A new study revealed 2 of the 42 human monoclonal antibodies targeting galactose-alpha-1,3-galactose (alpha-gal), AG028 and AG050, blocked the binding of serum immunoglobulin E (IgE) to major allergens in patients with alpha-gal syndrome (AGS).1
No disease-modifying therapy exists for AGS, leaving avoidance of mammalian meat and tick exposure as the only management strategy. Allergen-specific mAbs designed to block IgE engagement have advanced for birch, cat, and peanut allergy, supplying a rationale for a similar approach in AGS. Approximately 110,000 suspected cases have been identified in the US since 2010, a figure the investigators described as a substantial underestimate.¹
“Geography compounds the problem,” said investigator Scott Commins, MD, PhD, from UNC Health, in a guest post published on HCPLive.2 “AGS was long considered a southeastern US condition tied primarily to the lone star tick (Amblyomma americanum). However, the tick’s geographic range has expanded into increasingly diverse areas of the United States. Confirmed cases have now emerged farther north, including in Maine following bites from Ixodes scapularis and in Washington State following exposure to Ixodes pacificus.”
Anti-Alpha-Gal Monoclonal Antibody Binding to AGS Allergens
The new study, led by Hyeseon Cho, PhD, and Youngsil Seo, PhD, both of the Malaria Infection Biology and Immunity Section at the National Institute of Allergy and Infectious Diseases in Rockville, Maryland, originated as an effort to identify antibodies targeting alpha-gal on the malaria parasite.
Cho and colleagues drew B cells from 18 participants in a Malian cohort who carried high anti-alpha-gal antibody levels, generating a panel of 42 fully human monoclonal antibodies. The antibodies bound the parasite only weakly, prompting a pivot to AGS.
The panel was then screened against 3 clinically relevant allergens: angiotensin-I-converting enzyme (ACE) and aminopeptidase-N (AP-N), both purified from porcine kidney and established triggers of delayed red meat anaphylaxis, plus cetuximab. Thirteen antibodies bound all 3. Sequence analysis showed predominant use of the IGHV3 gene family, with IGHV3-7 the most frequent heavy chain gene at 31% (13 clones).
Alpha-Gal Antibody Inhibition of IgE Binding and Basophil Activation
Screening against serum from patients with AGS narrowed the field to 2 antibodies, AG028 and AG050, with AG028 tested in 2 isotype formats. AG028 as IgA2 and as IgM blocked IgE binding to all 3 allergens, with inhibition ranging from roughly 60% to 97%. AG050 IgA1 blocked IgE binding to ACE and AP-N by approximately 81% to 91%.
The remaining antibodies achieved < 60% inhibition. Preincubating the antibodies with soluble alpha-gal abolished their binding to all 3 allergens, confirming they act on the alpha-gal epitope itself.¹
Investigators then tested whether the blocking translated into a cellular effect. Basophils from healthy donors were cleared of their own IgE via lactic acid stripping of membrane-bound IgE and resensitized overnight with serum from 2 patients with AGS, then challenged with allergen.
Against the first patient's serum, AG028 IgA2 and AG028 IgM cut ACE-driven basophil activation by 86.2% and 78.8%, respectively, at the highest concentration tested. Inhibition of AP-N-driven activation reached 60.1% and 68.8%. Against the second patient's serum, all 3 antibodies showed little effect, and blocking IgE binding in the plate assay did not reliably predict whether basophil activation would be suppressed.¹
Serologic profiling of 88 patient samples and 31 healthy controls found elevated IgE reactivity to ACE, AP-N, and cetuximab in AGS, but not to milk proteins. Patients also showed higher IgG1 through IgG3 binding, with little correlation to IgE levels.¹
“This study provides proof-of-concept that α-Gal–specific mAbs can inhibit IgE binding to key AGS allergens and attenuate downstream cellular activation,” investigators wrote. “These findings support continued efforts to discover and develop targeted antibody-based therapeutics for AGS.”
References
Cho H, Seo Y, Sohn H, et al. Human monoclonal antibodies targeting α-Gal restrict IgE engagement of α-Gal syndrome allergens. J Clin Invest. 2026;136(17):e192370. doi:10.1172/JCI192370
