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 receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral me ...

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 o ...

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, lymphatic or lymphoid o ...

cells. It binds

sialic acid Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone. The term "sialic acid" (from the Greek for saliva, - ''síalon'') was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this ...

s, therefore is a member of the SIGLEC family of

lectin Lectins are carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in rec ...

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 ac ...

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 Triggering receptor expressed on myeloid cells 2 (TREM2) is a protein that in humans is encoded by the ''TREM2'' gene. TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, which are immune cell ...

Clinical significance

CD33 is the target of gemtuzumab ozogamicin (trade name: Mylotarg®; Pfizer/Wyeth-Ayerst Laboratories), an

antibody-drug conjugate Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 phar ...

(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 normal blood cell production. Symptoms may inclu ...

. The drug is a recombinant,

humanized Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal an ...

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 antibodies ...

(IgG4 κ antibody hP67.6) covalently attached to the cytotoxic antitumor antibiotic

calicheamicin The calicheamicins are a class of enediyne antitumor antibiotics derived from the bacterium ''Micromonospora echinospora'', with calicheamicin γ1 being the most notable. It was isolated originally in the mid-1980s from the chalky soil, or "calic ...

(N-acetyl-γ-calicheamicin) via a bifunctional linker (4-(4-acetylphenoxy)butanoic acid). Several mechamisms 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 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 pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfize ...

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) Vadastuximab talirine is an antibody-drug conjugate (ADC) directed to CD33 (siglec-3) which is a transmembrane receptor expressed on cells of myeloid lineage. The experimental drug, being developed by Seattle Genetics, was in clinical trials for ...

, a novel

being developed by Seattle Genetics, utilizing this company's ADC technology.

References

External links

* {{Membrane proteins Lectins SIGLEC Alzheimer's disease