It is a little-known fact that llamas, alpacas, camels, other members of the camelid family and sharks make a unique class of antibodies that allow scientists to determine the structures of otherwise impossible-to-study proteins in the body, helping them to understand how those proteins malfunction in disease and how to design new drugs that act on them.
In the early 1990s, Belgium researchers accidently discovered that camels possess a unique class of antibodies. In addition to having normal antibodies, they have another unique class of antibodies naturally devoid of light chains but consisted of two heavy chains attached to variable domains (variable heavy homodimers, VHH), so called heavy- chain antibodies (HcAb). Other than camelids, HcAb has not been found in other organisms, with the curious exception of sharks and other cartilaginous fish (Chondrichthyes), the oldest living beings with an adaptive immune system. Cartilaginous fish possess a special form of HcAb termed immunoglobulin novel antigen receptor or IgNAR.
The VHH alone is about 12-15 kDa (4 nm long and 2.5 nm wide), much smaller than conventional antibodies, which is about 150 kDa. Typically, single-domain antibody (also known as "Nanobody®" ) is recombinant, the variable domain alone of HcAb (i.e. VHH) which is able to bind selectively to a specific antigen. Single domain antibodies are considered the smallest naturally derived antigen-binding fragments that can be isolated from a full-sized immunoglobulin.
In spite of an evolutionary gap of 425 million years, VHH and VNAR antibosies share some convergent features that differ from those found in conventional variable domains. More notably, changes in conserved amino acids make them soluble and independently folding domains, non-canonical Cys pairs increase their stability and diversity. Formed by fewer CDRs, the antigen-binding sites of VHH and VNAR domains are smaller than those of conventional antibodies, and are considered the smallest (12 kDa) antigen-binding domain. VHH and VNAR particularly capable of binding concave and hidden epitopes (e.g., enzyme active sites, cryptic viral epitopes, etc.) that are not accessible to conventional antibodies. Nevertheless, the reactivity of their antigen-binding site is not limited to hidden targets, and HcAbs reacting with a broad range of structurally diverse epitopes.
Advantages of Single Domain Antibodies
Nanobodies can recognize novel epitopes that conventional antibodies cannot.
They can be expressed in both eukaryotic and prokaryotic systems, readily produced in single cell organisms like bacteria and yeasts, ensuring their virtually unlimited supply and consistent quality without batch-to-batch variations.
There are many advantages of this novel class of antibodies:
Single domain antibodies also have great potential in downstream engineering (bispecific antibody, humanization). There is an increasing interest in developing single-domain antibodies for therapeutic and research uses. Nanobodies can be applied in the field of antibody-drug conjugate technologies (ADC), which uses antibodies or antibody-derived molecules to deliver highly potent anticancer agents to cancer cells. Single domain antibody takes great advantages of outstanding penetrability, they are able to cross the blood-brain barrier, and can improve bioavailability for pharmaceutical applications, which are essential to the development of antibody drugs or diagnostic tools. Therefore, the potential benefits of using single domain antibodies for both therapeutic and research applications are endless:
In summary, single domain antibodies can be used as potential tools for academic research, diseases diagnosis and treatment, and biotechnology development, due to the variety of their unique features.
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