- Single-domain VHH antibodies, also known as nanobodies, are small antibody fragments derived from a special type of antibody found in camelids such as camels, llamas, and alpacas.
- Unlike conventional antibodies, which are composed of two heavy chains and two light chains, camelids naturally produce heavy-chain–only antibodies that completely lack light chains. In these unique antibodies, the antigen-binding function is carried out by a single variable domain, referred to as the VHH domain. This domain retains the full binding specificity of a normal antibody but is only about one-tenth the size, with a molecular weight of roughly 12–15 kDa.
- The small size of VHH antibodies provides a number of functional advantages. They can penetrate dense tissues and access binding sites that are inaccessible to larger antibodies. Their structure is exceptionally stable, allowing them to remain functional even under extreme conditions such as high temperatures, acidic pH, or the presence of proteases.
- They are also highly soluble and less prone to aggregation, which facilitates their use in both laboratory and clinical settings. Despite their small size, VHHs maintain high affinity and specificity for their targets, comparable to that of full-size antibodies.
- From a production standpoint, VHH antibodies are easier and more cost-effective to manufacture compared to conventional IgGs. They can be produced efficiently in microbial expression systems like E. coli or yeast, eliminating the need for more expensive mammalian cell culture. The process typically involves immunizing a camelid with the target antigen, isolating lymphocytes, extracting the genes encoding the VHH domains, and using techniques like phage display to select high-affinity binders. These binders can then be expressed and purified at scale.
- VHH antibodies have found a wide range of applications. In therapeutics, they have been developed for the treatment of diseases such as autoimmune disorders, cancer, and infectious diseases. For example, caplacizumab, a nanobody approved by regulatory agencies, is used to treat thrombotic thrombocytopenic purpura. In diagnostics, VHHs are used in biosensors and imaging agents due to their stability and specificity.
- They are also valuable research tools, functioning as crystallization chaperones or intracellular binders to study protein function. Their unique ability to be engineered into multivalent or multifunctional formats makes them a versatile platform for next-generation biologics.
