Besides the therapeutic application, which requires complex engineering and optimization steps, nanobodies can be used as research tools. The most successful application is Caplacizumab-the first FDA-approved nanobody-based drug. The characteristics of small size and high specificity mean that nanobodies are suitable for many more applications than conventional antibodies. Moreover, nanobodies exhibited excellent binding affinities with low nanomolar or even picomolar K D (equilibrium dissociation constant) values. For example, nanobodies can interact with enzymes by entering the clefts of catalytic sites. Compared with conventional antibodies, nanobodies have longer CDR3, which provides them with more diverse paratopes. CDR3 is the dominating contributor, while CDR1 and CDR2 assist in the binding. CDRs are responsible for recognition and binding. The structural architecture of nanobodies comprises 2 β-sheets, one with 4 β-strands and the other with 5 β-strands, and CDRs form flexible antigen-binding loops between β-strands ( Figure 1). Nanobodies have four framework regions (FR1-4) and three hypervariable regions (CDR1-3). Their molecular weights are around 12 to 15 kDa, about one-tenth of conventional antibodies’ size. Nanobodies are functionally equivalent to conventional antibodies’ antigen-binding fragments in recognizing target antigens. The heavy chains from heavy-chain antibodies (HCAbs) comprise two constant domains (CH2 and CH3) and one antigen-binding domain that is termed nanobody, or VHH, or single-domain antibody. In Camelidae, a type of antibody is composed solely of heavy chains, but lacks light chains and the first constant domain (CH1) of conventional heavy chains. Conventional heterotetrameric antibodies are composed of two heavy chains and two light chains.
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