Hypersensitivity Reactions to Cetuximab Related to IgE Antibodies Against Oligosaccharides

Roxanne Nelson

March 12, 2008

March 12, 2008 — Hypersensitivity reactions to cetuximab (Erbitux) have been reported, and a significantly higher prevalence is found in the southeastern United States. In the March 13 issue of the New England Journal of Medicine, researchers report that severe hypersensitivity reactions to cetuximab appear to be associated with immunoglobulin (Ig)E antibodies against galactose-alpha-1,3-galactose that were present before cetuximab therapy.

Using a recently developed assay, the researchers found IgE antibodies in serum samples obtained from both from patients and controls. The results showed IgE antibodies specific for the oligosaccharide galactose-alpha-1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain.

"From the oncology point of view, we never thought that the sugars on these molecules would be a problem," said study author Thomas A.E. Platts-Mills, MD, professor of internal medicine and microbiology and head of the division of allergy and clinical immunology at the University of Virginia, in Charlotteville. "None of the manufacturers had any concerns about them. What we proved most clearly in our study is that the IgE antibodies are against the sugar."

The researchers also observed a high prevalence of the IgE antibody in regions where anaphylactic reactions to cetuximab have been previously reported.

Hypersensitivity Previously Reported

Recombinant monoclonal antibodies are playing an increasing role in the treatment of many conditions, including cancers, inflammatory bowel disease, rheumatoid arthritis, and asthma. However, these agents can cause rapidly developing and severe hypersensitivity reactions, which occur in about 3% of patients treated with cetuximab.

The prevalence of hypersensitivity reactions has been observed to occur at higher rates and in clusters of cases in several southeastern states, including North Carolina, Arkansas, Missouri, Virginia, and Tennessee. A study published in the August 20 issue of the Journal of Clinical Oncology (2007;25:3644-3648) found that the overall rate of grades 3 to 4 hypersensitivity reactions to cetuximab was 22% among patients treated in Tennessee and North Carolina. This was significantly higher than the rate noted in any large published trial, as previously reported by Medscape Oncology.

Analysis Finds Preexisting IgE Antibodies

Dr. Platts-Mills and colleagues investigated the hypothesis that severe hypersensitivity reactions experienced by patients during their initial infusion of cetuximab are mediated by preexisting IgE antibodies against cetuximab. They analyzed serum samples obtained from 4 groups of individuals for IgE antibodies against cetuximab.

In addition to analyzing serum samples from patients who had been treated with cetuximab, they also examined samples obtained from individuals residing in 3 distinct locations in the United States and investigated the geographic differences in rates of hypersensitivity reaction.

Group 1 consisted of samples from 76 cancer patients who had received cetuximab at multiple centers, predominantly in Tennessee, Arkansas, and North Carolina. The other 3 groups were control groups. Group 2 consisted of 72 healthy volunteers from Tennessee; group 3 consisted of 49 patients with cancer of the head and neck (3 had received cetuximab) from Northern California; and group 4 consisted of 341 women from the Boston area. Northern California and Boston are both regions in which a low prevalence (<1%) of hypersensitivity reactions during cetuximab treatment has been reported.

A total of 538 serum samples were obtained from all 4 groups, and 38 contained IgE antibodies against cetuximab. Among the 76 cancer patients from the first group, 25 had experienced a hypersensitivity reaction; 17 of them tested positive test for IgE antibodies against cetuximab in pretreatment serum, but only 1 of 51 patients who did not have a hypersensitivity reaction had these antibodies before beginning cetuximab treatment.

The researchers found that sensitivity and specificity of a positive assay for IgE antibodies for any hypersensitivity reaction were 68% and 98%, respectively; for severe reactions, those values were 92% and 90%. A higher rate of hypersensitivity reactions was observed among patients with IgE antibodies against cetuximab than among those without them.

In group 2, which consisted of healthy control subjects from Tennessee, 15 of 72 serum samples (20.8%) tested positive for IgE antibodies against cetuximab. Both the prevalence and titers of IgE antibodies against cetuximab were similar to those obtained from cancer patients in group 1.

Low levels of IgE antibodies were observed in groups 3 and 4. Among head and neck cancer patients in California, 3 of 49 serum samples (6.1%) tested positive; among female controls in Boston, only 2 of 341 (0.6%) showed IgE antibodies against cetuximab. These low rates, the researchers note, parallel the low rates of hypersensitivity reactions that have been reported with cetuximab treatment in those regions.

Reasons for Regional Differences Unclear

The explanation for the regional distribution of IgE antibodies against galactose-alpha-1,3-galactose in the United States remains unclear, but 1 hypothesis is that regional exposures to histoplasmosis, ameba, tick bites, coccidioidomycosis, nematodes, or cestodes can induce IgE antibodies to oligosaccharides.

"In an African village, we found that 80% of 11-year-old children had IgE antibodies to sugars, which is far higher than we saw in Tennessee," said Dr. Platts-Mills. "We looked at the correlation with different worms, and the one that correlated best was the echinococcus tapeworm."

In the United States, exposure to ticks might be the more likely explanation: 1 individual who was bitten by several hundred seed ticks subsequently developed antibodies to IgE. "At the moment, we have seen evidence in favor of tapeworms from African data and in favor of ticks from American data," said Dr. Platt-Mills. "But it is ongoing research.

The results of this study have implications for evaluating the risks associated with antibody-based therapeutics, as well as understanding the relevance of IgE antibodies specific for posttranslational modifications of natural and recombinant molecules, the authors conclude.

There are no recommendations for screening patients at the current time. "The company is investigating the possibility of screening, but 1 of the problems is that screening will probably not be recommended for individuals residing in low-risk areas," explained Dr. Platts-Mills. "It may be difficult to work out who should be screened."

This study was supported by Bristol-Myers Squibb, ImClone Systems, the Damon Runyon Clinical Investigator Award, the Robert J. and Helen C. Kleberg Foundation, grants from the National Institutes of Health, grants from the Vanderbilt University, and grants from the National Institute of Allergy and Infectious Diseases.

Dr. Platts-Mills and several other authors report having received honoraria for attending advisory meetings and lecture fees from Bristol-Myers Squibb; 2 authors are full-time employees of Bristol-Myers Squibb and 2 are full-time employees of ImClone.

N Engl J Med. 2008; 358:1109-1117.


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