Recognition of regional differences in the USA in the incidence of severe allergic reactions to cetuximab has led to the discovery that pre-existing antibody can react with the drug, according to an article in the March 13 issue of the New England Journal of Medicine.

Researchers at Vanderbilt-Ingram cancer Center realized that patients in their region (the southeastern USA) were significantly more likely to experience severe allergic reactions than patients in other areas. Christine Chung, MD, of the Department of Medicine and Cancer Biology and lead author of the study, led the work that clarified why this phenomenon occurred. Some of the observed reactions were life-threatening.

"When I saw my patients having these allergic reactions they looked very much like the anaphylactic reaction in its acuity and symptom presentation as you see with something like severe peanut allergy," said Chung. "The anaphylactic reactions are triggered by immunoglobulin E or IgE. Patients must be exposed to an antigen before the body becomes sensitized to it and generates IgE. But these cancer patients had never been exposed to the drug cetuximab.

"I thought there must be pre-existing IgE antibodies in these patients from an antigen that is similar to cetuximab," explained Chung. "While talking to other physicians, we noticed that we were seeing these reactions more frequently in the Southeast."

Chung and her collaborators contacted colleagues at the University of Virginia, Stanford, Duke, Harvard and the Allergy and Asthma Clinic of Northwest Arkansas, along with Bristol-Myers Squibb and ImClone Systems, the drug's manufacturers. The group pooled serum samples from cancer patients and control subjects. Then they tested the samples for the IgE antibody.

Among 76 cetuximab-treated subjects, 25 had a hypersensitivity reaction. Antibodies against cetuximab were found in pretreatment samples from 17 subjects. Only one of 51 subjects who did not have a reaction had the antibodies.

The geographic differences were striking. The antibodies were found in 20.8 percent of samples from control subjects in Tennessee, 6.1 percent of samples from Northern California and 0.6 percent from Boston.

The researchers determined that the antigen within the drug was carbohydrate added to the protein during drug manufacturing using a specific cell line.

Chung said the finding is significant because it was the first study to show that IgE antibody can be made against sugar molecules commonly present on proteins. Now manufacturers can avoid using that cell line for creation of antibody-based drugs to prevent such reactions. Based on this research, a commercial assay is being developed to allow physicians to test patients for the problematic antibody before deciding to use the drug.

The scientists are researching possible environmental antigens that may be involved in original antibody production, including histoplasmosis, amoebas or other parasitic infections.