9ncd
Crystal structure of the peanut allergen Ara h 9 with bound Fab IGX-3103 and antiFab nanobody
Structural highlights
Publication Abstract from PubMedBACKGROUND AND OBJECTIVES: Nonspecific lipid transfer proteins (nsLTPs) are frequently cross-reactive allergens that hamper diagnosis and avoidance. It is challenging to distinguish cross-reactivity from cosensitization with polyclonal serum owing to the presence of a few promiscuous antibodies or many highly specific antibodies. Objective: We hypothesized that a robust analysis of more human monoclonal antibodies (mAbs) would enable us to compare crossreactivity with cosensitization. METHODS: Human monoclonal antibodies were cloned from allergic patients via single cell sequencing and screened for affinity to extracts and recombinant allergens. Ara h 9 was expressed and crystallized with the mAb IGX-3103. Affinity for nsLTPs was explored using molecular modeling, site-directed mutagenesis, and ELISA. RESULTS: A human IgG4 mAb named IGX-3103 was discovered from a type 2-polarized memory B cell expressing CD23, IL-4Ra, and germline IGHE. IGX-3103 bound to 19 different type 1 nsLTP allergens and to extracts from sources without a characterized nsLTP allergen. The structure showed that IGX-3103 induced a conformational change in Ara h 9, enabling a hydrophobic residue from the antibody, Phe104, to enter the lipid binding cavity. Key residues in the epitope were identified to include Leu1, Ser2, Cys3, Lys39, and Asp43 in Ara h 9; these residues are conserved across type 1 nsLTPs, thus explaining the promiscuity of IGX-3103. CONCLUSIONS: IGX-3103 is an example of a human mAb with cross-reactivity to pollen, fruit, and seed type 1 nsLTPs. This observation anecdotally supports the possibility that a few promiscuous mAbs could be driving cross-reactivity. A Human Monoclonal Antibody Displays Promiscuous Binding to Multiple Type 1 nsLTP Allergens.,Leighton GO, Pedersen LC, Min J, Creeks P, Gabel SA, Perera L, Randall TA, Petrovich RM, Hamilton RG, Croote D, Mueller GA J Investig Allergol Clin Immunol. 2026 Feb 9:0. doi: 10.18176/jiaci.1143. PMID:41661651[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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