Rational attenuation of elapid long-chain neurotoxin by targeted residue substitution and disulfide architecture simplification: implications for receptor interaction and immune recognition

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  Rational attenuation of elapid long-chain neurotoxin by targeted residue substitution and disulfide architecture simplification: implications for receptor interaction and immune recognition Abstract Elapid long-chain neurotoxins (LNTxs) exert their toxicity through high-affinity binding to nicotinic acetylcholine receptors (nAChRs). Specific residues mediate this process, including basic (Lys23, Arg33, Arg36, Lys49), structural (Cys26, Cys30), and aromatic (Phe29) amino acids. To investigate the functional and immunogenic implications of modifying these residues, we designed two recombinant variants of a consensus LNTx. The first variant, rLcNTx V1, contains charge-reversal mutations at four key basic positions, while the second, rLcNTx V2, lacks the segment corresponding to the fifth disulfide bond. We expressed both variants in Escherichia coli Origami cells. rLcNTx V1 was recovered in a soluble form, but rLcNTx V2 was present only in inclusion bodies. We assessed the binding ...

Successful venom immunotherapy with avapritinib in a patient with systemic mastocytosis

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Successful venom immunotherapy with avapritinib in a patient with systemic mastocytosis

Systemic mastocytosis (SM) is a clonal mast cell (MC) disorder characterized by tissue infiltration of MCs driving clinical symptoms.1 The disorder is characterized by activating mutations in the KIT protein, classically KIT p.D816V. SM is treated in a symptom-guided manner with therapies targeted toward bioactive MC mediators. However, the recent discoveries of targeted tyrosine kinase inhibitors have changed the treatment paradigm of indolent SM (ISM).2 Tyrosine kinase inhibitors have demonstrated to reduce MC burden and improve quality of life. To date, they have not been used to facilitate venom immunotherapy (VIT). Patients with mastocytosis and Hymenoptera venom allergy may have recurrent anaphylaxis during VIT, and adjunctive therapies are a significant unmet need to protect this patient population. Although omalizumab has been found to be effective in a subset of patients, non-IgE-mediated mechanisms may be activated by Hymenoptera venom and an increased mutated MC burden may contribute to life-threatening symptoms. We report, here, the first case of successful VIT in a patient with ISM treated with avapritinib.

Depina, L., Karmarkar, S. N., Moeller, S., Lazarovich, M., De Magalhães, A. R., Castells, M., & Giannetti, M. P. (2025). Successful venom immunotherapy with avapritinib in a patient with systemic mastocytosis. Annals of Allergy, Asthma & Immunology, 135(3), 343-344. https://doi.org/10.1016/j.anai.2025.06.015