Nonclinical safety, pharmacokinetics, and pharmacodynamics of atacicept.
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.
Carbonatto
Michela
M
Merck Serono (Istituto di Ricerche Biomediche "Antoine Marxer" RBM SpA)-10010 Colleretto Giacosa, Italy.
Yu
Ping
P
Bertolino
Mauro
M
Vigna
Enrico
E
Steidler
Stephanie
S
Fava
Laura
L
Daghero
Chiara
C
Roattino
Bruno
B
Onidi
Manuela
M
Ardizzone
Michele
M
Peano
Sergio
S
Visich
Jennifer
J
Janszen
Derek
D
Dillon
Stacey
S
Ponce
Rafael
R
D000818:Animals; D019540:Area Under Curve; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics* / Q000633:toxicity*; D012727:Sex Characteristics; D013154:Spleen / Q000187:drug effects / Q000473:pathology
D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011993:Recombinant Fusion Proteins; C524618:TACI receptor-IgG Fc fragment fusion protein