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

SIMPLE SUMMARY: Targeted alpha therapy (TαT) has revolutionized cancer treatment by delivering high-energy but short-range particles directly to tumor cells. The discovery of single-domain antibodies, or nanobodies, has opened new avenues for TαT. Owing to their small size, nanobodies exhibit excellent binding affinity and specificity, along with significant tumor uptake. Radiolabeled nanobodies offer numerous advantages over traditional TαT delivery vehicles and can be utilized not only for therapeutic purposes but also for cancer imaging. This review will delve into the properties of nanobodies in more detail and highlight recent studies involving nanobody-based TαT. ABSTRACT: 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.