Experience with a chimeric monoclonal anti-CD4 antibody in the treatment of refractory rheumatoid arthritis.
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 > or = 50% improvement in tender joint counts at 5 weeks, and 33% at 6 months post-infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Moreland
L W
LW
Department of Medicine, University of Alabama, Birmingham 35294-0012.
Pratt
P W
PW
Sanders
M E
ME
Koopman
W J
WJ
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology / Q000628:therapy*; D015704:CD4 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D012449:Safety
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D011993:Recombinant Fusion Proteins