CD38

Official Full Name

CD38 molecule

Organism

Homo sapiens

GeneID

952

Background

The protein encoded by this gene is a non-lineage-restricted, type II transmembrane glycoprotein that synthesizes and hydrolyzes cyclic adenosine 5'-diphosphate-ribose, an intracellular calcium ion mobilizing messenger. The release of soluble protein and the ability of membrane-bound protein to become internalized indicate both extracellular and intracellular functions for the protein. This protein has an N-terminal cytoplasmic tail, a single membrane-spanning domain, and a C-terminal extracellular region with four N-glycosylation sites. Crystal structure analysis demonstrates that the functional molecule is a dimer, with the central portion containing the catalytic site. It is used as a prognostic marker for patients with chronic lymphocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

Synonyms

ADPRC1; cADPR1; ADPRC 1;

Bio Chemical Class

Glycosylase

Protein Sequence

MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI

Open

Disease

Acute myeloid leukaemia, B-cell lymphoma, Malignant haematopoietic neoplasm, Mature B-cell lymphoma, Multiple myeloma, Myasthenia gravis, Myelodysplastic syndrome, Postoperative inflammation, Solid tumour/cancer, Thrombocytopenia, Urinary system clinical sympton

Approved Drug

1 +

Clinical Trial Drug

22 +

Discontinued Drug

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Detailed Information

CD38 is a type II transmembrane glycoprotein that associates with cell-surface receptors in lipid rafts, regulates cytoplasmic Ca²⁺ flux, and mediates signal transduction in myeloid and lymphoid cells. CD38 is highly and uniformly expressed on multiple myeloma (MM) cells, and at relatively low levels on normal myeloid and lymphoid cells, but also in some tissues of non-hematopoietic origin such as smooth muscle, prostate, and eye. CD38 is a type 2 transmembrane protein with the function of adhesion molecules. Furthermore, CD38 also has ectoenzymatic activity and is involved in the generation of nucleotide metabolites, which play an important role in the regulation of intracellular calcium stores.

CD38 Functions

CD38 is functionally pleiotropic, functioning as an ectoenzyme and as a receptor simultaneously. The identification of CD31 as a non-substrate specific ligand was the key to recognize CD38 as a receptor. Importantly, in vitro experiments have shown that CD38/CD31 cross-talk is a crucial step in the regulation of cytoplasmic calcium fluxes and secretion of cytokines such as IL-6 and IL-10. Interestingly, this interaction may regulate the migration of leukocytes and CD38 positive cancer cells through the endothelial cell wall. In activated T lymphocytes, the formation of immunological synapses upon activation of CD38 indicated that CD38, in order to exert its biological function as a receptor, needs to be redirected to specialized phospholipid microdomains of the plasma membrane, in close proximity to professional receptors.

In addition to its receptor function, CD38 was recently described as part of the leukocyte ectonucleotidases family. CD38 converts nicotinamide adenine dinucleotide (NAD+) to ADP ribose (ADPR) directly (hydrolase activity) or through the formation and degradation of cyclic ADP ribose to ADPR (cyclase activity). The final result of these catalytic reactions is the generation of potent intracellular Ca²⁺ mobilizing compounds (cADPR, ADPR, and NAADP), which then activate signaling pathways that control various biological processes, such as lymphocyte proliferation. Interestingly, recent studies suggest a key role for CD38 involved in the production of adenosine, which has immunosuppressive effects. Thus, this enzyme is considered to function as an 'immunological switch' capable of converting a proinflammatory extracellular environment into an adenosine-rich, anti-inflammatory niche, suppressing antitumor immunity and promoting tumor progression.

CD38-targeting Antibodies in Multiple Myeloma

The highest levels of CD38 are observed on normal and malignant plasma cells, which renders the CD38 protein a valid target for antibody-based therapies in multiple myeloma (MM). Indeed, the molecule's broad expression on MM cells led to the development of the CD38 antibodies (anti-CD38 antibodies). The CD38-targeting antibodies have classic Fc-dependent immune effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP). These mechanisms of action are dependent on CD38 expression on the tumor cells. There is growing evidence that CD38 antibodies also improve host-anti-tumor immune response by eliminating CD38-positive immune suppressor cells, including regulatory B cells, regulatory T cells, and myeloid-derived suppressor cells.

CD38 Figure 1. Mechanism of action of CD38 antibodies. (van de Donk N W C J, et al., 2018)

Due to these pleiotropic mechanisms of action, CD38 antibodies have high single agent activity and strong synergy with other anti-cancer agents in MM patients. And these drugs are also well tolerated with infusion reactions as the most frequent adverse event. In MM, CD38 antibodies are currently incorporated in the treatment of both relapsed/refractory and newly diagnosed patients. Moreover, CD38 antibodies are evaluated in other CD38-positive malignancies such as T-cell acute lymphoblastic leukemia, acute myeloid leukemia, amyloid light-chain amyloidosis, and NK/T cell lymphomas. Based on their potent immunomodulatory activities, CD38 antibodies will also be valuable for CD38-negative cancers, probably in combination with other types of immunotherapies.

References:

Lokhorst H M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. New England Journal of Medicine, 2015, 373(13): 1207-1219.
van de Donk N W C J, et al. CD38 antibodies in multiple myeloma: back to the future. Blood, 2018, 131(1): 13-29.
Bonello F, et al. CD38 as an immunotherapeutic target in multiple myeloma. Expert Opinion on Biological Therapy, 2018, 18(12): 1209-1221.
Frerichs K A, et al. CD38-targeting antibodies in multiple myeloma: mechanisms of action and clinical experience. Expert review of clinical immunology, 2018, 14(3): 197-206.
van de Donk N W C J. Immunomodulatory effects of CD38-targeting antibodies. Immunology letters, 2018, 199: 16-22.
Baruch B B, et al. CD38 in cancer-associated fibroblasts promotes pro-tumoral activity. Laboratory Investigation, 2020: 1-15.

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