We all have come across the word “antibodies” at some point, if not frequently. These specialized Y-shaped proteins consist of two polypeptides — heavy and light chains — which bind to the body’s foreign invaders, whether they are bacteria, fungi, parasites, or viruses. A nanobody is the recombinant protein version of heavy-chain only antibodies. It is the smallest antigen-binding entity.
The term “nanobody” was introduced by the Belgian biopharmaceutical company Ablynx, which was acquired by Sanofi in 2018. About 30 years ago, a group of Belgian scientists discovered non-canonical types of heavy-chain only antibodies (hCAb) in the blood of Camelidae, in addition to conventional antibodies. hCAb contains one variable domain (VHH) and two constant domains (CH2, CH3).
The recombinant VHH-domain is usually referred to as a nanobody. The unique features of nanobodies — small size, high stability, strong antigen-binding affinity, solubility, and natural origin — make them suitable for development into next-generation bio-drugs.
Initially, nanobodies were used just for research purposes, until a few years ago, when the first nanobody drug, Ablynx’s Cablivi (caplacizumab), was approved by the EMA (2018) followed by the FDA (2019). Since then, research into nanobodies as a therapeutic has dramatically increased in the fields of oncology, neurodegenerative diseases, and viral infections. At least 20 different nanobodies are currently being tested in different clinical trials. In addition to these ongoing efforts, the superior properties of nanobodies have also led to research into their efficacy for passive treatment of type I allergy.
Why are nanobodies considered a better alternative to conventional antibodies to treat allergy?
Type I allergy is an immunoglobulin E (IgE) antibody-mediated hypersensitivity disease and a common health problem affecting almost 30% of the population worldwide. Although pharmacotherapy-based anti-inflammatory drugs are the most common approach for reducing allergy symptoms, only allergen-specific immunotherapy (AIT) is an effective treatment for type I allergy. In contrast to vaccination with allergens, which induces allergen-specific IgG “blocking” antibodies, AIT involves direct delivery of recombinant allergen-specific IgG antibodies in order to achieve passive immunization.
In total, at least 17 antibody-based treatments for allergy and atopic dermatitis have been under development in recent years. For example, omalizumab (Xolair) is a humanized monoclonal antibody that binds to free human IgE and is used as a medication for asthma.
The identification and generation of conventional blocking antibodies are associated with the high cost of production (omalizumab for example), validation, and application, while nanobodies represent a cost-effective alternative to blocking conventional antibodies.
Nanobodies overlapping with antibody binding sites on allergens prevent IgE-mediated allergic reactions
Source: Frontiers in Immunology
In addition to minimal production costs, nanobodies are highly stable as compared to conventional antibodies, which is important both for long-term safety as well as use in developing countries.
Along with unique features of nanobodies such as small size (12 to 15 kDa), natural origin, and extended CDR3 loop with the formation of unusual paratopes, their usefulness in modulating enzyme activity suggests that allergen-specific nanobodies could modulate or inhibit the proteolytic activity of certain allergens and reduce their penetration capacity through mucosal surfaces. In 2019, researchers from the University of Science and Technology of China isolated a nanobody specific for a major peanut allergen from a synthetic library of humanized nanobodies via phage display. However, the affinity of the nanobody needs improvement before it can be used for the first use case as a biosensor for peanut allergen detection.
Limitations to the use of nanobodies:
Like all therapies, nanobodies also have drawbacks. Their small size results in rapid clearance through the kidneys, leading to reduced half lives. Therefore, to ensure enough volume of nanobodies to achieve the specified effect, recurrent dosing is required, which can cause side effects like kidney toxicity. There could be a risk of immune reaction because they are biologics.
However, these problems could be overcome. For example, by fusing nanobodies to albumin, the half life could be increased and allow them to remain within the blood longer. Also, the immunogenicity of nanobodies could be tackled via the process of humanization.
Conclusion:
Not only do the unique features of nanobodies make them suitable for passive allergy treatment, but in addition, their ability to be modified as bi-valent or oligo-valent derivatives with inhibitory potential shows promise for the development of nanobody-based drugs against serious allergens.
