heavychainonly

Heavy-chain–only antibodies (HCAbs) are antibodies that lack the light chain. They occur naturally in certain species, notably camelids (camels, llamas, alpacas) and, in cartilaginous fish, the immunoglobulin NAR (IgNAR). In camelids, HCAbs bind antigen via a single variable domain known as VHH, while in sharks IgNAR-based antibodies use a distinct variable domain called VNAR. These antibodies function without a light-chain partner, and their antigen-binding is mediated primarily by the heavy-chain variable region.

In camelids, HCAbs retain the CH2 and CH3 constant domains and lack the CH1 domain. The VHH domain binds antigens with high affinity and often features elongated CDR3 loops that can access recessed or cryptic epitopes. The resulting nanobody is about 15 kDa, much smaller than conventional IgG. Sharks’ IgNAR-based antibodies use VNAR domains, which are even smaller and structurally distinct but serve a similar purpose as single-domain binding units.

HCAbs and their single-domain fragments are derived from immunized animals or synthetic libraries and can be produced in microbial systems such as Escherichia coli or yeast, as well as in mammalian cells. They are widely used in research, diagnostics, and therapeutics. Nanobodies can be fused to Fc or albumin-binding partners to extend half-life and are used in imaging, crystallography, and increasingly as therapeutics. Caplacizumab is a clinically approved nanobody that targets von Willebrand factor for the treatment of acquired thrombotic thrombocytopenic purpura.

Advantages of heavy-chain–only antibodies include small size, high stability, strong tissue penetration, and the ability to bind cryptic epitopes. Disadvantages include rapid renal clearance and potential immunogenicity; these can be mitigated by humanization and half-life-extension strategies.