monoclonal antibody (mAb), 4162W94, in the peripheral blood (PB) and synovial ... Treatment with 10 and 30 mg of 4162W94 for 5 consecutive days resulted.
Rheumatology 2000;39:1139–1146
Pharmacokinetic, pharmacodynamic and clinical effects of a humanized IgG1 anti-CD4 monoclonal antibody in the peripheral blood and synovial fluid of rheumatoid arthritis patients E. H. S. Choy, D. J. A. Connolly, N. Rapson1, S. Jeal1, J. C. C. Brown1, G. H. Kingsley2, G. S. Panayi and J. M. Johnston Department of Rheumatology, Guy’s, King’s College and St Thomas Hospitals School of Medicine, King’s College London, 1Glaxo Wellcome Research and Development, Stevenage, 2Guy’s and Lewisham Hospitals, London, UK and 3Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina, USA Abstract Background. CD4+ T cells are important mediators in the pathogenesis of rheumatoid arthritis (RA). In this open-label, dose-escalating study, we examined the pharmacokinetic (PK ), clinical, biological and immunological effects of a humanized IgG1 anti-CD4 monoclonal antibody (mAb), 4162W94, in the peripheral blood (PB) and synovial fluid (SF ) of RA patients. Method. Twenty-four patients in four cohorts (six patients in each cohort) were allocated to be treated with five consecutive daily doses of 4162W94 (10, 30, 100 or 300 mg i.v.). Disease activity was measured by the American College of Rheumatology (ACR) criteria and disease activity score (DAS ). We also measured 4162W94 concentration, the percentage of 4162W94-coated CD4+ lymphocytes, percentage down-modulation of CD4, interleukin-6 (IL-6) and tumour necrosis factor a (TNFa) levels in the PB and SF. Results. A direct relationship between 4162W94 dose, biological response and clinical outcome was seen. Treatment with 10 and 30 mg of 4162W94 for 5 consecutive days resulted in transient coating and down-modulation of CD4+ lymphocytes, with little effect observed beyond the final dose. However, treatment with 100 and 300 mg resulted in sustained coating and/or down-modulation for 3 weeks and 4 weeks, respectively, in PB and >4 weeks in SF in one patient from the 300 mg cohort. There was a dose-related moderate but transient depression in the CD4+ lymphocyte count in most patients, with all but three returning to >0.40 × 109/l or >75% baseline by the end of the study period. Significant clinical improvement (ACR 20%) was seen in only 1/6 patients in each of the 10- and 30-mg cohorts; however, 3/6 and 5/5 patients in the 100 and 300-mg cohorts, respectively, were ACR 20% responders. In addition, there were significant reductions in PB acute phase reactants as well as SF IL-6 and TNFa concentrations in parallel to clinical improvement. Conclusion. Data from this pilot study suggest that 4162W94 is a clinically active novel immunotherapeutic agent that may suppress inflammation in RA. K : Rheumatoid arthritis, Anti-CD4, Monoclonal antibodies, Pharmacokinetics, Pharmacodynamics, Clinical response.
Rheumatoid arthritis (RA) is characterized by a cellmediated immune response and is associated with the human leucocyte antigens DRB1*0404 or *0401 [1]. Therefore, it has been hypothesized that RA results Submitted 2 February 2000; revised version accepted 15 May 2000. Correspondence to: E. Choy, Clinical and Academic Rheumatology, King’s College Hospitals (Dulwich), East Dulwich Grove, London SE22 8PT, UK.
from presentation of a yet unidentified arthritogenic peptide or peptides to CD4+ T cells [2]. These CD4+ T cells activate, through either direct cell-to-cell contact [3] or the release of lymphokines [4], the inflammatory cascade involving macrophages and synoviocytes, resulting in synovitis and joint damage. A major goal for the treatment of autoimmune diseases is the selective and permanent induction of immunological tolerance among pathogenic
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T lymphocytes using a relatively short course of treatment. Tolerance to protein antigens can be readily induced in mice by administering anti-CD4 monoclonal antibodies (mAbs) at the same time as antigen [5, 6 ]. Treated animals mount normal responses to other antigens but fail to respond to subsequent challenge with the tolerizing antigen for as long as continued injections of the tolerizing antigen are given. Subsequently, antiCD4 mAb-mediated immunological tolerance has been demonstrated in animal models of autoimmune disease [7–10]. Rats treated prophylactically with antiCD4 mAb and then immunized with streptococcal cell walls not only failed to develop arthritis but were also resistant to further attempts to induce arthritis [8]. This tolerance to arthritis development did not require additional anti-CD4 mAb treatment and occurred at a time when antibodies could no longer be detected in the circulation. Furthermore, anti-CD4-mediated immunological tolerance can be induced even in models of established autoimmune disease, including diabetes [9] and established collagen-induced arthritis [10]. Clearly, if similar tolerance could be induced in established RA by anti-CD4 mAb, such a therapy would lead to prolonged disease remission, obviating the need for continuous, expensive and potentially toxic therapy. Several murine and chimaeric depleting antiCD4 mAbs have been studied in RA [11–13]. When the chimaeric depleting anti-CD4 mAb cM-T412 was used clinically, it caused profound and extended dosedependent CD4 lymphopenia [14–16 ]. Pharmacokinetic (PK ) and pharmacodynamic (PD) studies showed that the concentration of cM-T412 and the percentage of antibody-coated CD4 lymphocytes in the synovial fluid (SF ) were much lower than in the corresponding peripheral blood (PB) [17]. Interestingly, the percentage of cM-T412-coated lymphocytes in the SF, but not the PB, correlated with clinical improvement. Unfortunately, the dose of cM-T412 required to achieve a consistently high concentration in the joint will inevitably lead to unacceptably profound CD4 lymphopenia. Hence, the strategy of using depleting anti-CD4 mAb has been abandoned. This problem may be circumvented by using non-depleting immunomodulatory anti-CD4 mAbs. The correlation of cM-T412 SF PD effect and clinical outcome, as well as the finding that tolerance induction may require the persistence of antibody in the circulation for a prolonged period [6 ], emphasizes the importance of PK and PD studies in the early clinical development of anti-CD4 mAbs. Likewise, data on anti-tumour necrosis factor a ( TNFa) mAbs in RA patients have shown that the plasma antibody concentration correlates with the duration of clinical response [18]. However, as the PK of mAbs is affected by the intrinsic properties of both the antibody, such as the Fc, and those of the target antigen, generalization to the behaviour of new mAbs is not possible. In this open-label, doseescalating study, we examined the PK and PD of a humanized IgG1 anti-CD4 mAb, 4162W94 (Glaxo Wellcome), in patients with RA. We measured the biological and immunological effects in the PB and SF
to assess whether it was possible to deliver significant antibody into the synovial joint and inhibit local inflammation, with the ultimate goal of inducing SF T-cell tolerance.
Methods Patients Patients satisfying the 1987 American College of Rheumatology (ACR) diagnostic criteria for RA [19] were recruited from out-patient clinics at King’s College and Lewisham Hospitals. Patients had to have failed at least one standard disease-modifying anti-rheumatic drug (DMARD) and had to have clinically active disease as defined by the presence of at least three of the following: >3 swollen joints, >6 painful or tender joints, morning stiffness lasting >45 min and erythrocyte sedimentation rate ( ESR) >29 mm/h. Pregnant women, nursing women, and women of childbearing potential not using an effective method of contraception were excluded. Patients were also excluded if they had previous mAb therapy, CD4 lymphocyte count
