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ToxSci Advance Access originally published online on June 2, 2008
Toxicological Sciences 2008 105(1):200-210; doi:10.1093/toxsci/kfn105
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Nonclinical Safety, Pharmacokinetics, and Pharmacodynamics of Atacicept

Michela Carbonatto*, Ping Yu*, Mauro Bertolino*, Enrico Vigna*, Stephanie Steidler*, Laura Fava*, Chiara Daghero*, Bruno Roattino*, Manuela Onidi*, Michele Ardizzone*, Sergio Peano*, Jennifer Visich{dagger}, Derek Janszen{dagger}, Stacey Dillon{dagger} and Rafael Ponce{dagger},1

* Merck Serono (Istituto di Ricerche Biomediche "Antoine Marxer" RBM SpA)—10010 Colleretto Giacosa, Italy {dagger} ZymoGenetics, Inc., Seattle, Washington 98102

1 To whom correspondence should be addressed at Preclinical Safety Assessment, ZymoGenetics, Inc., 1201 Eastlake Ave. E., Seattle, WA 98102. Fax: (206) 442-6608. E-mail: reap{at}zgi.com.

Received March 27, 2008; accepted May 18, 2008


  Abstract

Atacicept, a soluble recombinant fusion protein of the human immunoglobulin (Ig) G1 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 t1/2 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.

Key Words: autoimmune; toxicity; chronic; immunotoxicity; pharmaceuticals.


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