From discovery to the clinic: structural insights, engineering options, clinical, and 'next wave' applications of...

Camelid-derived single domain antibodies (sdAbs), referred to as VHHs (variable domains of the heavy chain of a heavy chain-only antibodies), recently emerged as promising building blocks for the construction of therapeutic molecules. As of October 2025, on a global perspective, five therapeutics harboring VHH-based paratopes have been granted marketing access from different health authorities. VHHs possess several favorable attributes, such as classical antibody-like affinities and specificities, adequate stabilities and a relatively small size (i.e., low molecular weight) as independent paratopes. Moreover, due to the lack of -light chain association, these sdAbs afford the benefit of multiple reformatting options for engineering of bi- and multifunctional antibodies. In this review, we summarize the structural features of VHHs, discuss sequence diversities of sdAb repertoires found in different camelid species commonly used for VHH generation, and describe different platform technologies for the isolation of VHH paratopes and their humanization. Moreover, we briefly review the composition as well as mechanisms of action of marketed VHH-based therapeutics and present novel biological concepts that harness sdAbs as targeting compounds. Finally, we provide an in silico property analysis of 49 VHH sequences that have progressed into clinical studies, which may inform future development of VHH-based therapeutics.