Cetuximab

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Cetuximab

Existing structural data : 1YY8 , 1YY9

Mass / length primary structure 145.8  kDa
Identifier
External IDs
Drug information
ATC code L01 XC06
DrugBank DB00002
Drug class Monoclonal antibody

Crystal structure of cetuximab (Erbitux), Fab fragment (light and heavy chain)

Cetuximab (trade name: Erbitux ® , Eli Lilly and Company , Bristol-Myers Squibb and Merck KGaA ) is a therapeutic chimeric monoclonal antibody IgG1 against the epidermal growth factor receptor (EGFR) , which in the oncology (cancer medicine) for cancer immunotherapy is used .

Mechanism of action

The antibody is directed against a tumor antigen that can be found in the membranes of human body cells . This enzyme , a receptor tyrosine kinase called EGFR ( epidermal growth factor receptor , in English: epidermal growth factor receptor ) receives chemical signals, so-called growth factors , which are located in the tissue fluid, and then stimulates the cell metabolism. Cancer cells often have very many EGFR molecules in their cell membranes; in colorectal cancer EGFR is at 80% of the cells overexpressed , that is significantly more often than in normal tissue cells. Cetuximab binds to the EGFR. This binding inhibits the activation of the receptor and the downstream signal transmission system, which reduces the invasion of tumor cells into healthy tissue and the spread of the tumors into new body regions ( metastasis ).

In addition, cetuximab appears to inhibit the ability of tumor cells to repair damage caused by chemotherapy and radiation therapy. It is also believed to reduce the formation of new blood vessels in tumors, which counteracts tumor growth.

After a series of successful clinical trials, cetuximab was approved for the treatment of colon cancer in the United States in 2003, the European Community in 2004, and Japan in 2008 as an agent in cases where irinotecan- containing cytostatic chemotherapy has failed.

Compared to cytostatics , cetuximab has few side effects. The most common side effect of treatment with Erbitux is an acne-like rash , which in turn seems to correlate with a good response to therapy. Hypersensitivity reactions can occur in about 5 percent of all patients under treatment with Erbitux ; about half of these reactions are serious.

A study published in 2010 on Erbitux from Norway again questions the benefit. In 566 patients examined who were treated with Erbitux and triple chemotherapy, there was no evidence of an increase in survival time. This so-called FLOX therapy regimen is a bolus therapy regimen. As there are further indications of a previously unknown negative interaction with capecitabine and bolus 5-FU protocols, the combination of Erbitux with oral fluoropyrimidines and bolus 5-FU protocols is not recommended.

Development and sales

The development of the active ingredient goes back to the scientific work of Joseph Schlessinger , Michael Sela , and other scientists from the Weizmann Institute for Science . A short time later, cetuximab was patented by the New York biotech company ImClone Systems , which led to a patent dispute with Yeda Research and Development Company Ltd., which is part of the Weizmann Institute. which Yeda largely decided for itself. In the USA and Canada, cetuximab is sold under license by Bristol-Myers Squibb , outside the USA by the Darmstadt-based pharmaceutical company Merck KGaA . The three companies share the distribution rights for Japan. In 2002, the approval of Erbitux by the American health authorities was surprisingly refused at the first attempt, which led to a fall in the price of the ImClone share . According to press reports, the application documents were incomplete. Since the founders of ImClone, the brothers Samuel and Harlan Waksal, had sold their shares shortly before the crash, they came under suspicion of stock market manipulation at times. On June 12, 2002, Sam Waksal, former CEO of ImClone, was arrested on suspicion of insider trading . On June 10, 2003, he was sentenced to 7 years and 3 months in prison. A friend of his, Martha Stewart , was sentenced to six months in prison in this connection. In 2008 ImClone was taken over by Eli-Lilly . A 14-day therapy cycle with cetuximab costs around 5000 euros, twelve cycles are common in colorectal cancer therapy.

Indications or approval

  • for the treatment of metastatic, EGFR-expressing colorectal cancer with non-mutated Ras gene in combination with irinotecan- based chemotherapy, as first-line treatment in combination with the chemotherapy FOLFOX and as monotherapy, in which the therapy with oxaliplatin and irinotecan has failed and irinotecan cannot be tolerated becomes.
  • for the treatment of patients with squamous cell carcinoma of the head and neck area in combination with radiation therapy for a locally advanced disease and in combination with platinum-based chemotherapy for a recurrent and / or metastatic disease. (As of June 2014)

Erbitux is approved in over 90 countries worldwide for the treatment of colorectal and squamous cell carcinomas of the head and neck (SCCHN). (As of December 2013)

Approval for the first-line therapy of advanced or metastatic non-small cell lung cancer was applied for by the manufacturer on September 11, 2008. The application was based on the data from the so-called FLEX study, in which the addition of cetuximab to a platinum-containing standard therapy had improved the mean overall survival of the patients by around one month. This application for approval was withdrawn in 2012.

See also

Nomenclature of monoclonal antibodies , convention for naming monoclonal antibodies

Web links

Individual evidence

  1. ↑ Y. Humblet (2004): Cetuximab: an IgG1 monoclonal antibody for the treatment of epidermal growth factor receptor-expressing tumors. In: Expert Opinion on Pharmacotherapy . Vol. 5, pp. 1621-1633. PMID 15212612
  2. ↑ Avastin and Erbitux: Studies question the benefits of cancer drugs. In: Spiegel Online . October 11, 2010, accessed March 30, 2016 .
  3. ↑ Onkopedia guidelines for colon cancer
  4. ↑ Aboud-Pirak E, Hurwitz E, Pirak ME, Bellot F, Schlessinger J, Sela M .: Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice . In: J Natl Cancer Inst . . 80, No. 20, December 21, 1988, pp. 1605-11. PMID 3193478 .
  5. ^ European Medicines Agency .
  6. ↑ Merck KGaA press release ( Memento of the original dated November 2, 2015 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice.  @1@ 2Template: Webachiv / IABot / www.merck.de
  7. ↑ Europe-wide approval for cetuximab for the first-line treatment of non-small cell lung cancer applied for. In: Journal Onkologie from September 23, 2008.
  8. ↑ Merck waives extended use of anti-cancer drugs In: Handelsblatt message dated September 18, 2012.

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