IgE to Galactose-α-1,3-Galactose (α-Gal) and Relevance to Ustekinumab First-Dose Infusion Reactions and Allergenicity.

Aims: Ustekinumab, a monoclonal antibody (mAb) used to treat inflammatory bowel disease, has been associated with immediate hypersensitivity reactions during first intravenous infusion. While rare, the mechanism for these reactions is unclear. IgE to the oligosaccharide galactose-α-1,3-galactose (α-gal) is a cause of allergy to mammalian meat and other mammalian products that express α-gal. Given that ustekinumab (Stelara) is produced in murine SP2/0 cells, a cell line known to introduce α-gal during post-translational modification, we hypothesized that α-gal could explain some of these reactions. Methods and Results: We describe six patients with Crohn's disease who experienced acute reactions during ustekinumab infusion and were found to have IgE specific to α-gal. Serum or cells from a separate group of α-gal IgE-sensitized patients with red meat allergy were used for in vitro experiments to investigate ustekinumab allergenicity. ImmunoCAP binding assays confirmed that IgE from four red meat allergic patients, but not controls, bound to ustekinumab on the solid phase. This binding was inhibited by the α-gal-containing glycoprotein beef thyroglobulin. Basophil activation tests (BAT), carried out to assess functional activity, revealed dose-dependent activation with ustekinumab from four α-gal-sensitized individuals, but not controls. Two other mAbs produced in SP2/0 cells (cetuximab and infliximab) as well as a representative mAb produced in Chinese Hamster Ovary (CHO) cells (vedolizumab) were evaluated as comparators, with the mAbs from SP2/0 but not CHO cells eliciting BAT activity. Conclusions: Pre-existing IgE to α-gal may account for some first-dose infusion reactions to ustekinumab. Screening for α-gal sensitization in patients with alpha-gal syndrome should be considered prior to ustekinumab infusion.