title: Low immunogenicity of tocilizumab in patients with rheumatoid arthritis.
abstract: OBJECTIVE
  Subcutaneous (SC) and intravenous formulations of tocilizumab (TCZ) are available for the treatment of patients with rheumatoid arthritis (RA), based on the efficacy and safety observed in clinical trials. Anti-TCZ antibody development and its impact on safety and efficacy were evaluated in adult patients with RA treated with intravenous TCZ (TCZ-IV) or TCZ-SC as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).
  
  
  METHODS
  Data from 5 TCZ-SC and 8 TCZ-IV phase III clinical trials and 1 TCZ-IV clinical pharmacology safety study (>50 000 samples) were pooled to assess the immunogenicity profile of TCZ-SC and TCZ-IV (8974 total patients). The analysis included antidrug antibody (ADA) measurement following TCZ-SC or TCZ-IV treatment as monotherapy or in combination with csDMARDs, after dosing interruptions or in TCZ-washout samples, and the correlation of ADAs with clinical response, adverse events or pharmacokinetics (PK).
  
  
  RESULTS
  The proportion of patients who developed ADAs following TCZ-SC or TCZ-IV treatment was 1.5% and 1.2%, respectively. ADA development was also comparable between patients who received TCZ monotherapy and those who received concomitant csDMARDs (0.7-2.0%). ADA development did not correlate with PK or safety events, including anaphylaxis, hypersensitivity or injection-site reactions, and no patients who developed ADAs had loss of efficacy.
  
  
  CONCLUSIONS
  The immunogenicity risk of TCZ-SC and TCZ-IV treatment was low, either as monotherapy or in combination with csDMARDs. Anti-TCZ antibodies developed among the small proportion of patients had no evident impact on PK, efficacy or safety.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Free University and Humboldt University of Berlin, Berlin, Germany.
authors.forename: Gerd R
authors.initials: GR
authors.lastname: Burmester
authors.affiliation: Cardiff University, Cardiff, UK.
authors.forename: Ernest
authors.initials: E
authors.lastname: Choy
authors.affiliation: Altoona Center for Clinical Research, Duncansville, Pennsylvania, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Kivitz
authors.affiliation: Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan.|Division of Allergy, Rheumatology and Connective Tissue Diseases, Department of Internal Medicine, NTT West Osaka Hospital, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogata
authors.affiliation: Genentech, Inc., South San Francisco, California, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Bao
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nomura
authors.affiliation: Roche Products Limited, Welwyn Garden City, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Lacey
authors.affiliation: Genentech, Inc., South San Francisco, California, USA.
authors.forename: Jinglan
authors.initials: J
authors.lastname: Pei
authors.affiliation: Genentech, Inc., South San Francisco, California, USA.
authors.forename: William
authors.initials: W
authors.lastname: Reiss
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Attila
authors.initials: A
authors.lastname: Pethoe-Schramm
authors.affiliation: Roche Innovation Center, New York, New York, USA.
authors.forename: Navita L
authors.initials: NL
authors.lastname: Mallalieu
authors.affiliation: Genentech, Inc., South San Francisco, California, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wallace
authors.affiliation: Genentech, Inc., South San Francisco, California, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Michalska
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland.
authors.forename: Herbert
authors.initials: H
authors.lastname: Birnboeck
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Stubenrauch
authors.affiliation: Division of Immunology and Rheumatology, Stanford University Medical Center, Palo Alto, California, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
mesh_terms: D061605:Administration, Intravenous; D000707:Anaphylaxis / Q000139:chemically induced; D000906:Antibodies / Q000097:blood*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D017326:Clinical Trials, Phase III as Topic; D004342:Drug Hypersensitivity / Q000276:immunology*; D004359:Drug Therapy, Combination; D006801:Humans; D007279:Injections, Subcutaneous
chemical_list: D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab
keywords: Autoantibodies; DMARDs (biologic); Rheumatoid Arthritis