LeY) are synthetized in exocrine epithelial cells by fucosyltransferase (FUT) enzymes [52]. The antigens only differ in their glycosidic
bonds (Galβ1-3GlcNAc and Galβ1-4GlcNAc)[53]. Teng and coworkers showed that
Mab216 is highly selective for blood group antigen CDIM that is located on human
B cells. This antibody was then tested in a Phase 1 clinical trial, showing good
efficacy against lymphoblastic leukemia[20]. When the Mab216was progressed to
phase 2, the scale-up and production proved to be challenging and prevented further development. The only FDA-approved IgM antibody was called NeutroSpec
TM
otherwise known as fanolesomab-Tc99M, which was approved for use in 2004.
Fanolesomab was a murine-based monoclonal IgM antibody labeled with
technetium-99m and directed toward 3-fucosyl-N-acetyl lactosamine found on
CD15[19]. When clinical trials were first conducted, the results showed sufficient
public safety, so fanolesomab was approved for further clinical trials that eventually
led to FDA approval. The main use was for scintigraphic imaging of patients who
showed symptoms of appendicitis. Ultimately, fanolesomab was removed from the
market by the FDA in 2005, when reports arose that patients taking the drug were
suffering from serious cardiopulmonary events, leading to fanolesomab being discontinued by Palatin Technologies in 2008[18, 19, 21].
7.6.2 Mucin-Attached Glycans
One of the more studied groups are the mucin-attached glycans, which consist of Tn
(GalNAc), Tf (Galβ1-3GalNAc), and STn (Neu5Acα2-6GalNAc). These antigens are
attractive targets because of their absence from healthy tissues[52–55]. STn is the
most targeted of all the mucin glycans, as it has a lot of notoriety with Theratope,
which was tested in Phase 3 for breast cancer[56]. The first anti-STn mAb was initially used for cancer detection rather than vaccine[57]. After being humanized, the
mAb CC49 showed a modest immune response and a 40% increase in survival vs.
controls[58]. An anti-Tn mAb, Gatipotuzumab, was tested in a phase 1 study and
showed that it was safe and well tolerated. Gatipotuzumab was moved to phase 2
and failed to demonstrate an improvement vs. the placebo in progression-free survival[59, 60]. Gatipotuzumab in combination with anti-epidermal growth factor
receptor (EGFR) antibody was tested in a Phase 1 study and showed promising
results for colorectal cancer patients. This study went onto Phase 2 and is waiting for
the results[61].
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,
7.7 New Treatment Options forNeuroblastoma
In the United States, neuroblastomas affect 1in 100 000 children, and approximately
700 children under the age of 15 suffer from the disease annually [62, 63].
Approximately 50% of the diagnosed patients are in advanced stage IV of the disease, and the five-year survival rate of these patients is 20–25%[64]. Neuroblastoma
is the most common extracranial solid tumor in children[65]. It accounts for about
7% of children with cancer who are under the age of 15. About 90% of patients diagnosed with neuroblastoma are under the age of 5, and about 40% of diagnosed
patients will have high-risk neuroblastoma[66]. Relapse in neuroblastoma tumor
cells is not only probable but also highly incurable [63, 67]. Therefore, novel
7 Carbohydrate-Specific Monoclonal Antibody Therapeutics
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208
therapeutic strategies are highly needed. Frequent relapses are often caused by the
loss of heterozygosity of 1p and 11p chromosomes and partial deletions of other
chromosomes, which can lead to a loss of critical genes, leaving patients more susceptible to further gene mutations, cancer, and other diseases. Other major problems can be due to amplification of tumor cell growth because of mutations in the
MYCN oncogene, which controls the growth, proliferation, and apoptosis of cell,
and metastasis of cancerous cells in the liver, bone, and bone marrow [67].
Treatments using dinutuximab or naxitamab are necessary because the complex
and aggressive nature of neuroblastoma tumor cells allows them to avoid regular
immune responses by evading T cells through down-regulation or losing human
leukocyte antigen (HLA) expression. This is a challenge because it interferes with
the afferent arm, with the T cells’ ability to find neuroblastoma tumor cells, and
with the cytotoxic T lymphocyte (CTL) effector phase of adaptive immunity. Cellular
immunity is further impaired by soluble inhibitors such as FAS ligand (FASL) and
gangliosides, pro-tumor macrophages, myeloid suppressor cells, and regulatory T
cells[68]. Neuroblastoma patients tend to be young with underdeveloped or compromised immune systems because of the burden of living with an aggressive, highrisk disease and receiving intensive chemotherapy, radiation, or other rigorous
treatment that can strain the patient [69]. Because neuroblastoma is so poorly
immunogenic for T cells, the patient’s natural immune responses and common cancer treatments, such as chemotherapy, surgery, or radiation, are not as effective in
high-risk neuroblastoma patients[66]. Before immunotherapy options like Unituxin
were available, about 40% of high-risk neuroblastoma patients were able to achieve
long-term remission, and the 5-year event-free survival (EFS) rates were less than
50%[62, 65, 70]. Because complete eradication of neuroblastoma is rarely possible,
dinutuximab is used as a second-line treatment to target any surviving cancer cells
and prevent relapse, especially in patients with an advanced version of the disease.
In therapeutic trials, patients who received Unituxin had significantly higher EFS
rates and overall survival (OS) rates when compared to standard therapy options
without Unituxin. EFS rates increased from about 46% to 66%, and OS rates increased
from about 75% to 86%[62, 66, 71]. Therefore, including Unituxin treatment cycles
as part of the postconsolidation therapy for a patient with high-risk neuroblastoma
would help improve patient survival[70].
7.7.1 History ofUnituxin
Milstein and Koehler invented monoclonal antibody technology in 1975, but
Unituxin was discovered in the late 1980s by Alice Yu, M.D., at the University of
California, San Diego Medical Center[72–75]. Dr. Yu’s research used laboratorymade mAbs as a possible treatment for neuroblastoma. Many versions of the mAbs
were tested before a final version, ch14.18, was settled on[74]. In 2001, Dr. Yu and
colleagues in the Children’s Oncology Group tested ch14.18monoclonal antibody
on neuroblastoma patients[71]. For this immunotherapy treatment, children were
initially treated with chemotherapy, radiation, and stem cell transplantation before
OH
HO
HO
ch14.18was administered[70, 71]. Immune-stimulating agents known as GM-CSF
and interleukin 2 (IL-2) were administered with the mAb to increase the drug’s
effectiveness at killing tumor cells. The NCI’s National Clinical Trails Network was
a major contributor to these trials [70]. Also, the NCI’s Biopharmaceutical
Development Program (BDP) produced the ch14.18 for clinical trials and worked on
its process development in order to make the drug available for eligible children suffering from high-risk neuroblastoma. In 2010, NCI partnered with a branch of the
United Therapeutics Corporation (UTC) to manufacture dinutuximab and gain
regulatory approval from the FDA. UTC conducted safety, efficacy, and optimal use
studies and gained licensure to manufacture and market dinutuximab under the
brand name Unituxin. In 2015, the FDA and European Commission approved
Unituxin as a treatment option for pediatric cancer[1, 71, 76].
7.7.2 What is Unituxin?
Dinutuximab, also named ch14.18 or Unituxin, is a chimeric human–mouse IgG
mAb [67, 72, 73, 77]. It is composed of murine variable heavy- and light-chain
regions and human constant regions[78–81]. All approved therapeutic mAbs are
N-glycosylated in the Fc region[80]. For Unituxin, glycosylation of the conserved
asparagine position 297 (Asn-297) occurs in the heavy-chain CH2 domain of the Fc
region. Because the Fc region is the receptor-binding region, posttranslational modifications in this region create the molecule’s high heterogeneity and affect the functions of the key antibody effectors[72].
United Therapeutics manufactures dinutuximab by industrial fermentation using
SP2/O, which is a murine myeloma cell line[71, 82]. However, mAbs produced in
nonhuman cells tend to express oligosaccharides that are not found in normal IgG
serum, and their presence can cause immunogenicity issues in patients [72]. Even
with the potential issues, Unituxin is used as a second-line treatment for children with
high-risk neuroblastoma because of its ability to target neuroblastoma cells by binding
to the glycolipid antigen disialoganglioside, known as GD2, which is highly expressed
on the neuroblastoma cell’s surface[71, 76]. The chemical structure of GD2 is shown
in Figure7.2. The binding of dinutuximab and GD2 to neuroblastoma induces tumor
cell lysis, apoptosis, and proliferation inhibition. During invitro testing, dinutuximab
was shown to bind to tumor cells and was more effective at inducing lysis of tumor
cells than the murine version 14.G2a[71]. This cell death occurs through two major
209
HO
COOH
O
HO
HO
AcHN
O
HO
HO
OH
COOH
O
NHAc
O
OH
O
O
OH
O
OH
O
O
HO
OH
O
HN
H
O
H
OH
Cer
HO
AcHN
Figure7.2 Chemical structure of glycolipid disialoganglioside (GD2)[83, 84].
7 Carbohydrate-Specific Monoclonal Antibody Therapeutics
(a)
C
Memrane
ll
s
granulocytes
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210
attack complex
Complement
C′1-9
ascade
Tumor
cell
activation
Tu mor
cell
(b)
IL-2
NK Cell
GM-CSF
Monocyte
macrophage
Killer
cell
FCrR
Perforin
granzyme
FAS ligand
Tu mor
cell
Necrosis
and
apoptosis
Figure7.3 Illustration of mechanisms for GD2 antibody-targeted destruction of
neuroblastoma. (a) is the CDC pathway, and (b) is the ADCC pathway. (a) CDC: Complement
dependent cytotoxicity. (b) ADCC: Antibody-dependent cell-mediated cytotoxicity. Source:
Adapted from Matthay etal.[85].
Ce
lysi
pathways: ADCC and CDC [67, 69]. Figure 7.3 illustrates these two pathways.
.
Following the mechanisms of the ADCC pathway, the mAb’s Fc fragment binds the Fc
receptors on monocytes, macrophages, granulocytes, or natural killer (NK) cells,
allowing these cells to engulf and destroy bound tumor cells. NK cells can also secrete
cytokines that lead to cell death [69, 85, 86]. The Fc-receptors for granulocytes are
FcgRIIA/CD32, and the Fc-receptors for NK cells are FcRIIIA/CD16A. In CDC, C1q
binds to the Fc section of mAbs bound to the tumor cells. This binding activates a
complement cascade and forms membrane attack complexes to create pores in the cell
membrane and cause lysis of the tumor cells[87]. Following the mechanisms of the
CDC pathway, the mAb binds to the receptor and initiates the complement cascade to
clear damaged cells and microbes from the system and attack the cell membrane of
the identified pathogen. The complement cascade causes the formation of a membrane attack complex to make a hole within the tumor cell membrane, causing cell
lysis and death[85, 86]. Unituxin is an intravenous drug that is used as a postconsolidation therapy when combined with GM-CSF, IL-2, and isotretinoin (RA) [78, 82].
The recommended dosage for this drug is 17.5
20-hour period for four consecutive days in a four-week cycle[41]. When dinutuximab
mg a day administered over a 10-to
was tested using the Scatchard analysis, it showed acceptable binding to a series of
neuroblastoma cell lines and the melanoma M-21 cell line with a K
value of 11.2 nM
D
and nonspecific binding between 5% and 10% total bound[88].
Despite problems and limitations, several anti-GD2 antibodies have been developed. Four, in particular, have been extensively studied in clinical studies: 3F8,
hu3F8, ch14.18, and hu14.18[83]. Ch14.18 (dinutuximab) was the first antibody to
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-GD2 monoclonal 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
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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
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 minutes compared to the
10–20 hours needed for Unituxin), and it can be used in a greater age range of
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
value of 9.19, a k
on
value of
off
GD2[91]. In fact, naxitamab’s affinity for GD2 is 10 times higher than dinutuximab’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)
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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
tumor-associated carbohydrate antigens TACAs
antibody-dependent cell-mediated cytotoxicity ADCC
complement-dependent cytotoxicity CDC
monoclonal antibodies mAbs
natural killer NK
gra nulocyte–macrophage colony-stimulating
factor GM-CSF
interleukin 2 IL-2
isotretinoin 13-cis-retinoic acid- RA
Biopharmaceutical Development Program BDP
United Therapeutics Corporation UTC
Food and Drug Administration FDA
European Commission EC
event-free survival EFS
overall survival OS
human anti-mouse antibodies HAMA
human leukocyte antigen HLA
cytotoxic T lymphocyte CTL
FAS ligand FASL
polysialic acid PSA
NK cell-mediated antibody-dependent
cell-mediated cytotoxicity NK-ADCC
granulocyte-mediated ADCC granulocyte ADCC
complement-mediated cytotoxicity CMC
membrane attack complex MAC
chimeric antigen receptors CARs
single-chain Fv fragments scFvs
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
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