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Dupilumab-scFv deeply reaches HNEC and inhibits CCL26 expression

2024-07-13 13:36
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(developed by Regeneron/Sanofi)is an IgG4 subclass monoclonal antibody that targets and blocks the IL-4receptor alpha (IL-4Rα), a key ...
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Dupilumab (developed by Regeneron/Sanofi) is an IgG4 subclass monoclonal antibody that targets and blocks the IL-4 receptor alpha (IL-4Rα), a key regulatory cytokine in type 2 inflammation. The drug has shown impressive therapeutic efficacy in a variety of allergic diseases, including atopic dermatitis, chronic rhinosinusitis with nasal polyps (CSwNP), and asthma.However, adverse events associated with dupilumab injection, such as serum sickness syndrome and dose-dependent injection site reactions, have been sporadically reported. So there is a need for ways to mitigate injection-related side effects while maintaining the efficacy of dupilumab.

In the study, two variants of Dup-scFv were first generated: one has endoplasmic reticulum (ER) signal sequence, HDEL, at the C-terminus of the scFv and the other has no sequences. Each construct was co-infiltrated intoN. benthamiana leaves with p19 using the Agrobacterium-mediated method for transient expression. Then the authors evaluated the expression levels of these variants at different stages of tobacco plants, and estimated the expression efficiency of each variant. The results showed that the expression levels of Dup-scFv variants were not affected by the growth stage of the tobacco plants used, and the ER-retained form, Dup-scFv with HDEL, yielded higher expression, and was not lost during the purification steps.

They also determined the binding affinity of Dup-scFv to cells by flow cytometry and Surface Plasmon Resonance (SPR), and founded that Dup-scFv has a significant decrease in binding capacity. Next they assessed the blocking activity in IL-4/IL-13 cytokine signal transduction by Dup-scFv and dupilumaband founded that Dup-scFv efficiently masks the IL-4/IL-13-induced cytokine signaling transduction as a functional antibody. Finally, paracellular permeability of Dup-scFv and its signalling blocking activity on human nasal epithelial cells was investigated, and it was found that Dup-scFv, which exhibits paracellular permeability, is more effective compared to dupilumab in blocking receptors located deep in the cell layer.

In summary, they demonstrated that scFv derived from dupilumab was produced in plants and applied non-invasively to effectively suppress inflammation in human nasal epithelial cells cultured at the air–liquid interface. These results suggest the potential of plant-based small antibodies as a non-invasive route of treatment for autoimmune diseases.


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