Thomas A. Platts-Mills, MD, PhD
Hypersensitivity reactions to Cetuximab
In 2002, Dr. Roger Cohen first asked us to investigate hypersensitivity reactions to Cetuximab. Initial experiments using a Cetuximab Cap produced by Phadia identified positive results for IgE antibodies in pretreatment sera. Following the delayed (by the FDA) release of Cetuximab for treatment of colon cancer, and head and neck cancer, we became involved again because of severe reactions during the first infusion of this MAb. However, it also became obvious that these severe reactions were primarily in N. Carolina, Tennessee, Arkansas, Missouri and Virginia. Taking advantage of pre-treatment sera available from Dr. Chung and her colleagues in Nashville, we established that the reactions are caused by pre-existing IgE antibodies to the glycosylation on Asn-43 of the FAB portion of the MAB. (See Chung et al NEJ Med 358:1109, 2008). This MAB is heavily glycosylated with galactose-alpha-1, 3-galactose, and the IgE antibodies specific for this oligosaccharide cross react with many different mammalian glycoproteins. These findings have important implications for the development of recombinant molecules to treat cancer and other conditions:
Firstly, it is important to be aware that post-translational modifications of a molecule can be the target for IgE antibodies; and secondly that relevant sensitization giving rise to hypersensitivity reactions can be regional. We are currently working on developing screening assays for monoclonal antibodies, and also investigating IgE antibodies to other mammalian oligosaccharides that could create a risk for other hypersensitivity reactions.
The evidence that Cetuximab carries the oligosaccharide alpha-gal raises a second issue that we have already discussed with Dr. Paula Fracasso. The serum of all immuno-competent adults contains IgG antibodies specific for alpha-gal which could theoretically influence either the half life or the biological activity of Cetuximab. This question could be addressed in two ways either to test the titer of IgG ab to alpha-gal in pretreatment sera, and alternatively to test the effect of Cetuximab treatment on the titer of IgG ab to alpha-gal.