Chimeric mAbs may be substituted for their murine equivalents when used in therapy to minimize the immune response directed against species-specific antigenic determinants. Open-labeled and placebo-controlled trials of the mouse/human chimeric CD4 mAb, cM-T412, were conducted in patients with rheumatoid arthritis refractory to treatment with disease-modifying anti-rheumatic drugs. The treatment was safe and well-tolerated. Doses above 10 mg caused an immediate depletion of 50–70% of circulating CD4+lymphocytes lasting longer than was observed in trials using the murine parental antibody and possibly due to enhanced mediation of ADCC by the chimeric mAb. Depletion of circulating CD4+cells did not correlate with clinical efficacy. Despite the depletion of CD4+cells, cM-T412 therapy did not increase the incidence of opportunistic infection. Patients remained immunocompetent and 20–40% mounted an anti-chimeric antibody response. Infusion-related adverse events included fever, chills, nausea, headache, and transient hypotension. These symptoms generally correlated with an increase in serum levels of IL-6. In nonblinded studies, cM-T412 significantly decreased swollen joints in 57% of patients in one trial and reduced Ritchie articular index by ≥20% in 67% of patients in a second trial. Results of double-blind studies were mixed; some showed no significant improvement in the clinical parameters measured. The exception was a controlled trial in which patients received five consecutive 50-mg doses. This regimen resulted in high serum levels of free cM-T412 leading to the coating and depletion of synovial as well as peripheral CD4+cells. Positive correlation was observed between clinical efficacy and the proportion of cM-T412-coated synovial CD4+cells, in contrast with the lack of correlation between clinical efficacy and depletion of circulating CD4+lymphocytes.[ep [rs