title: A Dual Target-directed Agent against Interleukin-6 Receptor and Tumor Necrosis Factor α ameliorates experimental arthritis.
abstract: A considerable proportion of patients with rheumatoid arthritis (RA) do not respond to monospecific agents. The purpose of our study was to generate a hybrid form of biologics, targeting tumor-necrosis factor alpha (TNFα) and interleukin-6 receptor (IL-6R), and determine its anti-arthritic properties in vitro and in vivo. A novel dual target-directed agent (DTA(A7/sTNFR2)) was generated by conjugating soluble TNF receptor 2 (sTNFR2) to the Fc region of A7, a new anti-IL-6R antibody obtained by screening the phage display human antibody library. DTA(A7/sTNFR2) inhibited the proliferation and migration of fibroblast-like synoviocytes from patients with RA (RA-FLS) more efficiently than single target-directed agents. DTA(A7/sTNFR2) also blocked osteoclastogenesis from bone marrow cells. The arthritis severity scores of the experimental arthritis mice with DTA(A7/sTNFR2) tended to be lower than those of mice with IgG, A7, or sTNFR2. Histological data suggested that DTA(A7/sTNFR2) is more efficient than single-target drugs in preventing joint destruction and bone loss. These results were confirmed in vivo using the minicircle system. Taken together, the results show that DTA(A7/sTNFR2) may be a promising therapeutic agent for the treatment of RA.
authors: CiSTEM laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea.
authors: Youngkyun
authors: Y
authors: Kim
authors: CiSTEM laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea.
authors: Hyoju
authors: H
authors: Yi
authors: CiSTEM laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea.
authors: Hyerin
authors: H
authors: Jung
authors: CiSTEM laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea.
authors: Yeri Alice
authors: YA
authors: Rim
authors: CiSTEM laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea.
authors: Narae
authors: N
authors: Park
authors: CiSTEM laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea.
authors: Juryun
authors: J
authors: Kim
authors: CiSTEM laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea.|Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea.
authors: Seung Min
authors: SM
authors: Jung
authors: Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea.
authors: Sung-Hwan
authors: SH
authors: Park
authors: Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, South Korea.
authors: Young Woo
authors: YW
authors: Park
authors: CiSTEM laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea.|Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea.
authors: Ji Hyeon
authors: JH
authors: Ju
mesh_terms: D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D010012:Osteogenesis / Q000187:drug effects; D019151:Peptide Library; D019947:Receptors, Interleukin-6 / Q000276:immunology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000494:pharmacology / Q000627:therapeutic use; D000070918:Synoviocytes / Q000166:cytology / Q000378:metabolism
chemical_list: D000906:Antibodies; D007141:Immunoglobulin Fc Fragments; D019151:Peptide Library; D019947:Receptors, Interleukin-6; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins