title: Allele and antigen-specific treatment of rheumatoid arthritis: a double blind, placebo controlled phase 1 trial.
abstract: OBJECTIVE
  Human cartilage glycoprotein 39 (HC gp-39) appears to be a relevant autoantigen in patients with rheumatoid arthritis (RA). Administration of major histocompatibility complex (MHC) Class II complexed antigens without requisite costimulatory signals can induce immunologic tolerance. We evaluated the safety, pharmacokinetics, and preliminary efficacy of AG4263 in patients with RA. AG4263 is a soluble complex of native HLA-DR4 (beta*0401) complexed to Org 36601, a 13-mer peptide derived from HC gp-39 (also referred to as CDP263).
  
  
  METHODS
  Thirty-one HLA-DRB1*0401 positive patients with persistent RA disease activity despite concurrent methotrexate were randomized to 7 infusions of AG4263 (n = 24) or placebo (n = 7) over 6 weeks. The initial dose of 0.5 micro g/kg was escalated in subsequent cohorts to a maximum of 150 micro g/kg. Safety analyses included recording of adverse events and measurement of CD4/CD8 counts, reactivity to recall antigens, and development of antibodies to HLA-DR4. Efficacy was assessed using the Paulus 20 criteria.
  
  
  RESULTS
  Treatment was well tolerated, with injection site reaction the most common adverse event. There was no loss of reactivity to recall antigens, change in cell counts, or antibodies to HLA-DR. The mean half-life of AG4263 was 12.5 h. Some evidence of clinical response was seen; responses were more common among patients receiving the highest doses of AG4263 and among those with baseline T cell reactivity to CDP263.
  
  
  CONCLUSIONS
  AG4263 was safe, well tolerated, and without evidence of generalized immune suppression. Along with the observed trend toward clinical efficacy, the results suggest that this therapeutic approach warrants further investigation in patients with RA.
authors.affiliation: Division of Rheumatology, Allergy and Immunology, University of California, San Diego, San Diego, CA 92037-0943, USA. akavanaugh@ucsd.edu
authors.forename: Arthur
authors.initials: A
authors.lastname: Kavanaugh
authors.forename: Mark
authors.initials: M
authors.lastname: Genovese
authors.forename: Jan
authors.initials: J
authors.lastname: Baughman
authors.forename: Alan
authors.initials: A
authors.lastname: Kivitz
authors.forename: Ken
authors.initials: K
authors.lastname: Bulpitt
authors.forename: Nancy
authors.initials: N
authors.lastname: Olsen
authors.forename: Michael
authors.initials: M
authors.lastname: Weisman
authors.forename: Eric
authors.initials: E
authors.lastname: Matteson
authors.forename: Daniel
authors.initials: D
authors.lastname: Furst
authors.forename: Ronald
authors.initials: R
authors.lastname: van Vollenhoven
authors.forename: James
authors.initials: J
authors.lastname: Anderson
authors.forename: Stanley
authors.initials: S
authors.lastname: Cohen
authors.forename: Nathan
authors.initials: N
authors.lastname: Wei
authors.forename: Jan
authors.initials: J
authors.lastname: Meijerink
authors.forename: Cindy
authors.initials: C
authors.lastname: Jacobs
authors.forename: Simonetta
authors.initials: S
authors.lastname: Mocci
mesh_terms: D000368:Aged; D000483:Alleles; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D004311:Double-Blind Method; D015804:HLA-DR4 Antigen / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D010919:Placebos; D011379:Prognosis; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D001324:Autoantigens; D015804:HLA-DR4 Antigen; D010919:Placebos; D011948:Receptors, Antigen, T-Cell