Recently, Rheumatology published a research paper entitled "An immunomodulatory antibody-drug conjugate (ADC) targeting BDCA2 strongly suppresses pDC function and glucocorticoid responsive genes. glucocorticoid responsive genes" [1]. The study identified a novel BDCA2 antibody-drug conjugate (BDCA2-ADC) that effectively inhibits Systemic Lupus Erythematosus (SLE). In SLE, plasma cell-like dendritic cell (pDC) overproduce type I interferon (IFN-I). BDCA2/CLEC4C is thought to be critical for this autoimmune response.
CLEC4C or BDCA2 is a novel marker expressed on plasmacytoid dendritic cell (pDC). Investigators conjugated anti-BDCA2 antibody to a glucocorticoid receptor agonist to form BDCA2-ADC. Experiments showed that BDCA2-ADC inhibited IFN-I expression and glucocorticoid response in pDC. These data suggested that CLEC4C/BDCA2 has a dual mechanism of action on pDC. Successive studies have confirmed that BDCA2 is expected to be the world's first ADC for the treatment of SLE, providing a better therapeutic option for SLE patients!
1. What is Plasmacytoid Dendritic Cell (pDC)?
3.The Mechanism of CLEC4C as Negative Regulator in Plasmacytoid Dendritic Cell (pDC)
5. CLEC4C Clinical Trials for Drug Development
6. CLEC4C Recombinant Proteins & Antibodies for Research Use
Plasmacytoid dendritic cells (pDCs) are a specialized subclass of dendritic cells (DCs) that primarily secrete interferon type I (IFN-I). These cells play a crucial role in antiviral immunity by activating adaptive immune responses through the secretion of abundant IFN-I. pDCs achieve this activation by recognizing pathogen-associated molecules through Toll-like receptors 7 and 9 (TLR7 and TLR9), triggering the production of interferon alpha (IFN-α). IFN-α exhibits potent antiviral effects, inhibiting viral replication, promoting immune cell activation, and enhancing overall immune response. Notably, pDCs are renowned for their remarkable capacity to secrete IFN-α [2-4].
In various human tissues, including lymph nodes, tonsils, peripheral blood, umbilical cord blood, adult and fetal thymus, fetal liver, and fetal bone marrow, immature pDCs can be found. Abnormal activation and excessive production of IFN-α by pDCs have been linked to several conditions, such as autoimmune diseases (e.g., systemic lupus erythematosus), viral infections (e.g., HCV, HIV, hepatitis B virus), and specific neoplasms like leukemias and lymphomas [2, 5-8]. Nevertheless, the pathogenesis of these diseases remains complex. Recent studies have identified four new surface markers specific to human pDCs: BDCA2, BDCA4, ILT-7, and CD123 [2, 5-8].
CLEC4C, also known as BDCA-2 or CD303, is a type II transmembrane glycoprotein expressed on plasmacytoid dendritic cells (pDCs). It belongs to the C-type lectin domain family and contains an extracellular C-type carbohydrate recognition domain (CRD) that shares similarities with mannose-, glucose-, or glucosamine-bound C-type animal lectins. The specific natural ligand for this receptor remains unknown, but it has been observed that BDCA-2 selectively binds galactose-terminated bis-crown N-linked sugars. Crystallography and mutation studies have shown that mannose binds to the conserved Ca2+ at the major binding site of the C-type CRD (Figure 1) [7-9].
CLEC4C/BDCA-2 serves as one of the markers of plasma dendritic cells. It plays an important role in the immune system, especially in autoimmune diseases such as systemic lupus erythematosus (SLE). Studies suggest that BDCA-2 may effectively inhibit the induction of interferon α/β production in plasma cell-like dendritic cells through calcium mobilization-dependent mechanisms and protein tyrosine. Since interferon α/β production by plasmacytoid dendritic cells is considered a major pathophysiologic factor in SLE. Therefore, CLEC4C/BDCA-2 becomes a potential target to block interferon α/β production in SLE [7-9]!
Figure 1. The structure of BDCA-2 and other type 2 transmembrane receptors containing C-type CRDs [9]
CLEC4C/BDCA-2 is a recently discovered surface marker on plasmacytoid dendritic cells (pDCs). It contains a carbohydrate recognition domain that binds mannose, glucose, or N-acetylglucosamine. While the intracellular portion of BDCA-2 does not have known signaling motifs, it can associate with and signal through the FcR γ chain in B-cell antigen receptor-like signalosomes. Activation of BDCA-2 leads to the activation of tyrosine kinase (Syk), aggregation of B-cell connexin (SLP65), and activation of phosphatidylinositol-specific phosphodiesterase (PLCγ2). This process demonstrates how BDCA-2 regulates immune response and interferon production in pDC (Figure 2) [3, 10].
Activation of PLCγ2 can cause an influx of Ca2+ and act as a negative regulator in pDCs. By activating the NFκB pathway, BDCA-2 inhibits the production of type I interferons (IFN-I). Consequently, BDCA-2 influences the immune response in pDCs by suppressing interferon production, thereby playing a significant role in immune system regulation (Figure 2) [3, 10].
Figure 2. The mechanism of CLEC4C as negative regulator in plasmacytoid dendritic cell (pDC) [10]
Systemic lupus erythematosus (SLE) is a group of autoimmune diseases involving multiple organs, the pathogenesis of which is still unknown. As mentioned earlier, pDCs are important antiviral defense cells in the immune system, and they are responsible for producing large amounts of IFN-I in response to infection. However, in patients with SLE, abnormal pDC function and excessive production of IFN-I exacerbate SLE by triggering an immune response and promoting an inflammatory response. Therefore, IFN-I is considered to be one of the key factors contributing to the development of SLE [11].
Recent research has revealed that CLEC4C/BDCA-2, primarily found in plasma cell-like dendritic cells, plays a crucial role in trapping antigens and acts as a potent inhibitor of interferon α/β. This interference with interferon production is particularly significant in autoimmune diseases such as SLE. One specific study focused on 24F4A, a humanized monoclonal antibody designed to target BDCA-2. In vitro experiments utilizing blood samples from both healthy individuals and SLE patients have confirmed that 24F4A binds to BDCA2, initiating internalization, and effectively inhibiting pDCs from producing IFN-I upon stimulation by Toll-like receptors (TLRs) [12-13].
Research has found that DCA-2/CLEC4 interacts with hepatitis C virus (HCV) particles or infected cell surfaces, recognizing pathogens and initiating immune response. Besides HCV, BDCA-2 also recognizes other viruses such as HIV, influenza virus, and dengue virus. Once attached to the pathogen, BDCA-2 activates pDC, stimulating it to produce significant amounts of IFN-I, thereby impeding viral replication and transmission [14].
The study demonstrated that BDCA-2/CLEC4 interacts with HCV E2 protein and influences the immune response of pDC to HCV infection. The influence of E2 on the production of IFN-α and other inflammatory factors by pDC was assessed through ELISA and RT-PCR assays, while its impact on signaling pathways within pDC was examined using Western blot analysis. The findings revealed that E2 could bind to BDCA-2 and hinder the response of pDC to HCV-infected hepatocytes or TLR7 agonists, leading to a reduction of IFN-α and other inflammatory factors [14].
Currently, despite limited reports and studies on CLEC4C/BDCA-2 globally, relevant research suggests that BDCA-2 may play a crucial role in various diseases, including chronic inflammation, infectious diseases, and autoimmune diseases. These diseases encompass endometriosis, rhinitis, asthma, diabetes, and lymphadenitis [15-17]. Moreover, BDCA-2 has been associated with the Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and certain fungal infections [10-18]. Furthermore, BDCA-2 may also contribute to the treatment of hematologic and solid tumors [19-22].
For instance, BDCA-2 serves as a highly specific marker for tumorigenic plasma cell-like dendritic cells, and further investigations have indicated that the anti-BDCA-2 (CD303) antibody holds potential as a diagnostic aid for improving the accuracy of diagnosing blastic plasmacytoid dendritic cell neoplasms (BPDCN) [21]. Additionally, the expression of CD4+CD56+BDCA-2 in hematological skin tumors correlates with tumor characteristics and survival time. A study involving 19 CD4+CD56+hematodermal tumors revealed that 10 of these tumors expressed BDCA-2, while no expression was observed in tumors of the NK cell line [22].
Data from Pharmsnap indicates that there are currently four drugs worldwide targeting CLEC4C/BDCA-2, namely Litifilimab, DB-2304, CBS-004, and CDX-1402. Among these, Litifilimab (BIIB 059), a BDCA-2 monoclonal antibody developed by Biogen, Inc., is the most rapidly advancing. This drug effectively treats lupus by inhibiting the BDCA-2 protein and reducing the production of inflammatory cytokines like IFN-I. BIIB-059 is the only BDCA-2 monoclonal antibody undergoing clinical trials globally. In the United States, it has reached phase III for SLE treatment and phase II for chronic cutaneous lupus erythematosus (CLE) treatment. Although significant findings have yet to occur, ongoing research in this field gives hope for the CLEC4C in SLE therapy.
In conclusion, CLEC4C or BDCA2, is a potential future target for drug development. It functions as a novel biomarker found on plasmacytoid dendritic cell (pDC), which play a crucial role in the immune response. The most advanced drug currently under investigation for lupus treatment is BIIB 059 (Litifilimab), suggesting that targeting CLEC4C may offer a novel therapeutic strategy for autoimmune disorders like SLE. All in all, CLEC4C holds significant potential as a future drug target. More innovative CLEC4C drugs are expected in the future.
To fully support researchers and pharmaceutical companies in their research on CLEC4C in SLE and other diseases, CUSABIO presents CLEC4C active proteins & antibodies to support your research on the mechanism of CLEC4C or its potential clinical value.
CLEC4C protein
Purity was greater than 95% as determined by SDS-PAGE. SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.
Immobilized Human CLEC4C at 2μg/mL can bind Anti-CLEC4C recombinant antibody (CSB-RA855470MA1HU), the EC50 is 7.658-12.99 ng/mL.
CLEC4C antibody
CLEC4C Recombinant Monoclonal Antibody (Code: CSB-RA855470MA1HU)
References
[1] Li, Xi, et al. "An immunomodulatory antibody-drug conjugate (ADC) targeting BDCA2 strongly suppresses pDC function and glucocorticoid responsive genes." Rheumatology (Oxford, England) (2023): kead219-kead219.
[2] Wu, Jing, et al. "pDC activation by TLR7/8 ligand CL097 compared to TLR7 ligand IMQ or TLR9 ligand CpG." Journal of Immunology Research 2019 (2019).
[3] Santana-de Anda, Karina, et al. "Plasmacytoid dendritic cells: key players in viral infections and autoimmune diseases." Seminars in arthritis and rheumatism. vol. 43. no. 1. wb Saunders, 2013.
[4] Rogers, N. M., J. S. Isenberg, and A. W. Thomson. "Plasmacytoid dendritic cells: no longer an enigma and now key to transplant tolerance?" American Journal of Transplantation 13.5 (2013): 1125-1133.
[5] Hardy, Andrew W., et al. "HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll- like receptor 7-induced IFN-α." Proceedings of the National Academy of Sciences 104.44 (2007): 17453-17458.
[6] Fitzgerald-Bocarsly, Patricia, and Evan S. Jacobs. "Plasmacytoid dendritic cells in HIV infection: striking a delicate balance." Journal of leukocyte biology 87.4 (2010): 609-620.
[7] Reizis, Boris. "Regulation of plasmacytoid dendritic cell development." Current opinion in immunology 22.2 (2010): 206-211.
[8] Toma-Hirano, Makiko, et al. "Type I interferon regulates pDC maturation and Ly49Q expression." European journal of immunology 37.10 ( 2007): 2707-2714.
[9] Jégouzo, Sabine AF, et al. "A novel mechanism for binding of galactose-terminated glycans by the C-type carbohydrate recognition domain in blood dendritic cell antigen 2." Journal of Biological Chemistry 290.27 (2015): 16759-16771.
[10] Wilson, Nathaniel R., et al. "CD303 (BDCA-2)-a potential novel target for therapy in hematologic malignancies." Leukemia & lymphoma 63.1 (2022): 19-30.
[11] Furie, Richard A., et al. "Trial of anti-BDCA2 antibody litifilimab for systemic lupus erythematosus." New England Journal of Medicine 387.10 (2022). 894-904.
[12] Furie, Richard, et al. "Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus." The Journal of clinical investigation 129.3 (2019): 1359-1371.
[13] Gardet, Agnes, et al. "Effect of in vivo hydroxychloroquine and ex vivo anti-BDCA2 mAb treatment on pDC IFNα production from patients affected with cutaneous lupus erythematosus." Frontiers in immunology 10 (2019): 275.
[14] Florentin, Jonathan, et al. "HCV glycoprotein E2 is a novel BDCA-2 ligand and acts as an inhibitor of IFN production by plasmacytoid dendritic cells." Blood, The Journal of the American Society of Hematology 120.23 (2012): 4544-4551.
[15] Lynch, Jason P., et al. "The plasmacytoid dendritic cell: at the cross-roads in asthma." European Respiratory Journal 43.1 (2014): 264-275.
[16] Van Brussel, Ilse, et al. "Expression of dendritic cell markers CD11c/BDCA-1 and CD123/BDCA-2 in coronary artery disease upon activation in whole blood ." Journal of immunological methods 362.1-2 (2010): 168-175.
[17] Migita, K., et al. "Reduced blood BDCA-2+ (lymphoid) and CD11c+ (myeloid) dendritic cells in systemic lupus erythematosus." Clinical & Experimental Immunology 142.1 (2005): 84-91.
[18] Ibrahim, Hazem Ahmed Hamed. "Pathogenesis of B-cell post-transplant lymphoproliferative disorders and HIV-associated B-cell lymphomas." (2010).
[19] Palma, Giuseppe, et al. "Plasmacytoids dendritic cells are a therapeutic target in anticancer immunity." Biochimica et Biophysica Acta (BBA)-Reviews on Cancer 1826.2 (2012): 407-414.
[20] Wertel, F., et al. "Myeloid and lymphoid dendritic cells in the peritoneal fluid of women with ovarian cancer." Adv Med Sci 51 (2006): 174-177.
[21] Boiocchi, Leonardo, et al. "BDCA-2 (CD303): a highly specific marker for normal and neoplastic plasmacytoid dendritic cells." Blood, The Journal of the American Society of Hematology 122.2 (2013): 296-297.
[22] Jaye, David L., et al. "Expression of the plasmacytoid dendritic cell marker BDCA-2 supports a spectrum of maturation among CD4+ CD56+ hematodermic neoplasms." Modern pathology 19.12 (2006): 1555-1562.
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