CD33 or Siglec-3 (sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC-3, gp67, p67) is a

transmembrane receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptor (biochemistry), receptors that are embedded in the cell membrane, plasma membrane of cell (biology), cells. They act in cell signaling by receiving (binding to) ex ...

expressed on cells of

myeloid Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + '' -oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue ...

lineage. It is usually considered myeloid-specific, but it can also be found on some

lymphoid The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphoid organs, lympha ...

cells. It binds

sialic acid Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone. The term "sialic acid" () was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this group is ''N''-acetylneuraminic acid ...

s, therefore is a member of the SIGLEC family of

lectin Lectins are carbohydrate-binding proteins that are highly specific for sugar Moiety (chemistry), groups that are part of other molecules, so cause agglutination (biology), agglutination of particular cells or precipitation of glycoconjugates an ...

Structure

The extracellular portion of this receptor contains two

immunoglobulin domain The immunoglobulin domain, also known as the immunoglobulin fold, is a type of protein domain that consists of a 2-layer sandwich of 7-9 antiparallel β-strands arranged in two β-sheets with a Greek key topology, consisting of about 125 amino ...

s (one IgV and one IgC2 domain), placing CD33 within the

immunoglobulin superfamily The immunoglobulin superfamily (IgSF) is a large protein superfamily of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily ...

. The intracellular portion of CD33 contains

immunoreceptor tyrosine-based inhibitory motif An immunoreceptor tyrosine-based inhibitory motif (ITIM), is a conserved sequence of amino acids that is found intracellularly in the cytoplasmic domains of many inhibitory receptors of the non-catalytic tyrosine-phosphorylated receptor family fou ...

s (ITIMs) that are implicated in inhibition of cellular activity.

Function

CD33 can be stimulated by any molecule with

residues such as glycoproteins or glycolipids. Upon binding, the immunoreceptor tyrosine-based inhibition motif (ITIM) of CD33, present on the cytosolic portion of the protein, is phosphorylated and acts as a docking site for Src homology 2 (SH2) domain-containing proteins like SHP phosphatases. This results in a cascade that inhibits phagocytosis in the cell.

Alzheimer's disease

CD33 controls microglial activation but in Alzheimer disease it goes overdrive in presence of amyloid and tau proteins, its expression is known to be tied to TREM2.

Clinical significance

CD33 is the target of gemtuzumab ozogamicin (trade name: Mylotarg®; Pfizer/Wyeth-Ayerst Laboratories), an antibody-drug conjugate (ADC) for the treatment of patients with

acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...

. The drug is a recombinant, humanized anti-CD33

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodie ...

(IgG4 κ antibody hP67.6) covalently attached to the cytotoxic antitumor antibiotic calicheamicin (N-acetyl-γ-calicheamicin) via a bifunctional linker (4-(4-acetylphenoxy)butanoic acid). Several mechanisms of resistance to gemtuzumab ozogamicin have been elucidated. On September 1, 2017, the FDA approved Pfizer's Mylotarg. Gemtuzumab ozogamicin was initially approved by the

U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

in 2000. However, during post marketing clinical trials researchers noticed a greater number of deaths in the group of patients who received gemtuzumab ozogamicin compared with those receiving chemotherapy alone. Based on these results,

Pfizer Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...

voluntarily withdrew gemtuzumab ozogamicin from the market in mid-2010, but was reintroduced to the market in 2017. CD33 is also the target in Vadastuximab talirine (SGN-CD33A), a novel antibody-drug conjugate being developed by

Seattle Genetics SeaGen was the world's first large scale commercial tidal stream generator. It was four times more powerful than any other tidal stream generator in the world at the time of installation. It was decommissioned by SIMEC Atlantis Energy Li ...

, utilizing this company's ADC technology.

References

External links

* {{Membrane proteins Lectins SIGLEC Alzheimer's disease