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Treatment of Psoriatic Arthritis with hOKT3γ(Ala-Ala): Psoriatic Arthritis Research Trial (PART)

Principal Investigator

Marcus Clark | University of Chicago | Chicago, IL

Locations

Chicago, IL

Study Code

ITN011AI

Study Status

Completed

Abstract

Psoriatic Arthritis (PsA) is a chronic inflammatory seronegative arthritis which occurs in approximately 6-7% of individuals with psoriasis. Up to 57% of PsA patients develop erosive disease after eight-year follow-up, and 19% have moderate to severe functional impairment. While methotrexate is the gold-standard treatment for PsA, many individuals ultimately fail methotrexate or are unable to tolerate its' long-term use.

Both psoriasis and PsA are associated with specific MHC Class I alleles. Analysis of synovial fluid from PsA patients reveals an increase in CD8+ T lymphocytes and cytokine expression in the synovium is consistent with a Th1-type response. Furthermore, autologous reconstitution of SCID mice transplanted with uninvolved skin from psoriasis patients with lymphocyte subsets indicates that both peripheral CD4+ and intradermal CD8+ cells are required to induce psoriasis. These observations indicate that therapeutic stategies which target Th1 cells may be efficacious in the treatment of psoriasis and the associated arthritis. Non-FcR binding anti-CD3 antibodies have been shown to preferentially anergize Th1 and stimulate Th2 lymphocytes. To repolarize peripheral T cells, repeated rounds of stimulations are usually required.

In a phase I/II trial, hOKT3γ(Ala-Ala) was given to eight patients with PsA who had failed at least one remittive agent. The monoclonal antibody was given as a daily infusion for up to 14 days with a variable escalation of dose to a maximum of 4 mg. Of the seven patients who completed the trial, six had dramatic improvement in their tender and swollen joint counts. Indeed, 5 of 6 had no swollen joints at 30 days. Symptoms from hOKT3γ(Ala-Ala) were mild when given as an escalating dose. Emesis and fevers occured in one patient receiving an initial maximum dose.

We now propose a phase II/III blinded placebo controlled trial to demonstrate the safety and efficacy of hOKT3γ(Ala-Ala) in the treatment of PsA. Based on previous mechanistic studies and clinical experience, we postulate that hOKT3γ(Ala-Ala) will induce remission in patients by selectively anergizing Th1 populations. We will recruit 112 patients failing Methotrexate at seven academic centers and administer either antibody with a rapid dose escalation or placebo daily for 5 days once every 4 weeks for 4 cycles total. Patients will be followed for one year.

Mechanistic Studies: To complement the clinical trial, we propose an extensive array of mechanistic studies to address several questions including:

  1. Does hOKT3γ(Ala-Ala) selectively induce the anergy of pathogenic Th1 cells in vivo?
  2. Are other changes in T cell populations induced by hOKT3γ(Ala-Ala)?
  3. Can specific gene products be identified which are either required for or predict angery?

The completion of the proposed investigations will determine the efficacy and in vivo immunomodulatory effects of a non-mitogenic anti-CD3 antibody in the treatment of a chronic T cell-mediated autoimmune disease. Preliminary evidence indicates that such treatment will preferentially induce anergy in Th1 populations leading to drug free remission in some patients.

[Clinicaltrials.gov]

Principal Investigator

Marcus Clark | University of Chicago | Chicago, IL

Locations

Chicago, IL

The Immune Tolerance Network and is sponsored by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

National Institute of Allergy and Infectious Diseases

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