Hyaluronate-Death Receptor 5 Antibody Conjugates for Targeted Treatment of Liver Metastasis

Hwiwon Lee, Beom Ju Hong, Jeong Ho Lee, Sujin Yeo, Hoe Yune Jung, Junho Chung, G. One Ahn, Sei Kwang Hahn

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3 Citations (Scopus)

Abstract

The liver is the most frequent site of metastasis with a 5-year survival rate of only 20-40%. In this work, hyaluronate (HA)-death receptor 5 antibody (DR5 Ab) conjugate was synthesized as a dual targeting therapeutic agent to treat liver metastasis. Dual targeting was achieved by DR5 Ab, a humanized agonistic monoclonal antibody binding to DR5 frequently overexpressed in many kinds of cancer cells, and by HA, a natural polysaccharide binding to HA receptors highly expressed in both the liver and cancer cells. Thiol end-modified HA was site-specifically conjugated to N-glycan on Fc region of oxidized DR5 Ab using a heterobifunctional linker of 3-(2-pyridyldithio)propionyl hydrazide (PDPH). The successful synthesis of HA-DR5 Ab conjugate was confirmed by 1H NMR, purpald assay, dynamic light scattering (DLS), and high-performance liquid chromatography (HPLC). In vitro analysis of HA-DR5 Ab conjugate revealed that the conjugation of HA to DR5 Ab did not affect the binding affinity and anticancer efficacy of DR5 Ab. Remarkably, according to in vivo bioimaging study, HA-DR5 Ab conjugate appeared to be highly accumulated in the liver and dramatically effective in inhibiting the tumor growth in liver metastasis model mice.

Original languageEnglish
Pages (from-to)3085-3093
Number of pages9
JournalBiomacromolecules
Volume17
Issue number9
DOIs
StatePublished - 12 Sep 2016

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TNF-Related Apoptosis-Inducing Ligand Receptors
Antibodies
Liver
Polysaccharides
Cells
Antibodies, Monoclonal, Humanized
Monoclonal antibodies
High performance liquid chromatography
Dynamic light scattering
Sulfhydryl Compounds
Tumors
Assays
Nuclear magnetic resonance

Cite this

Lee, Hwiwon ; Hong, Beom Ju ; Lee, Jeong Ho ; Yeo, Sujin ; Jung, Hoe Yune ; Chung, Junho ; Ahn, G. One ; Hahn, Sei Kwang. / Hyaluronate-Death Receptor 5 Antibody Conjugates for Targeted Treatment of Liver Metastasis. In: Biomacromolecules. 2016 ; Vol. 17, No. 9. pp. 3085-3093.
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title = "Hyaluronate-Death Receptor 5 Antibody Conjugates for Targeted Treatment of Liver Metastasis",
abstract = "The liver is the most frequent site of metastasis with a 5-year survival rate of only 20-40{\%}. In this work, hyaluronate (HA)-death receptor 5 antibody (DR5 Ab) conjugate was synthesized as a dual targeting therapeutic agent to treat liver metastasis. Dual targeting was achieved by DR5 Ab, a humanized agonistic monoclonal antibody binding to DR5 frequently overexpressed in many kinds of cancer cells, and by HA, a natural polysaccharide binding to HA receptors highly expressed in both the liver and cancer cells. Thiol end-modified HA was site-specifically conjugated to N-glycan on Fc region of oxidized DR5 Ab using a heterobifunctional linker of 3-(2-pyridyldithio)propionyl hydrazide (PDPH). The successful synthesis of HA-DR5 Ab conjugate was confirmed by 1H NMR, purpald assay, dynamic light scattering (DLS), and high-performance liquid chromatography (HPLC). In vitro analysis of HA-DR5 Ab conjugate revealed that the conjugation of HA to DR5 Ab did not affect the binding affinity and anticancer efficacy of DR5 Ab. Remarkably, according to in vivo bioimaging study, HA-DR5 Ab conjugate appeared to be highly accumulated in the liver and dramatically effective in inhibiting the tumor growth in liver metastasis model mice.",
author = "Hwiwon Lee and Hong, {Beom Ju} and Lee, {Jeong Ho} and Sujin Yeo and Jung, {Hoe Yune} and Junho Chung and Ahn, {G. One} and Hahn, {Sei Kwang}",
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Lee, H, Hong, BJ, Lee, JH, Yeo, S, Jung, HY, Chung, J, Ahn, GO & Hahn, SK 2016, 'Hyaluronate-Death Receptor 5 Antibody Conjugates for Targeted Treatment of Liver Metastasis', Biomacromolecules, vol. 17, no. 9, pp. 3085-3093. https://doi.org/10.1021/acs.biomac.6b01022

Hyaluronate-Death Receptor 5 Antibody Conjugates for Targeted Treatment of Liver Metastasis. / Lee, Hwiwon; Hong, Beom Ju; Lee, Jeong Ho; Yeo, Sujin; Jung, Hoe Yune; Chung, Junho; Ahn, G. One; Hahn, Sei Kwang.

In: Biomacromolecules, Vol. 17, No. 9, 12.09.2016, p. 3085-3093.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Hyaluronate-Death Receptor 5 Antibody Conjugates for Targeted Treatment of Liver Metastasis

AU - Lee, Hwiwon

AU - Hong, Beom Ju

AU - Lee, Jeong Ho

AU - Yeo, Sujin

AU - Jung, Hoe Yune

AU - Chung, Junho

AU - Ahn, G. One

AU - Hahn, Sei Kwang

PY - 2016/9/12

Y1 - 2016/9/12

N2 - The liver is the most frequent site of metastasis with a 5-year survival rate of only 20-40%. In this work, hyaluronate (HA)-death receptor 5 antibody (DR5 Ab) conjugate was synthesized as a dual targeting therapeutic agent to treat liver metastasis. Dual targeting was achieved by DR5 Ab, a humanized agonistic monoclonal antibody binding to DR5 frequently overexpressed in many kinds of cancer cells, and by HA, a natural polysaccharide binding to HA receptors highly expressed in both the liver and cancer cells. Thiol end-modified HA was site-specifically conjugated to N-glycan on Fc region of oxidized DR5 Ab using a heterobifunctional linker of 3-(2-pyridyldithio)propionyl hydrazide (PDPH). The successful synthesis of HA-DR5 Ab conjugate was confirmed by 1H NMR, purpald assay, dynamic light scattering (DLS), and high-performance liquid chromatography (HPLC). In vitro analysis of HA-DR5 Ab conjugate revealed that the conjugation of HA to DR5 Ab did not affect the binding affinity and anticancer efficacy of DR5 Ab. Remarkably, according to in vivo bioimaging study, HA-DR5 Ab conjugate appeared to be highly accumulated in the liver and dramatically effective in inhibiting the tumor growth in liver metastasis model mice.

AB - The liver is the most frequent site of metastasis with a 5-year survival rate of only 20-40%. In this work, hyaluronate (HA)-death receptor 5 antibody (DR5 Ab) conjugate was synthesized as a dual targeting therapeutic agent to treat liver metastasis. Dual targeting was achieved by DR5 Ab, a humanized agonistic monoclonal antibody binding to DR5 frequently overexpressed in many kinds of cancer cells, and by HA, a natural polysaccharide binding to HA receptors highly expressed in both the liver and cancer cells. Thiol end-modified HA was site-specifically conjugated to N-glycan on Fc region of oxidized DR5 Ab using a heterobifunctional linker of 3-(2-pyridyldithio)propionyl hydrazide (PDPH). The successful synthesis of HA-DR5 Ab conjugate was confirmed by 1H NMR, purpald assay, dynamic light scattering (DLS), and high-performance liquid chromatography (HPLC). In vitro analysis of HA-DR5 Ab conjugate revealed that the conjugation of HA to DR5 Ab did not affect the binding affinity and anticancer efficacy of DR5 Ab. Remarkably, according to in vivo bioimaging study, HA-DR5 Ab conjugate appeared to be highly accumulated in the liver and dramatically effective in inhibiting the tumor growth in liver metastasis model mice.

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U2 - 10.1021/acs.biomac.6b01022

DO - 10.1021/acs.biomac.6b01022

M3 - Article

VL - 17

SP - 3085

EP - 3093

JO - Biomacromolecules

JF - Biomacromolecules

SN - 1525-7797

IS - 9

ER -