Single-domain antibody (VHH) (sdAb)

Single-domain antibodies, widely known by the trademarked name Nanobodies, are the recombinant variable domains (VHH) derived from the heavy-chain-only antibodies (HCAbs) found in camelids such as llamas and alpacas (Hamers-Casterman et al., 1993, Nature). Unlike conventional antibodies, they lack a light chain and consist of a single polypeptide chain, making them the smallest naturally occurring antigen-binding fragments at approximately 12-15 kDa. Their unique structure, featuring long CDR3 loops, allows them to bind to cryptic or recessed epitopes, such as enzyme active sites or GPCR clefts, which are often inaccessible to standard monoclonal antibodies (Jovčevska & Muyldermans, 2020, BioDrugs). Nanobodies are characterized by high thermal and chemical stability, excellent solubility, and ease of manufacturing in microbial systems. In a clinical context, Nanobodies are not biological targets but rather a therapeutic modality; for example, Caplacizumab is a nanobody that targets von Willebrand factor to treat thrombotic thrombocytopenic purpura (Duggan, 2018, Drugs). Their modular nature allows for the rapid development of multivalent or multispecific constructs to improve binding avidity or target multiple pathways simultaneously.

Other names

NanobodyVHH domainCamelid antibody fragmentHeavy-chain-only antibody fragment

Nanobodies function as therapeutic agents by binding with high specificity and affinity to target antigens, thereby inhibiting protein-protein interactions, neutralizing pathogens, or acting as delivery vehicles for diagnostic or therapeutic payloads (Muyldermans, 2013, Annual Review of Biochemistry).