title: Monoclonal anti-HMGB1 (high mobility group box chromosomal protein 1) antibody protection in two experimental arthritis models.
abstract: High mobility group box chromosomal protein 1 (HMGB1) is a DNA-binding nuclear protein that can be released from dying cells and activated myeloid cells. Extracellularly, HMGB1 promotes inflammation. Experimental studies demonstrate HMGB1 to be a pathogenic factor in many inflammatory conditions including arthritis. HMGB1-blocking therapies in arthritis models alleviate disease and confer significant protection against cartilage and bone destruction. So far, the most successful HMGB1-targeted therapies have been demonstrated with HMGB1-specific polyclonal antibodies and with recombinant A box protein, a fragment of HMGB1. The present study is the first to evaluate the potential of a monoclonal anti-HMGB1 antibody (2G7, mouse IgG2b) to ameliorate arthritis. Effects of repeated injections of this antibody have now been studied in two conceptually different models of arthritis: collagen type II-induced arthritis (CIA) in DBA/1 mice and in a spontaneous arthritis disease in mice with combined deficiencies for genes encoding for the enzyme DNase type II and interferon type I receptors. These mice are unable to degrade phagocytozed DNA in macrophages and develop chronic, destructive polyarthritis. Therapeutic intervention in CIA and prophylactic administration of anti-HMGB1 monoclonal antibody (mAb) in the spontaneous arthritis model significantly ameliorated the clinical courses. Anti-HMGB1 mAb therapy also partially prevented joint destruction, as demonstrated by histological examination. The beneficial antiarthritic effects by the anti-HMGB1 mAb in two diverse models of arthritis represent additional proof-of-concept, indicating that HMGB1 may be a valid target molecule to consider for development of future clinical therapy.
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Schierbeck
authors.forename: Peter
authors.initials: P
authors.lastname: Lundbäck
authors.forename: Karin
authors.initials: K
authors.lastname: Palmblad
authors.forename: Lena
authors.initials: L
authors.lastname: Klevenvall
authors.forename: Helena
authors.initials: H
authors.lastname: Erlandsson-Harris
authors.forename: Ulf
authors.initials: U
authors.lastname: Andersson
authors.forename: Lars
authors.initials: L
authors.lastname: Ottosson
mesh_terms: D000818:Animals; D000843:Ankle Joint / Q000187:drug effects / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D024043:Collagen Type II; D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000235:genetics; D005260:Female; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000276:immunology; D007596:Joints / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008662:Metacarpophalangeal Joint / Q000187:drug effects / Q000473:pathology; D008683:Metatarsophalangeal Joint / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D024043:Collagen Type II; D024243:HMGB1 Protein; D053633:Receptor, Interferon alpha-beta; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II