Tu106 - Agonistic Anti-dcir Monoclonal Antibody Inhibits Itam-mediated Inflammatory Signaling and Promotes Immune Resolution

Liang Chen – AbbVie; Suresh Patil – AbbVie; Jeffrey Barbon – AbbVie; James Waire – AbbVie; Stephen Laroux – AbbVie; Pratibha Mishra – AbbVie; Suju Zhong – AbbVie; Feng Dong – AbbVie; Geertruida Veldman – AbbVie; Susan Westmoreland – AbbVie; Liang Jin – AbbVie; Yu Tian – AbbVie; Arun Deora – AbbVie; Timothy Radstake – AbbVie; Kevin White – AbbVie; Hsi-Ju Wei – AbbVie

Abstract Text: Dendritic cell inhibitory receptor (DCIR) is a C-type lectin receptor selectively expressed on myeloid cells, including monocytes, macrophage, dendritic cells, and neutrophils. Its role in immune regulation has been implicated in murine models and human genome-wide association studies (GWAS), suggesting defective DCIR function associates with increased susceptibility to autoimmune diseases such as rheumatoid arthritis, lupus and Sjogren’s syndrome. However, little is known about the mechanisms underlying DCIR activation to dampen inflammation. Here, we developed anti-DCIR agonistic antibodies that promote phosphorylation on DCIR’s immune receptor tyrosine-based inhibitory motifs (ITIM) and recruitment of SH2 containing protein tyrosine phosphatase-2 (SHP2) for reducing inflammation. We also explored the inflammation resolution by depleting DCIR+ cells with antibodies. Utilizing a novel human DCIR knock-in mouse model, we validated the anti-inflammatory properties of the agonistic anti-DCIR antibody in experimental peritonitis and colitis. These findings provide critical evidence for targeting DCIR to develop transformative therapies for inflammatory diseases.