CD33

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CD33 or Siglec-3 (sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC-3, gp67, p67) is a transmembrane receptor expressed on cells of myeloid lineage.[1] It is usually considered myeloid-specific, but it can also be found on some lymphoid cells.[2]

It binds sialic acids, therefore is a member of the SIGLEC family of lectins.

Structure

The extracellular portion of this receptor contains two immunoglobulin domains (one IgV and one IgC2 domain), placing CD33 within the immunoglobulin superfamily. The intracellular portion of CD33 contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that are implicated in inhibition of cellular activity.[3]

Clinical significance

CD33 is the target of gemtuzumab ozogamicin (trade name: Mylotarg®; Pfizer/Wyeth-Ayerst Laboratories), [4] an Antibody-drug conjugate for the treatment of patients with acute myeloid leukemia. The drug is a recombinant, humanized anti-CD33 monoclonal antibody (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).[5] On September 1, 2017, the FDA approved Pfizer's Mylotarg. [6]

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 voluntarily withdrew gemtuzumab ozogamicin from the market in mid-2010, but was reintroduced to the market in 2017. [7] [8] [9]

CD33 is also the target in Vadastuximab talirine (SGN-CD33A), a novel antibody-drug conjugate being developed by Seattle Genetics, utilizing this company's ADC technology.[10]

References

  1. Garnache-Ottou F, Chaperot L, Biichle S, Ferrand C, Remy-Martin JP, Deconinck E, de Tailly PD, Bulabois B, Poulet J, Kuhlein E, Jacob MC, Salaun V, Arock M, Drenou B, Schillinger F, Seilles E, Tiberghien P, Bensa JC, Plumas J, Saas P (Feb 2005). "Expression of the myeloid-associated marker CD33 is not an exclusive factor for leukemic plasmacytoid dendritic cells". Blood. 105 (3): 1256–64. doi:10.1182/blood-2004-06-2416. PMID 15388576.
  2. Hernández-Caselles T, Martínez-Esparza M, Pérez-Oliva AB, Quintanilla-Cecconi AM, García-Alonso A, Alvarez-López DM, García-Peñarrubia P (Jan 2006). "A study of CD33 (SIGLEC-3) antigen expression and function on activated human T and NK cells: two isoforms of CD33 are generated by alternative splicing". Journal of Leukocyte Biology. 79 (1): 46–58. doi:10.1189/jlb.0205096. PMID 16380601.
  3. Myeloid cell surface antigen CD33 precursor - Homo sapiens (Human)
  4. Walter RB, Gooley TA, van der Velden VH, Loken MR, van Dongen JJ, Flowers DA, Bernstein ID, Appelbaum FR (May 2007). "CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy". Blood. 109 (10): 4168–70. doi:10.1182/blood-2006-09-047399. PMC 1885511. PMID 17227830.
  5. Calicheamicin (LL-E33288 antibiotics); ADC Review / Journal of Antibody-drug Conjugates (March 20, 2015)
  6. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574507.htm
  7. Gemtuzumab ozogamicin (Mylotarg®) Drug Description; ADC Review / Journal of Antibody-drug Conjugates (July 19, 2015)
  8. Pfizer Voluntarily Withdraws Cancer Treatment Mylotarg from U.S. Market; FDA Press Release (June 21, 2010)
  9. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574507.htm
  10. Vadastuximab Talirine (SGN CD33a) Drug Description; ADC Review / Journal of Antibody-drug Conjugates (November 23, 2015)

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