Human monoclonal antibodies targeting α-Gal restrict IgE engagement of α-Gal syndrome allergens

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Abstract

Allergen-specific monoclonal antibodies (mAbs) that block IgE binding to allergens are emerging as new therapeutics for treating allergies to pollen, peanuts, and cats. Alpha-Gal syndrome (AGS) is an allergy to galactose-α-1,3-Galactose (α-Gal), which is present in mammalian meat and tissue-derived products. Initially aiming to identify mAbs targeting α-Gal on malaria parasites, we isolated 42 α-Gal–specific mAbs from B cells of individuals who had been exposed to malaria but found that they bound weakly to the Plasmodium falciparum parasite. These mAbs predominantly used the IGHV3 gene family and had a wide range of mutation frequencies. We then screened these mAbs for their ability to bind α-Gal on AGS allergens and to block the binding of serum IgE of patients with AGS to AGS allergens. Thirteen mAbs bound to the AGS allergens angiotensin-I-converting enzyme (ACE), aminopeptidase-N (AP-N), and cetuximab, and 2 mAbs— AG028 as both IgA2 and IgM, and AG050 IgA1 — blocked the binding of serum IgE from patients with AGS to ACE and AP-N. Additionally, AG028 IgA2 and AG028 IgM suppressed ACE-mediated activation of basophils sensitized with serum of patients with AGS. This study supports the development of α-Gal–specific mAbs as a new intervention to prevent α-Gal allergy.

Authors

Hyeseon Cho, Youngsil Seo, Haewon Sohn, Shailesh K. Choudhary, Jeff Skinner, Ming Zhao, Ludmila Krymskaya, Weizhi Zhong, Justin Lack, Shanping Li, Boubacar Traore, Joshua Tan, Scott P. Commins, Peter D. Crompton