Targeted Alpha Therapy (TAT) with Single-Domain Antibodies (Nanobodies)

The persistent threat of cancer necessitates the development of improved and more efficient therapeutic strategies that limit damage to healthy tissues. Targeted alpha therapy (TαT), a novel form of radioimmuno-therapy (RIT), utilizes a targeting vehicle, commonly antibodies, to deliver high-energy, but short-range, alpha-emitting particles specifically to cancer cells, thereby reducing toxicity to surrounding normal tissues. Although full-length antibodies are often employed as targeting vehicles for TαT, their high molecular weight and the presence of an Fc-region lead to a long blood half-life, increased bone marrow toxicity, and accumulation in other tissues such as the kidney, liver, and spleen. The discovery of single-domain antibodies (sdAbs), or nanobodies, naturally occurring in camelids and sharks, has introduced a novel antigen-specific vehicle for molecular imaging and TαT. Given that nanobodies are the smallest naturally occurring antigen-binding fragments, they exhibit shorter relative blood half-lives, enhanced tumor uptake, and equivalent or superior binding affinity and specificity. Nanobody technology could provide a viable solution for the off-target toxicity observed with full-length antibody-based TαT. Notably, the pharmacokinetic properties of nanobodies align better with the decay characteristics of many short-lived α-emitting radionuclides. This review aims to encapsulate recent advancements in the use of nanobodies as a vehicle for TαT.