Experience with a chimeric monoclonal anti-CD4 antibody in the treatment of refractory rheumatoid arthritis

Academic Article

Abstract

  • We have used a chimeric monoclonal anti-CD4 antibody (cM-T412) in a phase I trial involving patients with refractory RA. The objectives of this initial study were to evaluate the safety, immunogenicity, and biologic effects of cM-T412. Twenty-five patients with active refractory RA (all taking methotrexate concomitantly) were treated with incremental doses (10 to 700 mg) of cM-T412 in an open-label, escalating dose phase I trial. Levels of circulating CD4+ T-cells decreased rapidly post-infusion and remained significantly depressed even at 18 months following treatment. Repopulation of CD4+ T cells consisting of increased CD45RA+ (naive) and CD45RO+ (memory) CD4+ T-cells was observed in approximately 1/3 of the patients between day 14 and 6 months post-infusion. Proliferative responses of peripheral blood lymphocytes to mitogens and recall antigens were generally diminished following cM-T412 infusion, with mitogen responses normalizing more rapidly than responses to recall antigens. Adverse events during the first 6 months of follow-up included fever, often associated with myalgias, malaise, and asymptomatic hypotension; these symptoms were self-limited and appeared to correlate with transient elevations of interleukin-6. Negligible human antibody responses to the cM-T412 variable region were observed; indeed, only 2 patients developed transient low levels of antibodies reactive with cM-T412. Non-blinded assessment indicated that 43% of patients exhibited ≥50% improvement in tender joint counts at 5 weeks, and 33% at 6 months post-infusion. Similar improvements were noted in the swollen joint counts, but no significant changes were observed in the Westergren erythrocyte sedimentation rate, grip strength, duration of morning stiffness, or pain scores. We conclude that cM-T412 treatment of refractory RA appears to be safe and is associated with sustained decreases in circulating CD4+ T cells, depressed in vitro T cell function, and minimal human anti-chimeric antibody responses. Based upon these results and the encouraging clinical improvements observed, a randomized double-blind placebo controlled trial has been recently conducted with cM-T412 in patients with refractory disease.
  • Author List

  • Moreland LW; Pratt PW; Sanders ME; Koopman WJ
  • Volume

  • 11
  • Issue

  • SUPPL. 8