In the late 1980s, Dr. Hamers’ team in Belgium discovered that, besides conventional IgG1 antibodies, camel serum contains about 75% antibodies made of only heavy chains without light chains — the Heavy Chain-Only Antibodies (HCAbs). These are also present in llamas and alpacas. The N-terminal domain of HCAbs, capable of directly binding antigens, was later defined as a single-domain antibody (sdAb, VHH, or Nanobody) and has since been widely used in antibody drug development.

• High stability and solubility: Evolution increased hydrophilicity to compensate for the missing light chain, allowing them to remain stable even at 70 °C.
• Low immunogenicity: Despite evolutionary distance, camelid antibodies share higher homology with human antibodies than rodent ones.
• Deep epitope access: Longer CDR3 regions enable binding to recessed antigen sites.
• Easy engineering: Their simple structure facilitates affinity maturation, humanization, and bispecific antibody design.
• Small size: Llama-derived nanobodies (~15 kDa) can penetrate tissues more effectively.

VHH affinity (SPR)

VHH affinity maturation