Camelid heavy-chain-only antibody (HCAb)

Camelid heavy-chain-only antibodies (HCAbs) are a unique class of immunoglobulins naturally produced by members of the Camelidae family, such as camels, llamas, and alpacas (Hamers-Casterman et al., 1993). Unlike conventional IgG antibodies, which are heterotetramers of two heavy and two light chains, HCAbs lack light chains and the CH1 constant domain, consisting only of heavy-chain homodimers (Muyldermans, 2013). The antigen-binding site is contained within a single variable domain known as VHH, or a nanobody, which is characterized by a long complementary-determining region 3 (CDR3) capable of reaching into recessed epitopes like enzyme active sites or GPCR clefts (Jovčevska & Muyldermans, 2020). These antibodies are highly stable, soluble, and easy to produce in microbial systems, making them ideal scaffolds for therapeutic development (Bannas et al., 2017). Clinically, HCAbs and their derivatives are used to treat various conditions; for instance, Caplacizumab, a bivalent VHH, is approved for treating acquired thrombotic thrombocytopenic purpura by inhibiting von Willebrand factor (Duggan, 2019). Their small size and modular nature also allow for the creation of multispecific constructs and improved tissue penetration compared to traditional monoclonal antibodies.

Other names

Heavy-chain antibodyVHH antibodyCamelid antibodyNanobody-based antibodySingle-domain antibody

HCAbs and their derived VHH domains function by binding to specific antigens with high affinity and specificity, often neutralizing ligands, blocking receptor-ligand interactions, or inhibiting enzyme activity by binding to active site clefts (Muyldermans, 2013; Jovčevska & Muyldermans, 2020).