title: A RANKL mutant used as an inter-species vaccine for efficient immunotherapy of osteoporosis.
abstract: Anti-cytokine therapeutic antibodies have been demonstrated to be effective in the treatment of several auto-immune disorders. However, The problems in antibody manufacture and the immunogenicity caused by multiple doses of antibodies inspire people to use auto-cytokine as immunogen to induce anti-cytokine antibodies. Nevertheless, the tolerance for inducing immune response against self-antigen has hindered the wide application of the strategy. To overcome the tolerance, here we proposed a strategy using the inter-species cytokine as immunogen for active immunization (TISCAI) to induce anti-cytokine antibody. As a proof of concept, an inter-species cytokine RANKL was successfully used as immunogen to induce anti-RANKL immune response. Furthermore, to prevent undesirable side-effects, the human RANKL was mutated based on the crystal structure of the complex of human RANKL and its rodent counterpart receptor RANK. We found, the antibodies produced blocked the osteoclast development in vitro and osteoporosis in OVX rat models. The results demonstrated this strategy adopted is very useful for general anti-cytokine immunotherapy for different diseases settings.
authors.affiliation: Beijing Key Laboratory of Research of Chinese Medicine on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, NO.16, Dongzhimennei South Street, Dongcheng District, Beijing 100700, China.
authors.forename: Changzhen
authors.initials: C
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 1 Beichen Xilu, Beijing 100101, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 1 Beichen Xilu, Beijing 100101, China.
authors.forename: Wen
authors.initials: W
authors.lastname: He
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 1 Beichen Xilu, Beijing 100101, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 1 Beichen Xilu, Beijing 100101, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 1 Beichen Xilu, Beijing 100101, China.
authors.forename: Shiqian
authors.initials: S
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 1 Beichen Xilu, Beijing 100101, China.
authors.forename: Yijing
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Gohda
authors.affiliation: Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, The Henry Welcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Walter
authors.affiliation: Oxford Protein Production Facility UK, Research Complex at Harwell, Rutherford Appleton Laboratory Harwell, Science and Innovation Campus, Oxfordshire, OX11 0FA, UK.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Owens
authors.affiliation: Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, The Henry Welcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.affiliation: Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, The Henry Welcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Jingshan
authors.initials: J
authors.lastname: Ren
authors.affiliation: Abingen Ltd, Oxford, UK.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology / Q000494:pharmacology; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D007114:Immunization; D007167:Immunotherapy; D051379:Mice; D008958:Models, Molecular; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010024:Osteoporosis / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D010052:Ovariectomy; D011485:Protein Binding; D011487:Protein Conformation; D053245:RANK Ligand / Q000737:chemistry / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000737:chemistry / Q000378:metabolism; D014612:Vaccines; D055114:X-Ray Microtomography
chemical_list: D000906:Antibodies; D001324:Autoantigens; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D014612:Vaccines