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 (1)H 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.
authors: Hwiwon
authors: H
authors: Lee
authors: Beom-Ju
authors: BJ
authors: Hong
authors: Jeong Ho
authors: JH
authors: Lee
authors: Sujin
authors: S
authors: Yeo
authors: R&D Center, NovMetaPharma Co., Ltd., Jigokdong, Nam-gu, Pohang, 790-834, Korea.
authors: Hoe-Yune
authors: HY
authors: Jung
authors: Department of Biochemistry and Molecular Biology and Cancer Research Institute, Seoul National University College of Medicine , Seoul, Korea.
authors: Junho
authors: J
authors: Chung
authors: G-One
authors: GO
authors: Ahn
authors: Sei Kwang
authors: SK
authors: Hahn
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D018796:Immunoconjugates / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; D006820:Hyaluronic Acid