Camelid antibodies are specialized immunoglobulins naturally found in llamas, alpacas, and camels. Unlike conventional antibodies that use both heavy and light chains, camelids produce a unique form known as heavy-chain-only antibodies. Their variable domain, called the VHH or single-domain antibody, retains full antigen-binding activity even without light chains.
This feature of the camelid immune system reflects an evolutionary adaptation that broadens antigen recognition. The discovery of camelid antibodies challenged traditional views of antibody structure and introduced a simpler, stable, and highly versatile antibody format. These molecules, later called VHH antibodies (also known as nanobodies), became an important resource for biotechnology.
The discovery of heavy-chain-only antibodies occurred in 1989 following analysis of total and fractionated immunoglobulin G (IgG) molecules in the serum of a dromedary camel in the laboratory of Professor Raymond Hamers at the Vrije Universiteit Brussel (VUB). While studying the immune systems of camels, they observed antibodies that lacked light chains but still functioned normally.
This was unexpected, as conventional wisdom held that both heavy and light chains were required for antigen recognition. The observation sparked debate and scientific curiosity, opening a new field of research.
Beyond the initial discovery, early patent estates and company formation strongly influenced the pace of translation. Following the first reports in the early 1990s, foundational patents (1996–2001) from Belgian and Dutch groups shaped early research and commercialization. Ablynx (founded 2001) drove two decades of translational development culminating in caplacizumab (Cablivi) approval by EMA (2018) and FDA (2019) as the first VHH antibody drug. The long bench-to-market interval reflected novel modality risk and freedom-to-operate constraints. With key patents expiring (EU 2014; US 2017), broader participation and faster follow-on VHH programs have become feasible.
Follow-up studies revealed the distinctive features of the VHH domain. Structural analyses highlighted:
Extended CDR3 loops, which enabled binding to recessed or hidden epitopes.
Unique framework residues, which increased solubility and reduced aggregation.
Small size (~15 kDa), which improved tissue penetration.
These findings explained why camelid antibodies could achieve high stability and specificity, even without light chains. Subsequent crystallography refined these observations and revealed non-canonical binding modes. VHHs often feature extended CDR3 loops that can penetrate recessed epitopes (e.g., enzyme active sites). Unlike conventional antibodies, non-CDR regions (FR2, C″D, DE/“CDR4”) contribute meaningfully to paratope–epitope contacts, expanding binding modes beyond canonical VH/VL interfaces. This distributed paratope helps explain high stability, solubility, and access to conserved or geometrically constrained epitopes. These structural traits are rooted in distinct immunogenetic features of camelid heavy-chain antibodies.
Camelid heavy-chain-only antibodies arise by CH1 deletion and germline-encoded substitutions in FR2 (e.g., V37F/Y, G44E, L45R, W47G, Kabat numbering) that replace the former VH–VL interface with solubilizing residues. VHH repertoires show broader CDR3 length distributions and evidence of elevated somatic hypermutation, together diversifying recognition in the absence of VL.
By the late 1990s, VHHs had gained recognition as promising molecules for both research and therapeutic development.
The recognition of camelid antibodies led directly to the rise of nanobody technology. Academic labs began using VHHs as probes for structural biology and molecular imaging, while biotech companies explored their therapeutic potential.
A key milestone was the FDA approval of caplacizumab, the first nanobody drug, for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP). Since then, camelid-derived antibodies have continued to move through clinical pipelines for cancer, autoimmune disease, and infectious disease. The field progressed from immune library construction and phage display (nanomolar binders) to crystallographic validation of atypical binding topologies, then to clinical translation (imaging agents, anti-inflammatory targets, antivirals). Caplacizumab validated the modality clinically; meanwhile, VHH-containing CAR constructs (e.g., ciltacabtagene) underscore the platform’s modularity for cell therapy.
Modern immunization protocols in alpacas provide diverse repertoires of VHHs for library construction and selection.
Technologies such as phage display libraries and synthetic biology platforms have expanded the scope of VHH discovery.
The camelid immune system differs from humans in its antibody repertoire.
Human antibodies: consist of IgG molecules with heavy and light chains.
Camelid antibodies: produce special IgG2 and IgG3 isotypes that lack light chains and function as heavy-chain-only antibodies.
This natural variation explains why camelids are such a valuable source for antibody engineering. The ~15 kDa size yields rapid renal clearance and short serum half-life. Practical strategies such as multimerization, PEGylation, HSA-binding VHH fusion, or Fc-fusion extend exposure while preserving target engagement. These levers allow tuning of distribution/clearance for imaging vs therapeutic use cases.
The discovery of camelid antibodies in the 1990s revealed that antibodies could function without light chains, a finding that redefined long-standing views of immunology. These single-domain antibodies demonstrated that a simplified structure could maintain stability, specificity, and antigen-binding power. This breakthrough set the stage for nanobody development and positioned camelid antibodies as a valuable complement to conventional antibody formats.
Today, camelid antibodies are central to biotechnology and clinical research. Their small size, high stability, and ability to reach hidden epitopes have enabled progress in therapeutics, diagnostics, and biosensors. From the approval of caplacizumab to ongoing trials in cancer and autoimmune disease, they continue to expand possibilities in antibody science and remain one of the most significant antibody discoveries of modern times.
Molecular Imaging: Radiolabeled VHHs (e.g., anti-HER2) show rapid tumor penetration and fast background clearance, supporting high-contrast PET/CT.
CNS Delivery: Select VHHs exploit receptor-mediated transcytosis to cross the BBB, improving brain uptake of therapeutic cargo.
Intrabodies: Cytosol-competent VHHs (chromobodies) enable live-cell target tracking and can functionally inhibit intracellular pathways.
Multispecifics and Cell Engagers: VHH modularity supports bi/multispecifics, NK-cell engagers, and VHH-based CARs targeting difficult antigens.
References:
Arbabi-Ghahroudi, M. (2022). Camelid Single-Domain Antibodies: Promises and Challenges as Lifesaving Treatments. International Journal of Molecular Sciences, 23(9), 5009. https://doi.org/10.3390/ijms23095009
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