Allele and antigen-specific treatment of rheumatoid arthritis: A double blind, placebo controlled phase trial

Arthur Kavanaugh, Mark Genovese, Jan Baughman, Alan Kivitz, Ken Bulpitt, Nancy Olsen, Michael Weisman, Eric Matteson, Daniel Furst, Ronald Van Vollenhoven, James Anderson, Stanley Cohen, Nathan Wei, Jan Meijerink, Cindy Jacobs, Simonetta Mocci

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 (β*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 μg/kg was escalated in subsequent cohorts to a maximum of 150 μg/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. Conclusion. 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.

Original languageEnglish (US)
Pages (from-to)449-454
Number of pages6
JournalJournal of Rheumatology
Volume30
Issue number3
StatePublished - Mar 1 2003

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Rheumatoid Arthritis
Alleles
Placebos
Antigens
HLA-DR4 Antigen
Therapeutics
Safety
Antibodies
Histocompatibility Antigens Class II
Autoantigens
HLA-DR Antigens
CD4 Lymphocyte Count
Major Histocompatibility Complex
Methotrexate
Half-Life
Pharmacokinetics
Cell Count
T-Lymphocytes
Peptides
Injections

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Immunology and Allergy
  • Immunology

Cite this

Kavanaugh, A., Genovese, M., Baughman, J., Kivitz, A., Bulpitt, K., Olsen, N., ... Mocci, S. (2003). Allele and antigen-specific treatment of rheumatoid arthritis: A double blind, placebo controlled phase trial. Journal of Rheumatology, 30(3), 449-454.
Kavanaugh, Arthur ; Genovese, Mark ; Baughman, Jan ; Kivitz, Alan ; Bulpitt, Ken ; Olsen, Nancy ; Weisman, Michael ; Matteson, Eric ; Furst, Daniel ; Van Vollenhoven, Ronald ; Anderson, James ; Cohen, Stanley ; Wei, Nathan ; Meijerink, Jan ; Jacobs, Cindy ; Mocci, Simonetta. / Allele and antigen-specific treatment of rheumatoid arthritis : A double blind, placebo controlled phase trial. In: Journal of Rheumatology. 2003 ; Vol. 30, No. 3. pp. 449-454.
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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 (β*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 μg/kg was escalated in subsequent cohorts to a maximum of 150 μg/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. Conclusion. 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.",
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Kavanaugh, A, Genovese, M, Baughman, J, Kivitz, A, Bulpitt, K, Olsen, N, Weisman, M, Matteson, E, Furst, D, Van Vollenhoven, R, Anderson, J, Cohen, S, Wei, N, Meijerink, J, Jacobs, C & Mocci, S 2003, 'Allele and antigen-specific treatment of rheumatoid arthritis: A double blind, placebo controlled phase trial', Journal of Rheumatology, vol. 30, no. 3, pp. 449-454.

Allele and antigen-specific treatment of rheumatoid arthritis : A double blind, placebo controlled phase trial. / Kavanaugh, Arthur; Genovese, Mark; Baughman, Jan; Kivitz, Alan; Bulpitt, Ken; Olsen, Nancy; Weisman, Michael; Matteson, Eric; Furst, Daniel; Van Vollenhoven, Ronald; Anderson, James; Cohen, Stanley; Wei, Nathan; Meijerink, Jan; Jacobs, Cindy; Mocci, Simonetta.

In: Journal of Rheumatology, Vol. 30, No. 3, 01.03.2003, p. 449-454.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Allele and antigen-specific treatment of rheumatoid arthritis

T2 - A double blind, placebo controlled phase trial

AU - Kavanaugh, Arthur

AU - Genovese, Mark

AU - Baughman, Jan

AU - Kivitz, Alan

AU - Bulpitt, Ken

AU - Olsen, Nancy

AU - Weisman, Michael

AU - Matteson, Eric

AU - Furst, Daniel

AU - Van Vollenhoven, Ronald

AU - Anderson, James

AU - Cohen, Stanley

AU - Wei, Nathan

AU - Meijerink, Jan

AU - Jacobs, Cindy

AU - Mocci, Simonetta

PY - 2003/3/1

Y1 - 2003/3/1

N2 - 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 (β*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 μg/kg was escalated in subsequent cohorts to a maximum of 150 μg/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. Conclusion. 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.

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