Fel d 1‐Expressing Plant‐Derived Bioparticle: A Novel Treatment for Cat Allergy

Background Allergen immunotherapy (AIT) is the only disease‐modifying therapeutic approach for cat allergy, though it requires at least three years of treatment and can potentially induce severe systemic reactions. Plant‐derived bioparticles expressing Fel d 1 allergen (Fel d 1 e BP) have been developed as a novel therapeutic candidate for cat allergy. We aimed to investigate the allergenicity and immunogenicity profile of Fel d 1 e BP. Methods Fel d 1 e BP was synthesised in vivo in Nicotiana benthamiana and confirmed by cryo‐electron microscopy and tomography. Immune modulatory properties of purified natural Fel d 1 (nFel d 1) and Fel d 1 e BP were assessed at T and B cells by flow cytometry in 12 cat‐allergic subjects (CA) and 12 non‐atopic controls (NAC). Single‐cell RNA‐seq was used to assess molecular mechanisms of Fel d 1 e BP immune skewing. The safety of Fel d 1 e BP was assessed by measuring basophil responsiveness in whole blood and further confirmed in vivo by its administration as a skin prick test (SPT) in 20 cat‐allergic individuals. Results Fel d 1 e BP was shown to be a strong inducer of Th1 cells ( p < 0.05) and IL‐10 + non‐Th2 cells ( p < 0.05) in CA subjects. Fel d 1 e BP showed a stronger trend for inducing IL‐10 + Breg cells compared to nFel d 1, peaking at 3 μg/mL. scRNA‐seq analyses demonstrated that Fel d 1 e BP targets the induction of protective metallothionein genes, CCL18 + monocytes and naïve B cells that are interferon responsive and metabolically activated. Moreover, Fel d 1 e BP demonstrated reduced capacity to elicit basophil activation ( p < 0.001) and histamine release ( p < 0.01), indicating their hypoallergenic nature. Administration of titrated doses of Fel d 1 e BP through skin prick test revealed that they are well‐tolerated with reduced mean wheal compared to native Fel d 1 in an open‐label Phase 0 study (all, p < 0.001). Conclusions We demonstrate that Fel d 1 e BP is hypoallergenic and demonstrates tolerogenic properties, making it a novel candidate for use in AIT for cat allergy.