The epidermal growth factor receptor (egfr)


The epidermal growth factor receptor (EGFR) is known to play an important role in signalling pathways in tumour genesis. In numerous cancers, up regulation of EGFR contributes to better tumour survival and growth. In the last couple of years, there have been a number of new drugs targeted at the EGFR and blocking the receptor has proven to be a way to provide treatment against solid tumours.[1],[2] One of these agents targeted at the EFGR is cetuximab (Erbitux, Bristol-Myers Squibb and ImClone Systems). Cetuximab is a chimeric mouse-human IgG1 monoclonal antibody against the extracellular domain of the receptor. Being chimeric, it is composed of a human Fc-part and a murine Fab-part. The drug is approved for the treatment of colorectal cancer and squamous-cell carcinoma of the head and neck. Different side-effects are known for cetuximab, of which one is severe hypersensitivity reactions. These reactions were thought to occur in less than 3% of the patients given the drug. However, in certain parts of the USA there were reports of much higher prevalence of these reactions.[3] Chung et al. published a recent study in which they addressed this issue.[4]

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In several states, the number of people experiencing hypersensitivity reactions after receiving cetuximab was higher than expected. Up to 22% of patients receiving cetuximab in Tennessee and North Carolina experienced hypersensitivity reactions. Such reactions occurred within minutes after the first administration of the drug and was compatible with IgE-mediated anaphylaxis.3,[5] The study of Chung et al. focused on the hypothesis that the hypersensitivity reaction was mediated by pre-existing IgE antibodies against cetuximab.

Sera from patients who received cetuximab with or without a resultant hypersensitivity reaction (from Tennessee, North Carolina and Arkansas) were studied. A total of 25 patients from a group of 76 had had such a reaction. The serum was compared to control patients who were healthy or had cancer of the head and neck. Two groups of control patients came from areas where the rate of patients experiencing a hypersensitivity reaction after cetuximab was less than 1%. Serum of six patients, who had had a severe reaction, was used to develop assays.

The results show a high correlation between the presence of pre-existing IgE antibodies against cetuximab and the occurrence of hypersensitivity reactions. The antibodies against cetuximab were directed at the Fab portion of the heavy chain and were found to be specific for galactose-α-1,3-galactose.

The study concludes that the severe hypersensitivity reactions after receiving cetuximab were caused by pre-existing IgE antibodies against the galactose-α-1,3-galactose oligosaccharide on the Fab portion of cetuximab. There is a significant difference in the prevalence of pre-existing antibodies against cetuximab. The southeast of the USA has a higher number of people who already have such antibodies in comparison to other parts of the USA. The research is hereby the first to provide a mechanism for the anaphylactic reaction that some people experience after cetuximab is administered.

Although this study raises several questions, it also provides answers concerning the anaphylactic reactions. And being the first to publish a study on the presence of pre-existing IgE antibodies against an antibody-based therapeutic, it is of importance not only to physicians, but also to the pharmacological industry. A limitation in the study is the small number of patients with a severe hypersensitivity reaction and IgE antibodies in their blood, mainly because the prevalence of the antibodies is region specific. More studies should be done, to find out if higher numbers of anaphylactic reactions are also present in other regions and if they are caused by the same IgE antibody as in Tennessee. More remains unanswered. There are already antibodies present before cetuximab is given, which means there is a cross-reaction, but the source of the primary sensitization is unknown. Results show that the antibody reacts with galactose-α-1,3-galactose on cat, dog, beef and pork proteins. However, ingestion of beef or pork leads to either a delayed reaction or no reaction at all. Why there is no allergic reaction or merely a delayed reaction remains unanswered in the study. It is possible that the bivalent presentation of the epitope is the cause of the anaphylactic reactions, but this needs further investigation.

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This research leads to new perspectives. Now that it has been demonstrated how pre-existing IgE antibodies can cause a severe reaction directed against a therapeutic monoclonal antibody, the pharmaceutical industry can use this data in the production of new chimeric antibodies. New agents should be tested and existing product labels should be adjusted. The pharmaceutical industry could test newly produced monoclonal antibodies which have caused hypersensitivity with carbohydrate groups with sera of patients with different allergies against plants or pollen to see if cross-reactions take place.

The severe hypersensitivity reaction is, although treatable, a serious side effect of cetuximab, especially if the prevalence is as as seen in the Tennessee region. By providing the evidence that pre-existing IgE is the cause of the severe reaction, physicians in high-risk regions can take this into account when prescribing cetuximab and carry out a screening blood test for the specific IgE antibodies before administering the drug, thereby preventing a severe reaction in the patient. Numerous drugs are now being studied in clinical trials, of which some are fully human monoclonal antibodies, such as panitumumab.[6] Such agents can be the answer to IgE mediated responses against oligosaccharides on the murine Fab-portion.

In conclusion the study done by Chung et al. provides a plausible mechanism for the anaphylactic reactions and hopefully sheds light on a problem which is not universally recognised, thus, thereby contributing greatly to the understanding of the anaphylactic side effects of cetuximab. However, there are questions raised after this study for which they did not provide sufficient answers. What causes the region specific prevalence of antibodies against cetuximab and where do they come from? Why don't they cause a rapid onset of allergic symptoms after ingestion of beef and pork even though they are cross-reactive? Does primary sensitization not result in clinical reactions because the galactose-α-1,3-galactose is present in that source in a monovalent form only? Although one important question is answered, there are many new questions raised. Needless to say, further research is necessary.

[1] Baselga J. New technologies in epidermal growth factor receptor-targeted cancer therapy. Signal. 2000 1:12-21.

[2] Capdevila J, Elez E, Macarulla T, Ramos FJ, Ruiz-Echarri M, Tabernero J. Anti-epidermal growth factor receptor monoclonal antibodies in cancer treatment. Cancer Treat Rev. 2009 Jun;35(4):354-63.

[3] O'Neil BH, Allen R, Spigel DR, Stinchcombe TE, Moore DT, Berlin JD, Goldberg RM. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol. 2007 Aug 20;25(24):3644-8.

[4] Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, Murphy BA, Satinover SM, Hosen J, Mauro D, Slebos RJ, Zhou Q, Gold D, Hatley T, Hicklin DJ, Platts-Mills TA. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008 Mar 13;358(11):1109-17.

[5] Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD Jr, Hepner DL, Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW. Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006 Feb;117(2):391-7.

[6] Wu M, Rivkin A, Pham T. Panitumumab: human monoclonal antibody against epidermal growth factor receptors for the treatment of metastatic colorectal cancer. Clin Ther. 2008 Jan;30(1):14-30.