Phase I Trial Of Wutac, A Murine Anti-cd25 Monoclonal Antibody, Tolerance And Pharmacokinetics Of Multiple Doses In Renal Transplant Patients

Objective WuTac is a murine monoclonal antibody against CD25 antigen, The CD25 also named interleukin 2 [alpha] chain receptor (Tac) which exists on the surface of activated human T lymphocytes. This anti-CD25 monoclonal antibody is manufactured by Wuhan Institute of Biologic Products in China. This study examined the safety and tolerance, pharmacokinetics, and pharmacodynamics multiple doses of WuTac injection in renal transplant patients. The range of safety dose is provided in this study for phaseⅡclinical trial of WuTac. Methods The 18 recipients of living related transplants were matched for this study, recipients were divided 0.1 mg/kg dose(n=8) and 0.2 mg/kg dose(n=10). Triple combined immunesuppressive protocols consisted of cyclosporine A (CsA), mycophenolate mofetil (MMF) and prednisone. The first infusion of WuTac (0.1 mg·kg^-1 or 0.2 mg·kg^-1) was administered on day 0 approximately 2 hours before transplantation and received infusion once-daily for 7 days after transplantation. All patients were monitored until day 40 by serial laboratory tests, clinical examinations, and recording of adverse events. Flow cytometry enumeration of lymphocyte subsets bearing the surface markers CD3, CD4, CD8, CD16CD56, CD19, CD25. Double-antibody-sandwich ELISA was used to quantitate WuTac in serum. Parameters of pharmacokinetics were calculated by software DAS 2.0(Drug and Statistics Software), the law of HAMA in renal transplant recipients is explained by indirect ELISA. All data are inputted and analysised by EpiData 3.1, SPSS 15.0,α=0.05,graphics were done using Origin Pro 8.0 program. Results The clinical trial was successfully performed in 17 of the 18 renal transplant recipients, all participants in two doses didn't have acute rejection in the observation period. 8 participants in 0.1 mg/kg dose recovered successfully. 10 renal transplant recipients participated in the trial of 0.2 mg/kg dose, participants GZ06 in 0.2 mg/kg dose quited from this study because serum creatinine increasing, so 9 participants accomplished trial, one case of 0.2 mg/kg dose suffered delayed renal graft function, one case occurred serum creatinine increasing, pneumonia developed in another case, the weight of those three cases and the patient who quited this program all exceeded 50 kg, the daily dose is greater than 10 mg, others participants in 0.2 mg/kg dose recovered smoothly. First-dose reaction and cytokine release syndrome were not observed in all participants, the incidence of adverse reactions was not statistically different in the two doses in 40 days after renal transplantation. Parameters of pharmacokinetics: t1/2, tmax, Vd, CL, AUCss/D, AUC0-t/D, AUC0-∞/D are no significant difference between two doses (P>0.05), except Cmax/D (P<0.05). Enzyme-linked immunosorbent assay (ELISA) of WuTac indicate that circulating through blood level exceed effective concentration (1000μg·L^-1) and peaked at day 7 after renal transplantation. T cell (CD3+CD19-), Th cell (CD3+CD4+), CTL(CD3+CD8+), B cell(CD3-CD19+), NK cell(CD3-CD16+CD56+) was not statistically different between preoperative and postoperative in the two doses(P>0.05), except CD25+ lymphocyte cell decreased significantly after the first dose in the patients who received WuTac, the level of the cells that expressed CD25 was significantly decreased about 10 to 14 days and 14 to 21 days in the two doses after transplantation. Both doses with one patient developed HAMA after transplantation. Conclusion The maximum dose of WuTac is 0.2 mg·kg^-1·d^-1 and daily dose is not more than 10 mg. The biological tolerance of WuTac is well tolerated and safety by participants in recommended safe and tolerable dose. WuTac distribute in the blood plasma in the body. Complete and consistent binding to IL-2Rαin adults is maintained as long as serum WuTac levels exceed 1000μg·L^-1. As concentrations fall below this threshold, the IL-2Rαsites are no longer fully bound and the number of T-cells expressing unbound IL-2Rαreturns to pretherapy values within 1-2 weeks. Fewer of HAMA in renal transplant recipients did not influence curative effect of WuTac.