Nanobodies and methods of increasing their half-lives

The development of antibody fragments is growing due to problems associated with commercially available antibodies including their large size and expensive and time-consuming production processes. Nanobodies are fragmented antibodies that are found naturally in the serum of the Camelidae family. Nanobodies, as the smallest functional part of antibodies, have many applications in the diagnosis and treatment of various diseases, especially in tumors. However, their small size causes them to be quickly removed from the blood circulation after administration, which restricted their use in the clinics. To solve this issue, various methods have been proposed to increase their plasma half-life, generally using two mechanisms: (1) the endosomal recycling of neonatal Fc receptor and (2) the increase of the hydrodynamic volume. The first mechanism naturally occurs in the body and leads to an increase in the plasma half-life of immunoglobulins and albumin. The chemical conjugation of nanobodies to the synthetic polymers, genetic fusion to polymer-mimetics peptides, and dimerization of the nanobodies increase the plasma half-life of nanobodies via the second mechanism. In this review, first, we will introduce the nanobodies, and in the following, we will discuss various methods that have been developed to increase their plasma half-lives.