Translation of BAFF Inhibition from Mouse to Non-human Primate and Human

Abstract

The identification of BAFF as a fundamental B cell survival factor in mouse and man, its over-expression in certain autoimmune disease patient populations , and the discovery of three cognate receptors, stimulated interest in understanding the role of BAFF in the pathogenesis of autoimmunity, and designing novel therapeutics to blunt B cell participation in disease pathogenesis via blockade of this pathway. Positive clinical trial results with B cell depletion have demonstrated beyond doubt the pathogenic B cell component in human rheumatoid arthritis [1, 2]. This current chapter focuses on data obtained in mice (both normal and disease models), non-human primates and human clinical trials with several large molecule inhibitors of the BAFF B cell survival pathway. The focus is on normal, non-diseased animals as well as rheumatology diseases and disease models although implications are clear for all other diseases with a B cell pathogenic component. Three strategies for blocking BAFF/receptor interactions have been used in mice and primates, 1) blocking antibodies directed specifically against BAFF, 2) receptor/ receptor fragment-Fc fusion proteins (receptor:Fc) to act as decoys, and 3) depleting mAb directed against BR3, the BAFF receptor responsible for transducing a survival signal and which is expressed on all mature B cells. The first two strategies target B cells indirectly by depriving them of a survival signal, while the third option utilizes an additional direct approach through antibody mediated cell killing. We described the experience with each of these types of molecules first in mice, then monkeys and human. Finally, we discuss the differences observed between species regarding in vivo blockade of this pathway and potential implications for human disease therapy.