The cold nights of winter are finally over, and it’s summer again; you’re outside enjoying the weather, when suddenly you notice your nose starting to run, and your eyes begin to tear up. Immediately, you know what it is: allergic rhinitis, more commonly known as “Hay Fever”, caused by an allergic reaction to pollen released by trees or grass in the warmer months of the year. According to the WHO, around 22% of the world population suffers from hay fever, and depending where you live and what you’re allergic against, symptoms can last anywhere from a week to multiple months.
In broad terms, allergies are caused by your body’s immune system overreacting; treating a harmless, foreign object as hostile. These foreign objects, called allergens, trigger an unwarranted immune response, causing mast cells and basophils to release a neurotransmitter called histamine. This histamine then travels through the blood and is primarily responsible for the typical symptoms of hay fever, such as sneezing, runny nose, and itchy eyes.
If you or someone you know has hay fever, you may have already heard of antihistamines, probably under their brand names such as Benadryl, Claritin, or Allegra. They work primarily by blocking the neuroreceptors that histamine binds to, and preventing the aforementioned symptoms. However, as a side-effect of blocking neuroreceptors, antihistamines often cause drowsiness or fatigue. What if there was a way to prevent an allergic reaction earlier in the pathway? What if there was a way to stop the allergen from even entering your body in the first place?
That’s precisely what professor Sabine Flicker and Ph.D. student Ines Zettl from the Medical University of Vienna suggested in their new paper titled “Generation of high-affinity ICAM-1-specific nanobodies and evaluation of their suitability for allergy treatment” published in Frontiers in Immunology early November 2022. They aim to use nanobodies as an external bioshield that would bind to allergens, preventing them from entering the bloodstream and triggering an allergic response in the first place.
So what are nanobodies? As the name suggests, nanobodies are very small parts of an antibody that are great at binding to an allergenic epitope. To put this into perspective, the average human antibody has a size of 150 kDa (kDa stands for kilo-Daltons, a unit used to measure the mass of proteins), whereas nanobodies are a measly 12-15 kDa. They are obtained by synthetically cutting off the variable domain of an antibody, only keeping the part that binds an allergen. Unfortunately, this smaller size means that nanobodies aren’t quite as good at slowing down allergens as their bulkier antibody cousins.
But nanobodies can be engineered to bind to almost anything: that’s why in their new paper, Dr. Flicker and Zettl engineered a nanobody to bind to intercellular adhesion molecule 1 (ICAM-1), which is naturally expressed on the surface of epithelial cells inside your nose. So, we now have a nanobody that binds to an allergen, and one that binds to cells in your nose. How do we bring them together?
At the end of their paper, Flicker and Zettl write: “We envision that [nanobodies] could be used to engineer allergen/ICAM-1-specific heterodimers to develop bispecific nanobodies for topical treatments of pollen allergy”. Indeed, Flicker, Zettl, and Christina Weichwald further expand on this idea in an article published in the International Journal of Molecular Sciences titled “Antibody Conjugates Bispecific for Pollen Allergens and ICAM-1 with Potential to Prevent Epithelial Allergen Transmigration and Rhinovirus Infection”. The idea is that two different nanobodies—one that binds to ICAM-1, the other to an allergen—can be brought together to create a double-nanobody heterodimer. This could be achieved by engineering a protein “zipper” to the ends of the nanobdies, that would pull and hold them together to form the heterodimer.
“We envision that [nanobodies] could be used to engineer allergen/ICAM-1-specific heterodimers to develop bispecific nanobodies for topical treatments of pollen allergy”. - Dr. Sabine Flicker and Ines Zettl, Medical University of Vienna
This bispecific nanobody could then potentially be applied as a nose spray, and act as a filter: catching any allergens that might be inhaled, by binding them to the inside of your nose. The next time you blow your nose, all the allergens will be swept out instead of entering the bloodstream and causing an allergic reaction.
But why go through the trouble of making hetero-dimers with nanobodies, instead of just using regular antibodies? Turns out that traditional antibodies are hard to produce and degrade very rapidly, making them expensive to manufacture and difficult to store. Their simple structure makes anobodies more robust, and allows researchers to attach other proteins for various functions, such as protein zippers for heterodimerization. Furthermore, nanobodies can easily be expressed in bacteria, and bind just as strongly to their epitope—if not stronger!
Although this technology is yet to be developed, nanobody heterodimers may one day be a viable alternative to antihistamines for millions of people who have pollen allergies.
Sources
Zettl I, Ivanova T, Zghaebi M, et al. Generation of high affinity ICAM-1-specific nanobodies and evaluation of their suitability for allergy treatment. Frontiers in Immunology. 2022 ;13:1022418. DOI: 10.3389/fimmu.2022.1022418. PMID: 36439110; PMCID: PMC9682242. https://europepmc.org/article/pmc/pmc9682242
Flicker S, Zettl I and Tillib SV (2020) Nanobodies—Useful Tools for Allergy Treatment? Front. Immunol. 11:576255. doi: 10.3389/fimmu.2020.576255 https://www.frontiersin.org/articles/10.3389/fimmu.2020.576255/full
Zettl, I, Ivanova, T, Strobl, MR, et al. Isolation of nanobodies with potential to reduce patients' IgE binding to Bet v 1. Allergy. 2022; 77: 1751– 1760. doi:10.1111/all.15191 https://onlinelibrary.wiley.com/doi/full/10.1111/all.15191
Weichwald, C.; Zettl, I.; Ellinger, I.; Niespodziana, K.; Waltl, E.E.; Villazala-Merino, S.; Ivanov, D.; Eckl-Dorna, J.; Niederberger-Leppin, V.; Valenta, R.; Flicker, S. Antibody Conjugates Bispecific for Pollen Allergens and ICAM-1 with Potential to Prevent Epithelial Allergen Transmigration and Rhinovirus Infection. Int. J. Mol. Sci. 2023, 24, 2725. https://doi.org/10.3390/ijms24032725
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