First-Dose Infusion Reaction to Ustekinumab is Associated With the Presence of Serum IgE Against Galactose-α-1,3-Galactose (α-gal)
Background:
Ustekinumab is a humanized monoclonal antibody (mAb) that targets the p40 subunit shared by interleukins 12 and 23, and is FDA-approved for the treatment of Crohn’s disease and ulcerative colitis. Hypersensitivity reactions to intravenous ustekinumab are reported to occur in 0.9-4.5% of cases. The cause of these reactions is uncertain, as type I IgE-mediated hypersensitivity reactions are unexpected without prior exposure to a given drug. One possible explanation involves IgE to galactose-α-1,3-galactose (α-gal), a glycan implicated in mammalian meat allergy and first-dose anaphylactic reactions to the monoclonal antibody cetuximab. Given that both cetuximab and ustekinumab are produced in the murine Sp2/0 cell line, we hypothesized that pre-existing IgE to α-gal could explain some first-dose infusion reactions to ustekinumab.
Methods:
Patients with Crohn’s disease who experienced first-dose infusion reactions to ustekinumab and were found to have detectable alpha-gal specific IgE in their serum were described from the practice of 2 academic providers’ clinics. An ImmunoCA<italic>P-</italic>based assay was used to test whether a separate cohort of patients with mammalian meat allergy had IgE that could bind to ustekinumab. We also tested serum reactivity of these patients against vedolizumab, a mAb generated in CHO cells that is not thought to express alpha-gal.
Results:
We identified 6 patients who had acute infusion reactions to the intravenous formulation of ustekinumab and had IgE specific for α-gal in their serum. All patients developed urticaria as part of the reaction and all went on to tolerate subcutaneous administration of ustekinumab at future visits. Serum-based ImmunoCAP testing in patients with mammalian meat allergy, but not controls, revealed high levels of IgE binding to cetuximab, moderate binding to ustekinumab, and no significant binding to vedolizumab.
CONCLUSION:
In this study, patients with the alpha-gal mammalian meat allergy exhibited IgE binding to ustekinumab, but not to a representative mAb generated in CHO cells. The level of IgE binding to ustekinumab was lower than that for cetuximab, but still detectable in the assay. The difference may be due to the established presence of α-gal on the Fab portion of cetuximab, whereas for ustekinumab it is reportedly limited to the Fc domain. When administered subcutaneously, ustekinumab was successfully tolerated by all of the patients who had reacted to the initial intravenous infusion. Additional studies evaluating the degree of IgE binding and basophil activation with exposure to various mAb concentrations would help determine if a dose-response relationship exists and could aid clinicians in optimizing the safe use of these monoclonal antibodies for patients with α-gal syndrome. For patients with mild to moderate hypersensitivity reactions to intravenous ustekinumab, switching to subcutaneous ustekinumab and considering referral to an allergist for monitored administration is advisable. In our experience, pre-medication before subcutaneous injections is reasonable but not required.
