A single domain antibody (sdAb), as the name indicated, consists of a single monomeric variable antibody domain. Though it can selectively bind to a specific antigen like a whole antibody, a single domain antibody is much smaller than traditional antibodies as it's a kind of antibody fragment that lacks light chains and CH domain of heavy chains in conventional Fab region, and that is the main reason why single domain antibodies are also known as nanobodies.

These antibody fragments can be divided into VHH and VNAR fragments. Most VHH fragments are obtained from heavy-chain antibodies of camelids and VNAR sdAbs are from that of Cartilaginous fishes, but some single domain antibodies could also be made from conventional antibodies and human single-domain antibodies.

Besides the smaller size aforementioned, single domain antibodies have several other advantages that make them potential tools for academic research, diseases diagnosis and therapy, and biotechnology development.

Namely, nanobodies are promising due to the production in single cell organisms like bacteria and yeasts, enhanced tissue penetration, impressive capacity to bind to small cavities or clefts, as well as high stability, affinity, specificity, and solubility. Their rapid clearance in vivo also makes these novel antibodies great imaging agents and less toxic when they are developed as antibody drugs or diagnostic tools.

The downstream engineering of single domain antibodies is also promising, in which an increasing interest occurs in developing nanobodies for therapeutic and research uses, for example, application in the field of antibody-drug conjugate technologies (ADC).

Due to these advantages, single domain antibody for targeted therapy has been widely studied for both therapeutic and research applications, including ongoing discovery for SARS-CoV-2 therapeutics.

SARS-CoV-2 that causes the COVID-19 pandemic belongs to betacoronaviruses, and researchers have noticed the importance of viral spike protein in developing therapeutic mAbs. Neutralizing antibodies (NAbs) can provide more immunity to new coronavirus variants and more effectively stop viruses from getting into human cells, can target the receptor-binding domain (RBD) of the spike protein and block interactions of spike with the cell receptor ACE2.

The main sources to get neutralizing antibodies include single domain human antibodies from existing libraries and alpaca nanobodies. Scientists have found 3 potent SARS-CoV-2 antibodies from a human combinatorial antibody library established about 20 years ago and have successfully characterized these antibodies to develop effective therapeutics.

However, many emerging variants of SARS-CoV-2, for example, the Beta variant B.1.351 (South Africa) and the Alpha variant B.1.1.7 (UK), have shown possible immune escape and increased resistance to neutralizing antibodies generated by current COVID-19 vaccines. Such inability to neutralize viruses presents a new challenge for scientists to develop therapeutic neutralizing single domain antibodies against COVID-19.

A recent study from the US reported that researchers have successfully isolated two VHH nanobodies, namely, 7A3 and 8A2, from dromedary camels (Camelus dromedaries) by conducting nanobodies screening with phage display. These Camelid VHH single domain antibodies are proven to be able to detect protein cavities that are featured with small size and conformations, exhibiting high affinity for the spike RBD and broad neutralization abilities against original SARS-CoV-2 and its existing variants, including the delta variant.