Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose

Abstract

Background: Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, is approved for use in colorectal cancer and squamous-cell carcinoma of the head and neck. A high prevalence of hypersensitivity reactions to cetuximab has been reported in some areas of the United States.

Methods: We analyzed serum samples from four groups of subjects for IgE antibodies against cetuximab: pretreatment samples from 76 case subjects who had been treated with cetuximab at multiple centers, predominantly in Tennessee, Arkansas, and North Carolina; samples from 72 control subjects in Tennessee; samples from 49 control subjects with cancer in northern California; and samples from 341 female control subjects in Boston.

Results: Among 76 cetuximab-treated subjects, 25 had a hypersensitivity reaction to the drug. IgE antibodies against cetuximab were found in pretreatment samples from 17 of these subjects; only 1 of 51 subjects who did not have a hypersensitivity reaction had such antibodies (P<0.001). IgE antibodies against cetuximab were found in 15 of 72 samples (20.8%) from control subjects in Tennessee, in 3 of 49 samples (6.1%) from northern California, and in 2 of 341 samples (0.6%) from Boston. The IgE antibodies were shown to be specific for an oligosaccharide, galactose-alpha-1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain.

Conclusions: In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy. The antibodies were specific for galactose-alpha-1,3-galactose.

Figure 1. IgE Antibodies Binding to Cetuximab in Serum Samples from 76 Case Subjects and 462 Control Subjects

Results are shown according to whether the treating physician reported a hypersensitivity reaction (HSR) to cetuximab or no HSR reaction. Results are also shown for pretreatment serum samples from control subjects and from subjects who had not received cetuximab. The horizontal lines indicate geometric mean values for the positive results. Values with multiplication signs indicate the number of negative values for each symbol.

Figure 2. Structure of Cetuximab

The amino acid sequence of cetuximab has potential glycosylation sites at Asn43 of the light chain and at Asn88 and Asn299 of the heavy chain. The sugars on the Fab portion include galactose-α-1,3-galactose and the sialic acid N-glycolylneuraminic acid. In contrast, the glycosylation site at Asn43 is not glycosylated, and glycosylation of the Fc portion of the heavy chain includes only oligosaccharides that are commonly present on human proteins., S–S denotes a disulfide bond.