Targeting Chemokine Receptor CCR4 in Adult T-Cell Leukemia-Lymphoma and Other T-Cell Lymphomas

Article (PDF Available)inCurrent Hematologic Malignancy Reports 7(3):235-40 · April 2012with25 Reads
DOI: 10.1007/s11899-012-0124-3 · Source: PubMed
Abstract
Peripheral T-cell lymphoma (PTCL) is a group of lymphoid malignancy that remains difficult to treat, as most PTCL becomes refractory or relapses, and thus there is an unmet medical need for novel treatment modalities. CC chemokine receptor 4 (CCR4) is expressed in various types of PTCL including adult T-cell leukemia-lymphoma (ATL), which has the worst prognosis among them. A phase II study of a defucosylated, humanized anti-CCR4 monoclonal antibody, mogamulizumab (KW-0761), yielded an overall response rate of 50 % (13/26) and a median progression-free survival of 5.2 months in relapsed patients with CCR4-positive ATL who had been previously treated with chemotherapy. Mogamulizumab also showed potential efficacy for cutaneous T-cell lymphoma in a US phase I/II study. Further preclinical and clinical investigations are needed to examine whether concomitant use of this novel agent with other agents with different mechanisms of action would be more effective for ATL and other PTCLs.

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LYMPHOMAS (J ARMITAGE AND P MCLAUGHLIN, SECTION EDITORS)
Targeting Chemokine Receptor CCR4 in Adult T-Cell
Leukemia-Lymphoma and Other T-Cell Lymphomas
Kensei Tobinai & Takeshi Takahashi & Shiro Akinaga
Published online: 27 April 2012
#
The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract Peripheral T-cell lymphoma (PTCL) is a group of
lymphoid malignancy that remains difficult to treat, as most
PTCL becomes refractory or relapses, and thus there is an
unmet medical need for novel treatment modalities. CC
chemokine receptor 4 (CCR4) is expressed in various types
of PTCL including adult T-cell leukemia-lymphoma (ATL),
which has the worst prognosis among them. A phase II
study of a defucosylated, humanized anti-CCR4 monoclonal
antibody, mogamulizumab (KW-0761), yielded an overall
response rate of 50 % (13/26) and a median progression-free
survival of 5.2 months in r elapsed patients with CCR4-
positive ATL who had been previously treated with chemo-
therapy. Mogamulizumab also showed potential efficacy for
cutaneous T-cell lymphom a in a US phase I/II study. Further
preclinical and clinical investigations are needed to examine
whether concomitant use of this novel agent with other
agents with different mechanisms of action would be more
effective for ATL and other PTCLs.
Keywords Chemokine receptor
.
CCR4
.
Adult T-cell
leukemia-lymphoma
.
ATL
.
Peripheral T-cell lymphoma
.
PTCL
.
Monoclonal antibody
.
Mogamulizumab
.
KW-0761
Introduction
Peripheral T-cell lymphoma (PTCL) represents a small,
heterogeneous group of non-Hodgkin lymphoma (NHL)
which is derived from more mature T-cells and natural killer
(NK) cells, and accounts for approximately 10 % of NHL
cases in Western countries [1, 2] and for approximately
20 %25 % of those in Japan [3, 4]. PTCL, a collective
entity of nearly 20 different subtypes defined according to
morphology, immunophenotype, genotype, and clinical fea-
tures [5], can be largely classified into the following two
groups according to clinical features including the sites of
lesions: (1) cutaneous T-cell lymphoma (CTCL), which is
the general term for diseases that initially or mainly occur in
the skin, and (2) PTCL other than CTCL. Treatment strategies
have been separately developed for these two groups [6].
Treatment options are substantially different for B-cell
and T-cell lymphomas. Rituximab, an anti-CD20 monoclo-
nal antibody, was developed for the treatment of B-cell
lymphomas. The introduction of this agent into clinical
practice has greatly improved the prognosis of patients with
B-cell lymphoma [7]. Recently, bendamustine, which has
little cross resistance with other chemotherapeutic age nts
presumably associated with its unique chemical structure
of an alkylating agent and a nucleoside analog, has been
developed as effective treatment of relapsed or refractory
B-cell lymphoma, considering its lack of cross resistance
with other chemotherap eutic agents [8]. However, PTCL
remains extremely difficult to treat, because most PTCL sub-
types become refractory to even aggressive chemotherapy
K. Tobinai (*)
Department of Hematology, and Hematopoietic Stem Cell
Transplantation, National Cancer Center Hospital,
5-1-1 Tsukiji, Chuo-ku,
Tokyo 104-0045, Japan
e-mail: ktobinai@ncc.go.jp
T. Takahashi
Clinical Development Department, Kyowa Hakko Kirin Co., Ltd,
1-6-1 Ohtemachi, Chiyoda-ku,
Tokyo 100-8185, Japan
e-mail: takeshi.takahashi@kyowa-kirin.co.jp
S. Akinaga
Development Division, Kyowa Hakko Kirin Co., Ltd,
1-6-1 Ohtemachi, Chiyoda-ku,
Tokyo 100-8185, Japan
e-mail: shiro.akinaga@kyowa-kirin.co.jp
Curr Hematol Malig Rep (2012) 7:235240
DOI 10.1007/s11899-012-0124-3
regimens or relapse, with the exception of anaplastic lympho-
ma kinase-positive anaplastic large cell lymphoma (ALK
+
ALCL), which responds well to the cyclophosphamide, doxo-
rubicin, vincristine, and prednisone (CHOP) regimen [9].
Among the various entities of PTCLs, adult T-cell leukemia-
lymphoma (ATL) harbors the worst prognosis [10]. Here, we
will discuss novel agents that have been developed for the
treatment of ATL and other PTCLs, mainly focusing on moga-
mulizumab/KW-0761, which is a humanized monoclonal an-
tibody tar geting CC chemokine receptor 4 (CCR4) that has
been actively developed for clinical use in Japan and the
United States.
PTCL and Novel Agents
PTCL-not otherwise specified (PTCL-NOS) and angioim-
munoblastic T-cell lymphoma (AITL), which are the most
common subtypes of PTCL (PTCL-NOS, 26 %; AITL,
19 %), show a poor prognosis with 5-year overall survival
(OS) and failure-free survival (FFS) of about 30 % and
20 %, respectively [10]. Several new agents have recently
been developed for the treatment of PTCL, mainly in patients
with relapsed or refractory disease. Such agents have various
mechanisms of actio n, including an immunomodulator
(lenalidomide), a proteasome inhibitor (bortezomib), histone
deacetylase inhibitors (vorinostat, romidepsin, panobinostat),
antifolate (pralatrexate), and biologics including antibodies
and antibody-toxin/drug conjugates (alemtuzumab, siplizu-
mab, denileukin diftitox, and brentuximab vedotin) as well
as nucleoside analogs such as fludarabine, gemcitabine, nelar-
abine, and forodesine [11]. Of these agents, pralatrexate and
romidepsin have been recently approved by the U.S. Food and
Drug Administration (FDA) and are now being used in the
U.S. for the treatment of relapsed or refractory PTCL. In 2011,
brentuximab vedotin (formerly known as SGN-35) was also
approved for the treatment of relapsed or refractory ALCL and
Hodgkin lymphoma.
ATL has the worst prognosis among PTCL, with 5-year
OS and FFS of 14 % and 12 %, respectively [10]. ATL is a
peripheral T-cell malignancy associated with human T-cell
lymphotropic virus type I (HTLV-1), and is relatively frequent
in southwestern Japan, West Africa, the Caribbean islands,
and Brazil, which are HTLV-1 endemic areas [12]. It is esti-
mated that there are about 1.2 million HTLV-1 carriers in
Japan, of whom a few percent develop ATL [13], and approx-
imately 700 to 1000 people die of this disease per year [14].
ATL is classified into four disease subtypes (acute, lymphoma,
chronic, and smoldering), based on clinical features including
leukemic changes, high lactate dehydrogenase, hypercalcemia
and organ infiltration, and the median survival time varies
according to the disease type: acute type, 6 months; lympho-
ma type, 10 months; chronic type, 24 months; and smoldering
type, 3 years or more [15]. It is recommended that treatment
strategies should be selected according to the disease subtype
[15]. In Japan, the acute type, lymphoma type, and chronic
type with unfavorable prognostic factors have been regarded
as aggressive ATL subtypes requiring immediate treatment,
and intensive combination chemotherapy or allogeneic hema-
topoietic stem-cell transplantation are generally recommended
therapeutic options [16].
The Japan Clinical Oncology Gro up-Lymphoma Study
Group (JCOG-LSG) has been investigating the efficacy of
combination chemotherapy for aggressive lymphomas in-
cluding ATL or for ATL alone since the early 1980s. At the
start of the investigation, CHOP-like regimens were evalu-
ated because ATL was considered to be a type of NHL, but
the outcom e was poor [17]. Then, the LSG15 r egimen
consisting of the drugs used in the CHOP regimen plus four
other drugs (ranimustine, vindesine, etoposide, and carbo-
platin) with the prophylactic use of g ranuloc yte colony-
stimulating factor (G-CSF) was evaluated. In a phase III
trial, JCOG 9801, this dose-intensified multiagent chemo-
therapy regimen was shown to be more effective than
CHOP-14 regimen, with a complete response rate of 40 %,
3-year OS of 24 %, and median survival time of 12.7 months
[18, 19]. However, since the outcome of this dose-intensified
regimen was still inferior to that in other PTCLs and B-cell
lymphomas, further improvement is necessary. In Western
countries, combination therapy with interferon-α and zidovu-
dine has been widely used for all disease subtypes of ATL. A
recently published meta-analysis suggested the effectiveness
of this combination therapy for ATL, especially leukemic
forms such as acute and chronic types [20].
Several new antibodies are currently under development
for the treatment of T-cell lymphoma. They are based on the
unique immunophenotypic features of ATL cells, which
express mature T-cell antigens such as CD2, CD25 (inter-
leukin [IL]-2 receptor), and CD52. Because of the unique
intense expression of CD25 compared to that in other
PTCL, monoclonal antibodies targeting the IL-2 receptor
(anti-Tac), either radiolabeled or unlabelled (daclizumab),
have been tested in patients with relapsed or refractory ATL.
However, the clinical efficacy appears to be limited [21]. An
anti-CD2 monoclonal antibody (siplizumab) [22], anti-CD52
antibody (alemtuzumab) [23, 24], and anti-transferrin receptor
antibody (A24) [25] are also under development, but data are
currently limited.
Currently Available Therapeutic Agents for ATL
Pentostatin and sobuzoxa ne are chemotherapeutic agents
that were previously approved for the treatment of ATL in
Japan. Pentostatin, a purine nucleoside analog that inhibits
adenosine deaminase, has been reported to be effective for
236 Curr Hematol Malig Rep (2012) 7:235240
T-cell malignancies, including T-cell prolymphoc ytic leuke-
mia, CTCL, and PTCL [26]. The clinical efficacy of pentos-
tatin was evaluated in patients with ATL from the 1980s to
1990s, and a phase II study of pentostatin revealed a re-
sponse rate of 32 % (10 of 31) in patients with relapsed or
refractory ATL [27]. Other drugs that are often used in
patients with relapsed or refractory ATL are some combina-
tion chemotherapy regimens, including EPOCH (etoposide,
prednisolone, vincristine, cyclophosphamide, and doxorubi-
cin) and ESHAP (etoposide, methylprednisolone, high-dose
cytarabine and cisplatin); however, there is no apparent
evidence of an advantage of these combination chemothera-
pies over other therapeutic options. In the U.S., pralatrexate
and romidepsin have been approved for the treatment of
PTCL and can also be used for ATL. The efficacy of these
drugs for ATL is not clear because they have been evaluated
only in a very limited number of p atients (the efficacy of
pralatrexate was evaluated in a clinical study in one patient)
[28].
CCR4 as a Novel Therapeutic Target
Chemokines act as signaling molecules in the migration and
tissue homing of various leukocytes. Among them, thymus
and a ctivation-regulated chemokine (TARC) and monocyte-
derived chemokine (MDC) induce the selective recruitment
of distinct subsets of T-cells through tri ggering of a chemo-
kine receptor, CCR4. CCR4 is a seven-transmembrane G-
protein coupled receptor and selective ly expressed on Th2
cells and regulatory T cells [29, 30]. The expres sion on
normal cells such as Th2 cells can be partly regulated by
the ligand, especially MDC [31], while the regulation by the
ligands on cancer cells are not yet understood. Ishida et al.
analyzed 103 patients with ATL, and found that tumor cells
from about 90 % of patients showed CCR4 expression [32].
They also found that patients with CCR4-positive ATL were
more likely to have skin infiltration and had a worse out-
come than those with CCR4-negative ATL, indicating that
CCR4 played an important pathogenetic role in ATL [32]. In
addition, Yoshie et al. found that the expression of CCR4
was increased in association of HTLV-1 and showed a
relationship to Fra-2/Jun D which induce s downstream
genes such as c-Myb and SOX4, and MDM2 which pro-
motes growth and inhibits apoptosis [33] . CCR4 is also
expressed on other types of PTCL (29 % of total cases;
PTCL-NOS, 38 %; AITL, 35 %; ALK
-
ALCL, 67 %; my-
cosis fungoides [MF], 41 %) [34]. Jones et al. independently
reported that some types of PTCL expressed CCR4, as well
[35]. In addition, analysis of 50 patients with PTCL-NOS
revealed that CCR4-positive patients had significantly
shorter survival than CCR4-negative patients [34]. Nakagawa
et al. analyzed 51 patients with PTCL-NOS using the array
comparative genomic hybridization technique, and found that
patients with PTCL-NOS with genomic aberrations had a
significantly higher frequency of CCR4 positivity and a worse
outcome than those with PTCL-NOS without genomic aber-
rations [36]. These findings rese mble those observed in
patients with ATL. Although the role of CCR4 in the tumor-
igenesis and progression of PTCL-NOS has not been fully
elucidated, CCR4 seems to be a promising target molecule in
the treatment of PTCL as well as in ATL.
Clinical Trials of Mogamulizumab
Mogamulizumab/KW-0761 is a humanized monoclonal an-
tibody that recognizes the N-terminal region of human
CCR4 [3739]. It is a thera peutic antibody produced using
a novel glycoengineering technology that enhances antibody-
dependent cellular cytotoxic (ADCC) activity [40]. Mogamu-
lizumab and its human-mouse chimeric version, KM2760,
showed potent antitumor activity mediated by enhanced
ADCC against ATL cell lines and primary ATL cells in vitro
and in vivo [39, 41, 42].
A phase I clinical study (07610501 Study: Clinical-
Trials.gov Identifier NCT00355472) has been conducted in
patients with CCR4-positive relap sed PTCL, including ATL
[43]. The primary objectives of the study were to assess the
safety of mogamulizumab, and analyze its maximum toler-
ated dose (MTD) and pharmacokinetics. The secondary
objectives were to determine the best overall response rate
(ORR) and progression-free survival (PFS). Mogamulizu-
mab was intravenously administered once a week for
4 weeks at four dose levels (0.01, 0.1, 0.5, and 1.0 mg/kg)
according to the conventional 3+3 design. Enrolled in the
study were 16 patients, of whom 13 had ATL (11 acute type,
2 lymphoma type), 1 had tumor-stage MF, and 2 had PTCL-
NOS. All 16 patients receiving mogamulizumab were in-
cluded in the safety and efficacy analyses. No dose-limiting
toxicity (DLT) was observed in any of the 13 patients who
received mogamulizumab at a dose of 0.011.0 mg/kg, and
thus MTD was not reached. Then, three additional patients
were enrolled to receive 1.0 mg/kg, the highest dose. One
patient showed grade 4 neutropenia, grade 3 febrile neutro-
penia, and grade 3 skin eruption, but these adverse events
occurred in only 1 of the 6 patients who received a dose of
1.0 mg/kg, indicating that this drug would be tolerated at
least up to 1.0 mg/kg. The best ORR in the total 16 patients
was 31 % (of those, 2 had complete response [CR] and 3
had partial response [PR]), and the best ORR was also 31 %
in patients with ATL (of those, 2 had CR and another 2 had
PR). Pharmacokinetic analysis revealed a plasma mogamu-
lizumab trough concentration of 7.519.6 μg/mL after the
1st to 4th administration of mogamulizumab at a dose of
1.0 mg/kg. These concentrations were sufficient to kill
Curr Hematol Malig Rep (2012) 7:235240 237
primary ATL cells by ADCC activity in vitro (10 μg/m L).
After the 4th administration of mogamulizumab at a dose of
1.0 mg/kg, its plasma half-life was approximately 18 days,
which is comparable to the half-life (14 to 21 days) of
endogenous human IgG. Lastly, although MTD was not
reached, a tendency toward an increased incidence of grade
3 or higher toxicity was observed at 1.0 mg/kg. Therefore, it
was concluded that a dose of 1.0 mg/kg should be recommen-
ded for a subsequent phase II trial of this novel agent [44].
A subsequent phase II study of mogamulizumab (0761
002 Study: ClinicalTrials.gov Identifier NCT 00920790)
was conducted in patients with CCR4-positive relapsed
ATL [45]. The primary endpoint was the best ORR, and
the secondary endpoints included the best response of each
disease site such as peripheral blood ATL cells, skin and
nodal/extranodal lesions as well as PFS and OS. It was
planned for 25 patients to be enrolled for efficacy analysis,
assuming the expected ORR of 30 % with a 5 % threshold
response rate. Mogamulizumab was intravenously adminis-
tered once a week for 8 weeks at a dose of 1.0 mg/kg. In this
study, 28 patients in total were enrolled. Of these, 27
patients who received mogamulizumab were included in
the safety analysis, and 26 patients, excluding 1 patient
who was judged ineligible for enrollment after starting
mogamulizumab administration, were evaluated in the effi-
cacy analysis. Of the 27 patients who received mogamuli-
zumab, 14 had acute type, 6 lymphoma type, and 7 chronic
type with unfavorable prognostic factors. The best ORR was
50 % (13/26) including 8 CR. With the lower limit of the
95 % confidence interval (30 % to 70 %) exceeding the
threshold response ra te of 5 %, the clinical efficacy of
mogamulizumab was confirmed. Responses according to
disease sites were 100 % (of 13 patients, all CR) for periph-
eral blood, 63 % (of 8 patients, 3 CR and 2 PR) for skin, and
25 % (of 12 patients, 3 CR/CRu) for nodal and extranodal
lesions. Median PFS and OS were 5.2 and 13.7 months,
respectively. The best ORR was also calculated for each
disease subtype, giving 43 % in patients with acute type
(of 14 patients, 5 CR and 1 PR), 33 % in patients with
lymphoma type (of 6 patients, 1 CR and 1 PR), and 83 %
in patients with unfavorable chronic type (of 6 patients, 2
CR and 3 PR). Thus, it was demonstrated that mogamuli-
zumab induced favorable responses in patients with any
disease subtype of ATL. In addition, for each age group,
the best ORR was 39 % (of 13 patients, 3 CR and 2 PR) in
patients younger than 65 years, and 62 % (of 13 patients, 5
CR and 3 PR) in patients 65 years or older. The most
common adverse events observed during the study were
lymphopenia (96 %), neutropenia (52 %), and thrombocyto-
penia (52 %) as hematologic toxicity, and acute infusion
reaction (89 %) and skin eruption (63 %) as non-
hematologic toxicity. There was no death related to mogamu-
lizumab in either the phase I or phase II study. Of 8 serious
adverse events with a relationship to mogamulizumab in the
phase I and II studies, 5 events including 4 cases of skin
eruption and 1 case of Stevens-Johnson syndrome occurred
during the phase II study. However, these reactions were
manageable with supportive measures including corticoste-
roid or other drugs in all patients. Considering the seriousness
of the disease, even skin eruption might be considered accept-
able for the treatment of ATL by treating physicians, while
close and appropriate follow-up of the event is necessary.
Elucidation of the mechanism of skin eruption and preventive
measures against it are awaited.
In the U.S., a phase I/II study (ClinicalTrials.gov Identi-
fier: NCT00888927) in patients with relapsed or refractory
PTCL including CTCL has been conducted [46]. Mogamu-
lizumab was well tolerated at doses of 0.11.0 mg/kg in 42
patients including 1 with PTCL-NOS. MTD was not
reached and t hu s 1. 0 mg /kg w as c ho se n for subsequent
studies. A promising ORR of 42 % (of 38 evaluable patients
with CTCL, 3 CR and 13 PR) was achieved, although
expression of CCR4 on lymphoma cells was not mandatory
for patient enrolment in this particular phase I/II study.
Regarding subtypes of CTCL, ORR in Sezary syndrome
(SS) patients was 50 % and in MF patients was 36 %.
Eighty-seven percent of SS patients had a response in pe-
ripheral blood, with 50 % CR. Further study of mogamuli-
zumab is warranted in patients with nodal PTCL as well as
CTCL.
Conclusions
It is evident that there are limitations to improvement of the
treatment outcome of PTCL, especially ATL, with the cur-
rently available chemotherapeutic agents alone. Mogamuli-
zumab has a less severe toxicity profile and induces a high
response rate in patients with ATL, even in elderly patients.
Fig. 1 Ongoing cli nic al st udi es o f mogamulizumab/KW-0761 for
peripheral T-cell lymphomas in Japan
238 Curr Hematol Malig Rep (2012) 7:235240
Therefore, it may provide an effective treatment option for
the disease, especially for elderly patients who are not eligible
for intensive ch emotherapy or h ematopoietic st em-cell
transplantation.
In Japan, based on the results of the clinical studies
mentioned above, a single-arm phase II study of mogamu-
lizumab monotherapy in patients with CTCL and PTCL
(ClinicalTrials.gov Identifier: NCT01192984) and a random-
ized phase II study of dose-intensified combination chemo-
therapy (mLSG15 regimen) with or without mogamulizumab
in untreated patients with ATL (ClinicalTrials.gov Identifier:
NCT01173887) are being conducted as shown in Fig. 1.
Patient enrollment has already been completed in these phase
II studies. In the U.S., based on the aforementioned phase I/II
study in patients with relapsed or refractory CTCL, a pivotal
phase III study in patients with relapsed or refractory CTCL is
being planned. In conclusion, mogamulizumab is expected to
provide new, promising treatment options in patients with
ATL and other T-cell lymphomas.
Acknowledgments We thank all the investigators who participated
in the multicenter clinical trials of mogamulizumab/KW-0761 in Japan.
Clinical studies of mogamulizumab were sponsored by Kyowa Hakko
Kirin Co. Ltd., Tokyo, Japan.
Disclosure K. Tobinai: research grant from Kyowa Hakko Kirin Co.
Ltd. and board membership for Merck, Mundipharma, Zenyaku,
Genzyme, Eisai, Symbio, Eli Lilly, Celgene, Kyowa-Kirin, Biomedics,
and Solasia Pharma; T. Takahashi: employee of Kyowa Hakko Kirin Co.
Ltd.; S. Akinaga: employee of Kyowa Hakko Kirin Co. Ltd.
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution License which permits any use, distribution,
and reproduction in any medium, provided the original author(s) and
the source are credited.
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240 Curr Hematol Malig Rep (2012) 7:235240
    • "The goal of Fc engineering is to manipulate coengagement between an antibody Fc region and FcγRs on immune effector cells. FcγRIIb-targeted Fc engineering has been shown to potentiate apoptosis and increase anti-tumour activity ( Ravetch 2012, 2013; Tobinai et al. 2012). Considerable progress has been made in generating optimised antibody Fc binding affinity for activating FcγRs, principally FcγRIIIa and FcγRIIa, resulting in enhanced ADCC and ADCP (Desjarlais et al. 2007; Stavenhagen et al. 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: Immunomodulatory monoclonal antibody (mAb) therapy is at the forefront of developing cancer therapeutics with numerous targeted agents proving highly effective in selective patients at stimulating protective host immunity, capable of eradicating established tumours and leading to long-term disease-free states. The cell surface marker CD40 is expressed on a range of immune cells and transformed cells in malignant states whose signalling plays a critical role in modulating adaptive immune responses. Anti-CD40 mAb therapy acts via multiple mechanisms to stimulate anti-tumour immunity across a broad range of lymphoid and solid malignancies. A wealth of preclinical research in this field has led to the successful development of multiple anti-CD40 mAb agents that have shown promise in early-phase clinical trials. Significant progress has been made to enhance the engagement of antibodies with immune effectors through their interactions with Fcγ receptors (FcγRs) by the process of Fc engineering. As more is understood about how to best optimise these agents, principally through the fine-tuning of mAb structure and choice of synergistic partnerships, our ability to generate robust, clinically beneficial anti-tumour activity will form the foundation for the next generation of cancer therapeutics.
    Full-text · Article · Feb 2015
    • "As well as being an effective method of improving activity, removal of fucose should not result in immunogenicity since 10–20% of normal human IgG lacks fucose [42]. Clinical trials have shown that non-fucosylated antibodies are tolerated and can give clinical effects at low doses [43,44]. This work has capitalised on a unique opportunity to compare the effects of alternative glycosylation profiles on the in vivo and in vitro properties of IgG molecules with the same amino acid sequence. "
    [Show abstract] [Hide abstract] ABSTRACT: We previously produced a recombinant version of the human anti-RhD antibody Fog-1 in the rat myeloma cell line, YB2/0. When human, autologous RhD-positive red blood cells (RBC) were sensitised with this IgG1 antibody and re-injected, they were cleared much more rapidly from the circulation than had been seen earlier with the original human-mouse heterohybridoma-produced Fog-1. Since the IgG have the same amino acid sequence, this disparity is likely to be due to alternative glycosylation that results from the rat and mouse cell lines. By comparing the in vitro properties of YB2/0-produced Fog-1 IgG1 and the same antibody produced in the mouse myeloma cell line NS0, we now have a unique opportunity to pinpoint the cause of the difference in ability to clear RBC in vivo. Using transfected cell lines that express single human FcγR, we showed that IgG1 made in YB2/0 and NS0 cell lines bound equally well to receptors of the FcγRI and FcγRII classes but that the YB2/0 antibody was superior in FcγRIII binding. When measuring complexed IgG binding, the difference was 45-fold for FcγRIIIa 158F, 20-fold for FcγRIIIa 158V and approximately 40-fold for FcγRIIIb. The dissimilarity was greater at 100-fold in monomeric IgG binding assays with FcγRIIIa. When used to sensitise RBC, the YB2/0 IgG1 generated 100-fold greater human NK cell antibody-dependent cell-mediated cytotoxicity and had a 103-fold advantage over the NS0 antibody in activating NK cells, as detected by CD54 levels. In assays of monocyte activation and macrophage adherence/phagocytosis, where FcγRI plays major roles, RBC sensitised with the two antibodies produced much more similar results. Thus, the alternative glycosylation profiles of the Fog-1 antibodies affect only FcγRIII binding and FcγRIII-mediated functions. Relating this to the in vivo studies confirms the importance of FcγRIII in RBC clearance.
    Full-text · Article · Oct 2014
    • "Studies in mouse disease models and clinical trials demonstrate that reducing T reg activity boosts endogenous anti-tumor immunity and increases the efficacy of active immune interventions [12]. The CC-chemokine receptor 4 (CCR4) is also highly expressed on tumor cells of T-cell derived variants of non-Hodgkin's lymphoma (NHL), such as adult T-cell leukemia/lymphoma (ATLL) [13,14], cutaneous T-cell lymphoma (CTCL) [15,16], and other kinds of malignancies belonging to the heterogeneous group of peripheral T-cell lymphoma (PTCL) [17]. In Western countries, PTCL accounts for 15–20% of aggressive lymphomas and 5–10% of all NHL [18]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background CC chemokine receptor 4 (CCR4) represents a potentially important target for cancer immunotherapy due to its expression on tumor infiltrating immune cells including regulatory T cells (Tregs) and on tumor cells in several cancer types and its role in metastasis. Methodology Using phage display, human antibody library, affinity maturation and a cell-based antibody selection strategy, the antibody variants against human CCR4 were generated. These antibodies effectively competed with ligand binding, were able to block ligand-induced signaling and cell migration, and demonstrated efficient killing of CCR4-positive tumor cells via ADCC and phagocytosis. In a mouse model of human T-cell lymphoma, significant survival benefit was demonstrated for animals treated with the newly selected anti-CCR4 antibodies. Significance For the first time, successful generation of anti- G-protein coupled chemokine receptor (GPCR) antibodies using human non-immune library and phage display on GPCR-expressing cells was demonstrated. The generated anti-CCR4 antibodies possess a dual mode of action (inhibition of ligand-induced signaling and antibody-directed tumor cell killing). The data demonstrate that the anti-tumor activity in vivo is mediated, at least in part, through Fc-receptor dependent effector mechanisms, such as ADCC and phagocytosis. Anti-CC chemokine receptor 4 antibodies inhibiting receptor signaling have potential as immunomodulatory antibodies for cancer.
    Full-text · Article · Jul 2014
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