Radioimmunotherapy for delivery of cytotoxic radioisotopes: current status and challenges

Abstract

Radioimmunotherapy (RIT) with monoclonal antibodies and their fragments labelled with radionuclides emitting α -particles, β-particles or Auger electrons have been used for many years in the development of anticancer strategies. While RIT has resulted in approved radiopharmaceuticals for the treatment of hematological malignancies, its use in solid tumors still remains challenging. Areas covered: In this review, we discuss the exciting progress towards elucidating the potential of current and novel radioimmunoconjugates and address the challenges for translation into clinical practice. Expert opinion: There are still technical and logistical challenges associated with the use of RIT in routine clinical practice, including development of novel and more specific targeting moieties, broader access α to α-emitters and better tailoring of pre-targeting approaches. Moreover, improved understanding of the heterogeneous nature of solid tumors and the critical role of tumor microenvironments will help to optimize clinical response to RIT by delivering sufficient radiation doses to even more radioresistant tumor cells.

HER2-directed antibodies, affibodies and nanobodies as drug-delivery vehicles in breast cancer with a specific focus on radioimmunotherapy and radioimmunoimaging

“…This results in an intensive energy deposition within a nanometer range, thus requiring the deposition of Auger electron radiation to the cell DNA. The therapeutic effect is achieved by inducing severe DNA damage [45,46]. Due to the different properties of the emitters, the effectiveness of radioimmunotherapy to a large extent depends on the selection of the isotope.…”

An Appendix of Radionuclides Used in Targeted Alpha Therapy

“…Alpha particles, ( 4 He) 2þ , are considered high linear energy transfer particles (80-100 keV/mm) because they deposit their energy (4-8 MeV) in a relatively short linear range (50-100 mm; few cell diameters). Beta particles have long intricate pathlengths (0.3-12 mm; several hundred cells diameter), making them low linear energy transfer particles (0.2 keV/mm) [7,8]. The distance travelled and the energy deposited in cells are of great importance because the main, and most efficient, route for cell destruction is related to direct interaction of ionization events with DNA.…”

Thorium chelators for targeted alpha therapy: Rapid chelation of thorium‐226

“…Chelation of 227 Th with two HOPO ligands, 1 and 2, and four pa ligands (3)(4)(5)(6), as well as the stability of the resultant chelates, were investigated. Additionally, limited studies involving chelation of 226 Th using the pa ligand 6 were conducted.…”

“…3 This therapeutic approach targets the radiation dose to diseased cells while minimizing damage to surrounding normal tissues, unlike β-emitting radionuclides having longer particle track ranges. [4][5][6] In 2013, the first α-emitting radiopharmaceutical (i.e., [ 223 Ra]RaCl 2 Xofigo™; Bayer Healthcare Pharmaceuticals, Inc.) was approved by the US Food and Drug Administration. The rapid success reignited interest in TAT and the need to find appropriate radionuclides for therapeutic applications.…”