Nonclinical Safety, Pharmacokinetics, and Pharmacodynamics of Atacicept

Abstract

Atacicept, a soluble recombinant fusion protein of the human immunoglobulin (Ig) G(1) Fc and the extracellular domain of the human transmembrane activator and calcium modulator and cyclophylin ligand interactor receptor, acts as an antagonist of both B lymphocyte stimulator and a proliferating-inducing ligand. Here we determined the nonclinical safety, pharmacokinetics and pharmacodynamics of atacicept in mice and cynomolgus monkeys. Subcutaneous atacicept treatment (twice weekly in cynomolgus monkeys, three times weekly in mice) was generally safe and well tolerated safe and well tolerated with dosing up to 10 mg/kg every other day for up to 39 weeks or up to 80 mg/kg when dosed for 4 weeks. At a dose of 1 mg/kg subcutaneous (sc) bioavailability of atacicept in mice and monkeys was 76 and 92%, with a mean serum t(1/2) of 44 and 179 h, respectively. In accord with its anticipated mechanism of action, repeated administration of atacicept decreased serum IgG concentrations up to 50%, IgM concentrations >99%, and circulating mature B-cell concentrations up to 60%. These effects were dose-related but reversible, as determined in a 25-week follow-up period. Microscopically, B cells numbers were reduced in the follicular marginal zone of the spleen and the mantle surrounding germinal centers of the lymph nodes. These data confirm the preclinical safety and the pharmacological activity of atacicept and support its clinical development.

BAFF Suppresses IL-15 Expression in B Cells

“…2A) mice. These data showed a strong correlation with previous studies suggesting that belimumab and TACI-IgG effectively reduce the number of circulating mature B cells but not memory B cells (10,11).…”

“…2D) were decreased in lupus-like mice. Previous studies have shown that TACI-IgG does not reduce memory B cells (10,11). However, there is no marker for memory B cells in mice (12).…”

“…Atacicept (TACI)-IgG shows similar clinical results to belimumab by binding a portion of the receptor TACI to block the effects of survival factors BAFF and a proliferating-inducing ligand (APRIL). It reduces levels of circulating mature B cells and plasma cells in the spleen and bone marrow as well as inhibiting T cell activation, but not memory B cells (10,11). As long as the reactive memory is maintained, it is probably acceptable that in principle humoral immunological response can be restored from immunological memory (12).…”

Ligation of metabotropic glutamate receptor 3 (Grm3) ameliorates lupus-like disease by reducing B cells

“…We and other researchers have shown that similar to belimumab, another BAFF inhibitor, atacicept (TACI-IgG), leads to some degree of B cell depletion, with the effect of atacicept being more rapid than that of belimumab [6,25,32]. To expand upon this, we isolated B cells from TACI-IgG-treated mice with lupus-like disease and used Affymetrix microarrays to detect overall changes in gene expression in these cells.…”

B cell activating factor (BAFF) induces the transcription of recombination-activating genes in transitional stage 1 B cells

“…It reduces circulating mature B-cell and plasma cell levels in the spleen and bone marrow, inhibits T-cell activation [15]. The EAE model on the background of C57BL/6 mice was induced with MOG33-55 in CFA and then treated with TACI-IgG described in Materials and methods.…”