tailieunhanh - Báo cáo hóa học: " Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys'

Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys | Vugmeyster et al. Journal of Translational Medicine 2010 8 41 http content 8 1 41 RESEARCH JOURNAL OF TRANSLATIONAL MEDICINE Open Access Correlation of pharmacodynamic activity pharmacokinetics and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys Yulia Vugmeyster Scott Allen Pamela Szklut Andrea Bree Mark Ryan Margery Ma Vikki Spaulding Deborah Young Heath Guay Laird Bloom Michael W Leach Margot O Toole and Karissa Adkins Abstract Background Anti-IL-21R antibodies are potential therapeutics for the treatment of autoimmune diseases. This study evaluated correlations between the pharmacodynamic PD activity pharmacokinetics and anti-product antibody responses of human anti-IL-21 R antibodies Ab-01 and Ab-02 following IV administration to cynomolgus monkeys. Methods The PD assay was based on the ability of recombinant human IL-21 rhuIL-21 to induce expression of the IL-2RA gene in cynomolgus monkey whole blood samples ex vivo. Monkeys screened for responsiveness to rhuIL-21 stimulation using the PD assay were given a single 10 mg kg IV dosage of Ab-01 Ab-02 or a control antibody 3 group and blood samples were evaluated for PD activity inhibition of IL-2RA expression for up to 148 days. Anti-IL-21R antibody concentrations and anti-product antibody responses were measured in serum using immunoassays and flow cytometry. Results Following IV administration of Ab-01 and Ab-02 to cynomolgus monkeys PD activity was observed as early as 5 minutes first time point sampled . This PD activity had good correlation with the serum concentrations and antiproduct antibody responses throughout the study. The mean terminal half-life t1 2 was and days for Ab-01 and Ab-02 respectively. PD activity was lost at 5-13 weeks for Ab-01 and at 2 weeks for Ab-02 when serum concentrations were relatively low. The estimated minimum concentrations needed to maintain PD activity were 4-6 nM .