Open AccessAnti‐ BDCA 2 monoclonal antibody inhibits plasmacytoid dendritic cell activation through Fc‐dependent and Fc‐independent mechanisms
Author(s) -
Pellerin Alex,
Otero Karel,
Czerkowicz Julie M,
Kerns Hannah M,
Shapiro Renée I,
Ranger Ann M,
Otipoby Kevin L,
Taylor Frederick R,
Cameron Thomas O,
Viney Joanne L,
Rabah Dania
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404719
Subject(s) - monoclonal antibody , chemistry , dendritic cell , antibody , plasmacytoid dendritic cell , immunology , microbiology and biotechnology , antigen , biology
Type I interferons ( IFN ‐I) are implicated in the pathogenesis of systemic lupus erythematosus ( SLE ). In SLE , immune complexes bind to the CD 32a (Fcγ RII a) receptor on the surface of plasmacytoid dendritic cells ( pDC s) and stimulate the secretion of IFN ‐I from pDC s. BDCA 2 is a pDC ‐specific receptor that, when engaged, inhibits the production of IFN ‐I in human pDC s. BDCA 2 engagement, therefore, represents an attractive therapeutic target for inhibiting pDC ‐derived IFN ‐I and may be an effective therapy for the treatment of SLE . In this study, we show that 24F4A, a humanized monoclonal antibody ( mA b) against BDCA 2, engages BDCA 2 and leads to its internalization and the consequent inhibition of TLR ‐induced IFN ‐I by pDC s in vitro using blood from both healthy and SLE donors. These effects were confirmed in vivo using a single injection of 24F4A in cynomolgus monkeys. 24F4A also inhibited pDC activation by SLE ‐associated immune complexes ( IC ). In addition to the inhibitory effect of 24F4A through engagement of BDCA 2, the Fc region of 24F4A was critical for potent inhibition of IC ‐induced IFN ‐I production through internalization of CD 32a. This study highlights the novel therapeutic potential of an effector‐competent anti‐ BDCA 2 mA b that demonstrates a dual mechanism to dampen pDC responses for enhanced clinical efficacy in SLE.