Severe anaphylactic reactions have been reported after treatment with several different monoclonal antibodies, but the mechanism of these reactions has not been defined, and their rates have generally been less than 1%.1-5,7,8,22
Our results show that most of the severe hypersensitivity reactions to cetuximab in the subjects we studied were associated with IgE antibodies against galactose-α
-1,3-galactose that were present before treatment with cetuximab. The assay we used identified 17 of the 21 subjects whose treatment had to be discontinued after the first infusion because of a hypersensitivity reaction.
Unlike most other monoclonal antibodies, cetuximab is produced in the mouse cell line SP2/0, which expresses the gene for α
The evidence that IgE antibodies that are specific for the post-translational modification of a molecule can cause severe infusion reactions may have relevance for an understanding of allergic responses to other recombinant molecules.
It is now recognized that all humans have IgG antibodies specific for the oligosaccharide galactose-α
-1,3-galactose, which is closely related to substances in the ABO blood group.23-25
This oligosaccharide is one of the major barriers to the transplantation of organs from other mammals in humans and has prompted the development of a strain of pigs in which the gene for α
-1,3-galactosyltransferase has been knocked out.24,26
Natural exposure to galactose-α
-1,3-galactose appears to induce the production of IgE antibodies against galactose-α
-1,3-galactose in some people. The presence of such IgE antibodies before treatment may put patients who receive monoclonal antibodies containing galactose-α
-1,3-galactose at risk for hypersensitivity reactions. The rapid reactions to cetuximab may be explained by intravenous injection, and the presence of galactose-α
-1,3-galactose on both Fab segments of the cetuximab antibody allows for the efficient cross-linking of IgE on mast cells (). Patients who have such antibodies do not report a rapid onset of allergic symptoms after the ingestion of beef, pork, or cow's milk. However, we have identified a series of patients with IgE antibodies against galactose-α
-1,3-galactose who reported having had episodes of anaphylaxis or severe angioedema 1 to 3 hours after eating beef or pork (unpublished data). The explanation for such a delayed reaction is not clear, but a similar delay has been reported in patients with IgE antibodies against carbohydrate epitopes of plant proteins.27,28
In addition, it has recently been reported that some patients with cat allergy have IgE antibodies that bind to a carbohydrate epitope on cat IgA.29
The high prevalence of hypersensitivity reactions to cetuximab in the Southeast is supported by our own data from the Tennessee group and in other recent studies.11
The striking difference in the prevalence of the IgE antibodies against cetuximab provides an explanation for the difference in rates of clinical hypersensitivity reaction between subjects in Boston or northern California and those in Tennessee, Arkansas, or North Carolina.6,11,30
A high prevalence of IgE antibodies against neuromuscular blocking agents in Norway was found to be associated with anaphylaxis, and the difference in incidence between Norway and Sweden was attributed to suxamethonium, an ingredient in a commonly used cough syrup in Norway.31,32
The explanation for the regional distribution of IgE antibodies against galactose-α
-1,3-galactose in the United States is not clear. Most humans have IgG antibodies against galactose-α
but we do not know why people in one area of the country have IgE antibodies against galactose-α
-1,3-galactose, whereas in other areas the incidence of such IgE antibodies is very low. The regional exposures that could be relevant include histoplasmosis, ameba, tick bites, coccidioidomycosis, nematodes, or cestodes. The effect does not appear to be a nonspecific enhancement of IgE production, since we found little or no association with IgE antibodies against allergens other than those derived from mammals.
In conclusion, we have identified a mechanism underlying a hypersensitivity reaction to cetuximab, preexisting IgE antibodies against an oligosaccharide present on the recombinant molecule. Our results have implications for evaluating risks associated with antibody-based therapeutics and for understanding the relevance of IgE antibodies specific for post-translational modifications of natural and recombinant molecules.