Details

Autor(en) / Beteiligte

• 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

Titel

Anti‐BDCA2 monoclonal antibody inhibits plasmacytoid dendritic cell activation through Fc‐dependent and Fc‐independent mechanisms

Ist Teil von

• EMBO molecular medicine, 2015-04, Vol.7 (4), p.464-476

Ort / Verlag

England: BlackWell Publishing Ltd

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Wiley Online Library All Journals

Beschreibungen/Notizen

• 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. Synopsis This study describes a novel therapeutic approach to dampen pDC responses whereby an anti‐BDCA2 mAb, 24F4A, internalizes BDCA2 and inhibits TLR7 and TLR9‐induced type I IFN while simultaneously down‐modulating CD32a through the Fc region, from the surface of pDCs. pDC derived type I IFN is thought to play an important role in the pathogenicity of systemic lupus erythematous (SLE). Blood Dendritic Cell Antigen (BDCA2) is a receptor that is specifically expressed on human and non‐human primates pDCs that inhibits TLR7 and TLR9‐mediated type I IFN. In vitro experiments indicate that BDCA2 is rapidly internalized and internalization correlates with type I IFN inhibition. 24F4A administration leads to BDCA2 internalization in vivo and dampens TLR9‐mediated type I IFN without depleting pDCs in cynomolgus monkeys. 24F4A inhibits type I IFN from immune complex‐stimulated pDCs through BDCA2 ligation as well as Fc‐dependent down‐modulation of CD32a. This study describes a novel therapeutic approach to dampen pDC responses whereby an anti‐BDCA2 mAb, 24F4A, internalizes BDCA2 and inhibits TLR7 and TLR9‐induced type I IFN while simultaneously down‐modulating CD32a through the Fc region, from the surface of pDCs.