Two doses of humanized anti-CD25 antibody in renal transplantation: a preliminary comparative study

Abstract

HuCD25mAb is a humanized anti-CD25 antibody which has the same amino acid sequence as daclizumab (Zenapax, Roche). HuCD25mAb is expressed in Chinese hamster ovary (CHO) cells while daclizumab is expressed in the NSO myeloma cell line. A comparative study was performed to evaluate the pharmacokinetics and pharmacodynamics between huCD25mAb and daclizumab in a two-dose regimen incorporating triple immunosuppressant treatment regimens (MMF, CsA and steroids). Fifteen patients were enrolled and randomized to receive intravenous infusion of either huCD25mAb (n = 10) or daclizumab (n = 5) at a dosage of 1 mg.kg(-1) on operation day 0 and post-operation day 14. Serum concentrations of huCD25mAb and daclizumab were measured by a validated competitive ELISA. Subgroups of CD3(+), CD25(+), CD4(+) and CD8(+) lymphocytes were monitored periodically by flow cytometry. The concentration-time curves of huCD25mAb and daclizumab were found to fit well to a one-compartment model. A significant decline of proportion (%) of CD3-CD25(+) and CD3(+)CD25(+) lymphocytes was observed 30 min after first infusion on day 0 (3.40 +/- 1.83 to 0.03 +/- 0.07, 3.35 +/- 2.02 to 0.37 +/- 0.49), and these levels remained low for at least 70 days (0.03 +/- 0.05, 0.31 +/- 0.47). All pharmacokinetic parameters of huCD25mAb seemed similar to those of daclizumab. The two-dose huCD25mAb regimen was as effective as daclizumab in rapidly achieving high therapeutic concentration in the treated patients, and a significant decrease of CD3(-)CD25(+) and CD3(+)CD25(+) lymphocytes was demonstrated. This suggests that two-dose regimen is feasible in maintaining host immunosuppression and may provide an effective and economical strategy for reducing incidence of acute graft rejection.

Keywords: CD25; enzyme immunoassay; flow cytometry; kidney transplantation; monoclonal antibody; pharmacokinetics.

Figure 1

Concentration-time curves of huCD25mAb and daclizumab after a two-dose regimen of intravenous administration in kidney transplantation recipients. ○, huCD25mAb group (n = 9); ■, daclizumab group (n = 4).

Figure 2

Mean CD3⁻CD25⁺ T-cell proportion (%) measured by flow cytometry. ○, huCD25mAb group (n = 9); ■, daclizumab group (n = 4).

Figure 3

Mean CD3⁺ CD25⁺ T cell proportion (%) measured by flow cytometry. ○, huCD25mAb group (n = 9); ■, daclizumab group (n = 4).

Figure 4

The concentration-effect plots display the coherence between huCD25mAb serum concentration and CD25⁺ cell proportion (%) (A). huCD25mAb concentration of about 5 mg·L⁻¹ is to be the cutoff point of significant drop in CD3⁻CD25⁺ and CD3⁺CD25⁺ cells and less than 1 mg·L⁻¹ is to keep saturation for up to 70 days (B). ■, huCD25mAb serum concentration (mg·L⁻¹); ○, CD3⁻CD25⁺ proportion(%); ▴, CD3⁺CD25⁺ proportion(%).