Zalutumumab

Source: Wikipedia, the free encyclopedia.
Zalutumumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetEpidermal growth factor receptor
Clinical data
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6512H10074N1734O2032S46
Molar mass146643.09 g·mol−1
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Zalutumumab (proposed trade name HuMax-EGFR) is a fully human IgG1

SCCHN), a type of cancer
.

Mechanism of action

Zalutumumab works through inhibition of the EGFR signal. The EGFR is a

lipophilic
segment, and an intracellular tyrosine kinase domain.

Mechanism of EGFR

EGFR is over-expressed by many tumor cells. Upon binding by a ligand, such as the

Mechanism of zalutumumab

In order to combat SCCHN, zalutumumab was designed to inhibit the EGFR signaling. Specifically, it binds to the EGFR Domain III on the cell surface. This locks the receptor in an inactive conformation, making the drug an

competitive antagonist for the EGF ligand. In the inactive conformation, the distance between the intracellular tyrosine kinase residues is larger, which inhibits dimerization. Phosphorylation is consequently inhibited, so that no signal is released. Without a signal, cell cycle characteristics to enhance tumor growth are inhibited and the cancer progression is suppressed.[2]

This is not the only way in which zalutumumab works. It also is responsible for some antitumor affects through

fragment antigen binding region of the antibody, binds to the antigen on the EGFr expressing tumor cells. Through an immunological response, the body’s natural killer (NK) cells, which are a type of lymphocyte, recognize and bind to the Fc portion on the antibody through an Fc receptor, CD16. The NK cell is then activated through the cross linking of the Fc receptors which sends a signal to induce apoptosis and cell death. The target tumor cell is then destroyed.[2]

Developmental status

2009: Zalutumumab treatment was approved for

U.S. Food and Drug Administration for patients suffering from SCCHN who have failed standard therapies and have no other options. The drug has undergone pre-clinical and Phase I and II studies and is also in Phases I and II for SCCHN front-line with chemo-radiation and SCCHN with radiation. Additionally, a Phase II is under way for SCCHN and Phase III studies are also being performed for SCCHN and SCCHN front-line with radio therapy.[3]

2010:A phase III study (of zalutumumab as an addition to 'best supportive care' in patients after failed standard platinum-based

2014:A study of zalutumumab as addition to chemoradiation for SCCHN showed no benefit,[5] and 94% developed a skin rash (11% severe enough to discontinue).

2015:Genmab not proceeding with zalutumumab.[6]

References

  1. ^ What is Cancer, MedicineNet.com
  2. ^
    PMID 18427122
    .
  3. ^ "Science and Research". Genmmab A/S. 2009.
  4. ^ http://www.genengnews.com/news/bnitem.aspx?name=77261239 March 2010
  5. ^ "OncoBriefs: Zalutumumab Misses Mark in H&N Cancer". medpagetoday.com. 22 February 2014.
  6. ^ Design, inNottingham Web. "Welcome to UKMi National Medicines Information". www.ukmi.nhs.uk. Archived from the original on 2012-05-26. Retrieved 2015-10-31.