New Data Suggest Low Risk in Hamster Ovary-Derived Therapies For Alpha-Gal Syndrome

Understanding Alpha-Gal Syndrome and Its Implications for Biologic Therapies

Alpha-gal syndrome is classified as an IgE mediated food allergy to the galactose-α-1,3-galactose (alpha-gal), a carbohydrate found in non-primate mammal meat and its derivatives. Alpha gal is also present in nonfood sources such as medications and vaccines, including monoclonal antibodies. This raises a concern for possible adverse reactions to monoclonal antibody (mAb) therapies used in patients with alpha-gal syndrome.

In 2008, Chung et al reported that IgE antibodies specific for alpha-gal were present in patients who had hypersensitivity reactions to the monoclonal antibody cetuximab (Erbitux; Eli Lilly), produced by the mouse cell line SP2/0 (murine myeloma). Murine cell lines, such as NS0 or SP2/0, possess the enzyme α-1,3-galactosyltransferase (α1,3GT), which leads to the incorporation of alpha-gal structures in their glycoproteins.¹

Other monoclonal antibodies, such as those produced using Chinese hamster ovary (CHO) cells, do not express α-1,3-galactosyltransferase, and thus are thought to lack alpha gal epitopes. However, Bosques et al identified a CHO ortholog of N-acetyllacetosaminide 3-a-galactosyltransferase-1, which can produce alpha gal epitopes.² They reported that glycosylated proteins produced using CHO cells do indeed contain alpha gal antigens.² Therefore, it is possible for patients with alpha gal syndrome to have hypersensitivity reactions to monoclonal antibodies produced using CHO cells.

To assess the risk of a hypersensitivity reaction to a monoclonal antibody in patients with positive serum IgE to alpha-gal, a retrospective chart review was performed using an electronic medical record data base of a large medical center. A total of 256 patients were identified as having the ICD-10 diagnosis code for alpha gal allergy, as well as having a J-code for having received a monoclonal antibody. Of these, 215 patients were excluded (132 with alpha gal serum IgE less than 0.10 kU/L, 24 without any laboratory evaluation of serum IgE to alpha gal level, 35 who were not on a biologic when alpha gal serum IgE was obtained, and 26 for whom a monoclonal antibody treatment was not detected in the chart).

Low Incidence of Adverse Reactions Supports CHO-Derived mAb Safety

Fourteen monoclonal antibody drugs were included, as shown in Figure 1 (11 produced with CHO cells, 2 from murine myeloma cells, and 1 from a yeast cell line). Forty-one patients were included in the study: 38 patients received mAbs derived from CHO cells, 2 patients received mAbs derived from murine myeloma cell lines, and 1 patient received a mAb produced from yeast cells.

Among the 41 patients included in the study, 3 adverse reactions occurred in 3 patients, 1 each to tezepelumab (Tezspire; Amgen), ustekinumab (Stelara; Janssen Biotech), and dupilumab (Dupixent; Regeneron). Tezepelumab and dupilumab are produced in CHO cells while ustekinumab is produced in a murine myeloma cell line. The patient who received tezepelumab (average alpha gal serum IgE = 0.94 kU/L) experienced localized redness and swelling at the injection site immediately after injection which resolved in a few hours. This patient reported dyspnea, arm pain and swelling, and a choking sensation 21 hours after receiving the injection which also resolved that same day. This occurred after the first injection, and the medication was discontinued after this episode.

The patient who received dupilumab (average alpha gal serum IgE = 0.21 kU/L) experienced redness and pain at the injection site after the first injection, but this resolved with subsequent injections. The patient who received ustekinumab (average alpha gal serum IgE = 1.18 kU/L) experienced redness at the injection site with all injections. Ustekinumab was continued, and the patient was given antihistamines prior to injections. The rate of adverse reaction to a mAb derived from CHO cells was 2 episodes in 822 administrations (0.024%). This incidence is at or below reported reaction rates in the general population.

The patient with a reaction after tezepelumab had also received 3 other mAbs produced with CHO cells (74 injections over 4 years) and did not have any reactions to these other mAbs. Therefore, it is unlikely that this patient’s reaction was triggered by alpha gal epitopes conferred via glycosylation to the monoclonal antibody. The reaction to dupilumab occurred with the first injection only, and the patient tolerated subsequent injections, so it is also unlikely that this was a reaction to alpha gal epitopes. The reaction to ustekinumab could have been due to pre-formed IgE to alpha gal, as this is a mAb produced from murine myeloma cells and is known to contain alpha-gal antigens.

Each patient noted that had an adverse reaction to their respective CHO cell monoclonal antibody treatment had lower alpha-gal IgE levels. In our study, higher alpha-gal serum IgE did not appear to be associated with a higher risk of reactions to CHO derived biologics (Figure 2).

While alternate therapies that are not murine derived would be the safest choice in patients with alpha-gal allergy, in the treatment of B-cell lymphomas, first line treatments of rituximab (Rituxan; Genentech) and Obinutuzumab (Gazyva; Roche) are both CHO derived, leading to limited non-mammalian treatment options.Based on the information in this retrospective chart review, the use of CHO-derived monoclonal antibodies in patients with an alpha-gal allergy is likely safe.

In conclusion, the data presented illustrates that the use of monoclonal antibodies produced with CHO cells in patients with an alpha-gal allergy is likely safe.

REFERENCES

1. Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358:1109-17.

2. Bosques CJ, Collins BE, Meador JW 3rd, Sarvaiya H, Murphy JL, Dellorusso G, et al. Chinese hamster ovary cells can produce galactose-α-1,3-galactose antigens on proteins. Nat Biotechnol. 2010;11:1153-6. doi: 10.1038/nbt1110-1153. Erratum in: Nat Biotechnol. 2011;5:459.