Targeted alpha therapy using short-lived alpha-particles and the promise of nanobodies as targeting vehicle

Abstract

Introduction: The combination of a targeted biomolecule that specifically defines the target and a radionuclide that delivers a cytotoxic payload offers a specific way to destroy cancer cells. Targeted radionuclide therapy (TRNT) aims to deliver cytotoxic radiation to cancer cells and causes minimal toxicity to surrounding healthy tissues. Recent advances using α-particle radiation emphasizes their potential to generate radiation in a highly localized and toxic manner because of their high level of ionization and short range in tissue.

Areas covered: We review the importance of targeted alpha therapy (TAT) and focus on nanobodies as potential beneficial vehicles. In recent years, nanobodies have been evaluated intensively as unique antigen-specific vehicles for molecular imaging and TRNT.

Expert opinion: We expect that the efficient targeting capacity and fast clearance of nanobodies offer a high potential for TAT. More particularly, we argue that the nanobodies' pharmacokinetic properties match perfectly with the interesting decay properties of the short-lived α-particle emitting radionuclides Astatine-211 and Bismuth-213 and offer an interesting treatment option particularly for micrometastatic cancer and residual disease.

Keywords: Cancer; astatine-211; bismuth-213; nanobody; radionuclide labeling; targeted alpha therapy; targeting vehicles.

Figure 1.

Schematic representation of antibodies and their derived antigen-binding fragments. a. Conventional mAb and the derived Fab, scFv, Fv domains V_L or V_H, Fab’₂, minibody and diabody. b. Camelid heavy-chain-only antibody and its V_HH (also known as nanobody).

Figure 2.

Nanobodies possess numerous advantageous characteristics, including their high antigen specificity (a) and high tumor targeting potential (b). a. ^99mTc-labeled-nanobody targeting the complement receptor of the Ig superfamily, CRIg, expressed on Kupffer cells in the liver. 3D-rendered SPECT/micro-CT images of naive wild-type (A.1.) and CRIg^−/− mice (A.2.) 1 h after intravenous injection of ^99mTc-labeled-nanobody. Representative images for 3 mice per group are shown. Figures adapted with permission from.[115] b. Dosimetry calculation of untagged ¹⁷⁷Lu-DTPA-anti-HER2 nanobody coinfused with 150 mg/kg Gelofusin, in HER2^pos tumor xenografted mice. Radiolabeling of nanobodies is characterized by significant retention of radioactivity at the kidneys, due to the charged-based aspecific tubular reuptake after glomerular filtration. Figure adapted with permission from.[109].

Figure 3.

Diagnostic tumor imaging using ⁶⁸Ga-HER2-nanobody in patients with HER2^pos-breast cancer. a. Time-activity curve of total blood activity, expressed in % of injected activity (%IA) (n=20). b. Fusion PET/CT images of the uptake of ⁶⁸Ga-HER2-nanobody in breast carcinoma lesions. (B.1.) Patient with the highest tracer uptake (SUVmean 11.8) in a primary breast carcinoma. (B.2.) Patient with moderate tracer uptake in the left breast, which is easily discernable from background (SUVmean 4.9). (B.3.) Patient with invaded lymph nodes in the mediastinum and left hilar region. Lesions are indicated by red arrows. Figures are adapted with permission from.[110].