Abstract
Type I interferons (IFN-I) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). In SLE, immune complexes bind to the CD32a (FcγRIIa) receptor on the surface of plasmacytoid dendritic cells (pDCs) and stimulate the secretion of IFN-I from pDCs. BDCA2 is a pDC-specific receptor that, when engaged, inhibits the production of IFN-I in human pDCs. BDCA2 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 (mAb) against BDCA2, engages BDCA2 and leads to its internalization and the consequent inhibition of TLR-induced IFN-I by pDCs 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 BDCA2, the Fc region of 24F4A was critical for potent inhibition of IC-induced IFN-I production through internalization of CD32a. This study highlights the novel therapeutic potential of an effector-competent anti-BDCA2 mAb that demonstrates a dual mechanism to dampen pDC responses for enhanced clinical efficacy in SLE.
Highlights
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that can affect multiple organs
There was no significant change in the frequency of circulating plasmacytoid dendritic cells (pDCs) after 24F4A administration (Supplementary Fig S6). These results demonstrate for the first time that administration of single dose of anti-Blood dendritic cell antigen 2 (BDCA2) monoclonal antibody (mAb) in cynomolgus monkeys causes rapid internalization of BDCA2 and a significant reduction in TLR9-induced IFN-I production in ex vivo whole-blood assays
We report the generation of an anti-BDCA2 mAb, 24F4A, that can potently inhibit TLR7 and TLR9-induced IFN-I in human pDCs from healthy and SLE patients, as has been shown with a previously described anti-BDCA2 mAb (Dzionek et al, 2001; Blomberg et al, 2003; Fanning et al, 2006; Cao et al, 2007; Rock et al, 2007)
Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that can affect multiple organs. SLE is a multifactorial disease, increasing evidence indicates that type I interferon (IFN-I) plays a pivotal role in the disease pathogenesis (Crow, 2010); (Elkon & Wiedeman, 2012). While most cells can produce IFN-I in response to nucleic acids, plasmacytoid dendritic cells (pDCs) are considered the major producers of IFN-I (Liu, 2005). PDCs accumulate in skin lesions of SLE patients as well as in other target organs and have been suggested to be a major source of IFN-I in SLE (Blomberg et al, 2001; Farkas et al, 2001; Tucci et al, 2008; Tomasini et al, 2010; Ghoreishi et al, 2012). Direct evidence of the critical role of pDCs in SLE pathogenesis has been recently obtained from animal models of SLE in which pDCs were depleted or inactivated (Rowland et al, 2014)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
