An EGFR ‐targeting antibody–drug conjugate LR 004‐ VC ‐ MMAE : potential in esophageal squamous cell carcinoma and other malignancies
Epidermal growth factor receptor ( EGFR ) is a rational target for cancer therapy, because its overexpression plays an important oncogenic role in a variety of solid tumors; however, EGFR ‐targeted antibody–drug conjugate ( ADC ) therapy for esophageal squamous cell carcinoma ( ESCC ) is exceedingly...
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Published in | Molecular oncology Vol. 13; no. 2; pp. 246 - 263 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
John Wiley & Sons, Inc
01.02.2019
|
Subjects | |
Online Access | Get full text |
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Summary: | Epidermal growth factor receptor (
EGFR
) is a rational target for cancer therapy, because its overexpression plays an important oncogenic role in a variety of solid tumors; however,
EGFR
‐targeted antibody–drug conjugate (
ADC
) therapy for esophageal squamous cell carcinoma (
ESCC
) is exceedingly rare.
LR
004 is a novel anti‐
EGFR
antibody with the advantages of improved safety and fewer hypersensitivity reactions. It may be of great value as a carrier in
ADC
s with high binding affinity and internalization ability. Here, we prepared an
EGFR
‐targeting
ADC
,
LR
004‐
VC
‐
MMAE
, and evaluated its antitumor activities against
ESCC
and
EGFR
‐positive cells.
LR
004 was covalently conjugated with monomethyl auristatin E (
MMAE
) via a
VC
linker by antibody interchain disulfide bond reduction.
VC
‐
MMAE
was conjugated with
LR
004 with approximately 4.0
MMAE
molecules per
ADC
.
LR
004‐
VC
‐
MMAE
showed a potent antitumor effect against
ESCC
and other
EGFR
‐positive cells with
IC
50
values of
nM
concentrations
in vitro
. The
in vivo
antitumor effects of
LR
004‐
VC
‐
MMAE
were investigated in
ESCC KYSE
520 and A431 xenograft nude mice models. Significant activity was seen at 5 mg·kg
−1
, and complete tumor regression was observed at 15 mg·kg
−1
in the
KYSE
520 xenograft nude mice after four injections, while the naked antibody
LR
004 had little effect on inhibiting tumor growth. Similar promising results were obtained in the A431 models. In addition, the tumors also remained responsive to
LR
004‐
VC
‐
MMAE
for large tumor experiments (tumor volume 400–500 mm
3
). The study results demonstrated that
LR
004‐
VC
‐
MMAE
could be a potential therapeutic agent for
ESCC
and other
EGFR
‐expressing malignancies. We also evaluated
PK
profile of
LR
004‐
VC
‐
MMAE ADC
in the mice model, which would provide qualitative guiding significance for the further research. |
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ISSN: | 1574-7891 1878-0261 |
DOI: | 10.1002/1878-0261.12400 |