A novel approach to predict cetuximab-induced hypersensitivity reaction: detection of drug-specific IgE on basophils.

Takuya Iwamoto,Alberto A Gayle,Masahiro Okuda,Akiharu Okamoto,Hajime Ishinaga,Kasumi Shimizu,Naoya Arai,Kazuhiko Takeuchi

doi:10.1002/cam4.658

Abstract

Cetuximab is remarkable for the relatively high rate and severity of hypersensitivity reactions (HR) being reported in the literature. Screening for cetuximab‐specific IgE in serum via immunoassay has been found to be useful in preventing HR; however, these tests are known to have a low positive predictive rate. In an attempt to remedy this, we evaluated the interaction between cetuximab and IgE on basophils for predicting severe cetuximab‐induced HR. Twelve head and neck cancer patients were enrolled in this single‐institution study: four with a history of cetuximab‐induced HR and eight with no such history. Cetuximab‐specific and galactose‐α‐1,3‐galactose (α‐gal) specific IgEs in serum were measured in vitro using an enzyme‐linked immunosorbent assay (ELISA). IgE‐cetuximab binding on basophils was also analyzed to evaluate the decrease in cetuximab molecules on basophils after dissociation of IgE from FcεRI. The positive predictive value associated with the presence of cetuximab‐ or α‐gal‐specific IgE in serum was found to be only 0.67, whereas the negative predictive value was 1.00. On the other hand, in all four patients who developed HR, the cetuximab molecules on basophils were decreased significantly due to the dissociation of IgE from basophils (P < 0.05). However, this was not the case in patients who did not develop HR. In conclusion, our results strongly imply that the IgE‐cetuximab interaction on basophils may be key to developing improved methods for predicting severe cetuximab‐induced HR.

Highlights

Cetuximab, a chimeric mouse–human IgG1 monoclonal antibody, is an epidermal growth factor receptor antagonist that is widely used for the treatment of metastatic colorectal cancer and squamous cell carcinoma of the head and neck [1]
Several studies have been conducted in order to predict cetuximab-induced severe hypersensitivity reaction (HR) based on the IgE antibody’s recognition of cetuximab’s Fab glycosylation site
We obtained similar results: the positive predictive value associated with the presence of cetuximab-or α-gal-specific IgE was found to be only 0.67, whereas the negative predictive value was 1.00, with a good linear relationship shown between the expression levels of the cetuximab-and α-gal-specific IgEs in all study patients (Fig. 1C)

Summary

Introduction

A chimeric mouse–human IgG1 monoclonal antibody, is an epidermal growth factor receptor antagonist that is widely used for the treatment of metastatic colorectal cancer and squamous cell carcinoma of the head and neck [1]. The reported incidence of cetuximab-associated severe HR (grade 3 or 4) has varied from 1.1% to 5.0% [1,2,3,4,5,6], with even higher rates having been reported in Tennessee and North Carolina (18.9% and 25.7%, respectively) [7, 8]. In such cases, the clinical symptoms most often associated with severe HR were rapid onset of airway obstruction, hypotension, shock, loss of consciousness, myocardial infarction, and/ or cardiac arrest [9, 10]. The acute nature and severity of these symptoms [11] are suggestive of a type I allergic reaction mediated by preexisting IgE antibodies cross- reactive with cetuximab.

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