Pharmacokinetics and immunological effects of exogenously administered recombinant human B lymphocyte stimulator (BLyS) in mice

B lymphocyte stimulator (BLyS; also known as TNFSF20, BAFF, TALL-1, zTNF4, and THANK), a tumor necrosis factor ligand family member, has recently been identified as a factor that promotes expansion and differentiation of the B cell population, leading to increases in serum immunoglobulin levels. Her e, pharmacokinetic parameters for BLyS administered i.v. and s.c. to mice a re described, and the effects of different dosing regimens on serum and sal ivary immunoglobulin levels as well as splenic cell populations are reporte d. The pharmacokinetics of BLyS following i.v. injection are monophasic wit h a half-life of 160 min, a clearance of 0.22 ml/min-kg, and a volume of di stribution of 53 ml/kg. Systemic administration of BLyS to mice resulted in increased serum IgG, IgA, IgM, and IgE and salivary IgA as well as splenic B cell population expansion and differentiation. The i.v. and s.c. routes of administration were pharmacologically equivalent, even though s.c. bioav ailability of BLyS is only 25%. BLyS (s.c.) dramatically elevated serum IgG and IgA levels, and the duration of the responses after cessation of treat ment (t(1/2) = 4.4 and 1.3 days, respectively) are similar to the half-live s of endogenous IgG and IgA in mice. The IgM response is more modest than t hat of IgG and IgA but lasts longer (t(1/2) = 7.0 days) than the half-life of endogenous IgM. A linear pharmacodynamic response was identified between days of dosing x log(dose), and increases in serum IgG, IgA, and IgM indic ating that the response is more sensitive to the duration of dosing than to the cumulative dose. The implications of these findings for therapeutic ad ministration of BLyS are discussed.