CD303, also known as BDCA2, DLEC, or CLEC4C, is a unique type II C-type lectin receptor (CLR) found on human plasmacytoid dendritic cells (pDCs). It assists TLR-7/9 in recognizing microorganisms and coordinating inflammatory immune responses. BDCA2 influences immune responses in pDCs by inhibiting interferon production, thereby regulating immune system function. It is a potential therapeutic target for systemic lupus erythematosus (SLE).

Expression distribution of CD303

CD303 is primarily expressed on plasmacytoid dendritic cells (pDCs). It is constitutively expressed on immature monocyte-derived dendritic cells (iMDDCs) and is significantly downregulated upon maturation in response to LPS but not TNF -α.

(Data source: Uniprot)

The structure of CD303 and its receptor

CD303 is a type II transmembrane protein composed of 213 amino acids with an extracellular C-terminal domain containing a carbohydrate recognition domain (CRD) and a short intracellular tail and transmembrane domain. Crystallographic analysis of the BDCA-2 CRD core domain revealed that its basic structure is consistent with that of a typical CLR composed of two α-helices and five β-sheets. Unlike the CRDs of other CLRs, the long loop region connecting the α2-helix and β3-sheet suggests the formation of a domain-swapped dimer lacking carbohydrate binding capacity.

(Data source: uniprot)

Signaling pathways and regulation of CD303

CD303 triggers a cascade of signaling events: activation of the tyrosine kinase Syk, recruitment of the B cell junction protein SLP65, and activation of the phosphatidylinositol-specific phospholipase PLCγ2. In plasmacytoid dendritic cells (pDCs) , PLCγ2 activation mediates calcium ion (Ca2+) influx and exerts a negative regulatory effect. This CD303 signaling pathway ultimately reduces nuclear factor κB ( NF-κB ) activation, thereby inhibiting type I interferon (IFN-I) production.

CD303 influences immune responses by inhibiting interferon production in pDCs, thereby regulating immune system function. Given that interferon α/β (IFNα/β) produced by pDCs is widely considered a major pathophysiological driver of systemic lupus erythematosus (SLE) , CD303 is considered a potential therapeutic target for blocking IFNα/β production in SLE.

(Data source: Wilson NR, et al. Leuk Lymphoma. 2022)

CD303 -targeted therapy

Litifilimab is a fully humanized IgG1 monoclonal antibody targeting CD303 developed by Bristol-Myers Squibb. It modulates the immune response by binding to CD303 and subsequently inhibiting the production of IFN-I. Currently, lixilimab is the most advanced CD303-targeted therapy and has entered Phase III clinical trials for the treatment of cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). In a Phase II clinical trial, 132 participants were randomly assigned to receive 50, 150, or 450 mg of rituximab or placebo. All doses of rituximab tested significantly improved skin lesions in SLE patients, and no serious adverse events were reported.

(Data source: Biogen official website)

DB-2304, a potential first-in-class CD303 ADC candidate independently developed by DualityBio，has demonstrated excellent immunomodulatory effects and a favorable safety profile in preclinical studies. Utilizing a novel payload (a GR agonist) , DB-2304 exhibits a broader and more potent inhibitory effect on inflammatory factors compared to monoclonal antibodies targeting the same target, and has demonstrated superior efficacy to antibody-based therapies in animal models of disease. Dr. Zhu Zhongyuan, CEO and Founder of Yingen Biopharmaceuticals, stated, " By leveraging the synergistic effects of both antibodies and glucocorticoids, the CD303 ADC achieves highly effective immunomodulation while minimizing hormonal exposure, resulting in improved therapeutic efficacy and safety ."

SSGJ-626 is a CD303-targeting monoclonal antibody developed by Sunshine Guojian for the treatment of systemic lupus erythematosus and cutaneous lupus. Its clinical trial application has been approved by the National Medical Products Administration (NMPA) and is currently in Phase 1 clinical trials. NCT06674525 is a randomized, double-blind, placebo-controlled, single-ascending-dose Phase 1 clinical study evaluating the safety, tolerability, PK, and immunogenicity of SSGJ-626 following a single subcutaneous injection in healthy adult subjects.