Previously, we introduced the regulatory protein CD35 (CR1) in the complement system. In this issue, we will introduce another complement system regulatory protein CD55. CD55 is the complement decay-accelerating factor (DAF), a cell-associated complement regulatory protein that can inhibit the classical and alternative pathways of complement activation. Loss of function mutations in CD55 can lead to abnormal complement activation, vasculothrombosis, and ultimately protein-losing enteropathy. CD55 plays an important role in disease prevention and treatment.

(Data source: Santarsiero D, et al. Cells. 2023)

CD55 distribution:

CD55 is an important regulatory protein expressed in a variety of cell types and plays a role in regulating the immune system and preventing pathological autoimmunity and inflammatory responses. CD55 is primarily expressed in endothelial cells, epithelial cells, immune cells, red blood cells, and other cells. The expression and function of CD55 are crucial for maintaining immune balance and health.

(Data source: uniprot)

CD55 structure and ligand CD97

CD55 is a membrane protein that is anchored to the membrane by a glycosylphosphatidylinositol (GPI) group. The CD55 protein has a C-terminal glycosylphosphatidylinositol anchor, an O-glycosylated serine/threonine/proline-rich region, and multiple copies of a short N-terminal consensus repeat domain of approximately 60 amino acids (CCP1, CCP2, CCP3, and CCP4). Among them, CCP2-4 and three consecutive lysine residues in the positively charged pocket between CCP2 and CCP3 are involved in its inhibition of the alternative complement pathway. CCP2 and CCP3, on the other hand, are solely involved in its inhibition of the classical pathway.

(Data source: Niu M, et al. J Biol Chem. 2021)

CD55 has an additional role: it serves as a binding partner for CD97 and is widely expressed on monocytes, granulocytes, lymphocytes, macrophages, dendritic cells, and smooth muscle cells. CD97 is also present in various tumors. The CD97 protein is a seven-transmembrane epidermal growth factor (EGF) protein that binds to its ligand, CD55, via the EGF domain. The binding of CD97 and CD55 is characterized by a rapid dissociation rate, low affinity, and calcium dependence. The binding between CD97 and CD55 proteins is involved in cancer dedifferentiation, invasion, migration, and metastasis. As potential biomarkers for various cancers, CD55 and CD97 are expected to become ideal targets for cancer therapy.

CD55 signaling pathway and regulation:

CD55 acts as a complement inhibitor, promoting the degradation of C3 and C5 convertases and preventing excessive complement activation. Furthermore, it mediates non-complementary functions in cancer. CD55 can initiate external signals, leading to the activation of multiple oncogenic pathways. Growth factors, cytokines, and prostaglandins can enhance or activate CD55 signaling. As a ligand for the epidermal growth factor seven-transmembrane (EGF-7TM) receptor CD97, CD55 triggers intracellular signaling through Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) and GSK3β. These pathways can activate cascades through Myc, driving tumorigenesis, activating chemoresistance through BRCA1 and MLH1, and stimulating CSC self-renewal through SOX2, OCT4, and NANOG. CD55 plays a complex role in cell signaling regulation, not only in the complement system but also potentially influencing immune cell function and inflammatory responses.

(Data source: Bharti R, et al. Cancer Lett. 2022)

Relationship between CD55 and disease:

CD55 is an inhibitor of the complement system, a nonspecific immune response. In contrast, CD55 has other functions beyond complement inhibition, such as being an infection receptor, a ligand for CD97, and an inhibitor of anti-tumor NK cell activity. Furthermore, CD55 has been extensively studied in a variety of diseases, including cancer, malaria, CHAPLE, paroxysmal nocturnal hemoglobinuria, multiple sclerosis, and autoimmune diseases. CD55 is expressed at high levels in various cancers and may serve as a potential biomarker for assessing cancer patient prognosis and therapeutic response in other diseases.

(Data source: Dho SH, et al. Immune Network 2018)

CD55 clinical drugs:

In August 2023, the monoclonal antibody drug Veopoz ( pozelimab-bbfg) was first approved in the United States for the treatment of protein-losing enteropathy (CHAPLE). It is a fully human monoclonal antibody designed to block the activity of complement factor C5 and is used to treat adults and children over 1 year old with CD55-deficient protein-losing enteropathy.