NEJM paper shows that geographic distribution correlates to patients having IgE antibodies to the drug prior to treatment.

Researchers funded by the NIAID discovered that specific pre-existing antibodies cause a severe reaction to cetuximab—a mAb produced by ImClone Systems and Bristol-Myers Squibb commonly used to treat persons diagnosed with head and neck or colon cancer.

Upon reviewing the scientific literature, the investigative team was intrigued by the unusual geographic distribution of patients with anaphylaxis. For example, 22% of patients treated with cetuximab in Tennessee and North Carolina had anaphylactic reactions and even higher rates and clusters of cases were reported from regions of Arkansas, Missouri, and Virginia. In contrast, less than 1% of patients receiving cetuximab in the Northeast region of the U.S. suffered such reactions, according to the investigators.

Anaphylactic reactions are typically triggered by immunoglobulin E (IgE) antibodies, which the immune system produces after being sensitized by prior exposure to an allergen. But when the investigators further reviewed the clinical data, they discovered that anaphylactic reactions in these individuals had occurred within minutes of their first exposure to cetuximab, suggesting that the patients had already been primed to respond to cetuximab.

The researchers then hypothesized that these patients had pre-existing IgE antibodies that cross-reacted with cetuximab and that these IgE antibodies were directed against a specific sugar molecule present on cetuximab. To test their hypothesis, they analyzed the antibodies present in serum of 538 individuals. They developed a technique for measuring IgE antibodies to cetuximab and, in further experiments, proved that the IgE antibodies were directe d against sugar molecules on cetuximab.

The 538 serum samples included pre-treatment samples taken from 76 cetuximab-treated cancer patients primarily from Tennessee, Arkansas, and North Carolina. The remaining serum samples from individuals in Nashville, Northern California, and Boston served as controls to investigate the geographical differences in hypersensitivity rates.

The researchers found that among the 76 cancer patients, 25 developed hypersensitivity reactions and 18 of these individuals showed a positive reaction for IgE antibodies to the drug. Among the 51 serum samples from patients who did not have a hypersensitivity reaction, only one had such antibodies. In control groups, IgE antibodies against cetuximab were found in 21% of the samples from Nashville, 6% of the samples from Northern California, and less than 1% of the samples from Boston.

The researchers involved came from the Vanderbilt University School of Medicine, Bristol-Myers Squibb, Stanford University School of Medicine, Duke University Medical Center, University of Virginia, ImClone Systems, Harvard University, and Allergy and Asthma Clinic of Northwest Arkansas. The findings of this investigation appear in a report published in the March 13 edition of the New England Journal of Medicine.

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