Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

Abstract

Targeted α therapy (TAT) offers the potential for the targeted delivery of potent α-particle-emitting radionuclides that emit high linear energy transfer radiation. This leads to a densely ionizing radiation track over a short path. Localized radiation induces cytotoxic, difficult-to-repair, clustered DNA double-strand breaks (DSBs). To date, radium-223 (²²³Ra) is the only TAT approved for the treatment of patients with metastatic castration-resistant prostate cancer. Thorium-227 (²²⁷Th), the progenitor nuclide of ²²³Ra, offers promise as a wider-ranging alternative due to the availability of efficient chelators, such as octadentate 3,2-hydroxypyridinone (3,2-HOPO). The 3,2-HOPO chelator can be readily conjugated to a range of targeting moieties, enabling the generation of new targeted thorium-227 conjugates (TTCs). This review provides a comprehensive overview of the advances in the preclinical development of TTCs for hematological cancers, including CD22-positive B cell cancers and CD33-positive leukemia, as well as for solid tumors overexpressing renal cell cancer antigen CD70, membrane-anchored glycoprotein mesothelin in mesothelioma, prostate-specific membrane antigen in prostate cancer, and fibroblast growth factor receptor 2. As the mechanism of action for TTCs is linked to the formation of DSBs, the authors also report data supporting combinations of TTCs with inhibitors of the DNA damage response pathways, including those of the ataxia telangiectasia and Rad3-related protein, and poly-ADP ribose polymerase. Finally, emerging evidence suggests that TTCs induce immunogenic cell death through the release of danger-associated molecular patterns. Based on encouraging preclinical data, clinical studies have been initiated to investigate the safety and tolerability of TTCs in patients with various cancers.

Keywords: 227Th; conjugate; precision oncology; targeted alpha therapy.

FIG. 1.

Decay cascade of ²²⁷Th purified from an ²²⁷Ac source. ²²⁷Th decay scheme. ²²⁷Th is purified from an ²²⁷Ac-generator and decays through its α- and β-particle-emitting daughters, ²²³Ra, ²¹⁹Rn, ²¹⁵Po, ²¹¹Pb, ²¹¹Bi, and ²⁰⁷Tl, to form a stable nonradioactive ²⁰⁷Pb. ²²⁷Ac, actinium-227; ²¹¹Bi, bismuth-211; d, days; m, minutes; ms, milliseconds; ²⁰⁷Pb, lead-207; ²¹¹Pb, lead-211; ²¹⁵Po, polonium-215; ²²³Ra, radium-223; ²¹⁹Rn, radon-219; s, seconds; ²²⁷Th, thorium-227; ²⁰⁷Tl, thallium-227; y, years.

FIG. 2.

Generation of TTCs. Schematic representation of the generation of TTCs. Monoclonal antibodies with tumor-targeting specificity are covalently linked to octadentate 3,2-HOPO chelator through the ɛ-amino groups of lysine residues to generate the antibody-3,2-HOPO chelator conjugate. The binding of a radionuclide (²²⁷Th or Zr) to the chelator involves the formation of several bonds, resulting in a stable radionuclide-labeled antibody-3,2-HOPO chelator complex. 3,2-HOPO, 3,2-hydroxypyridinone; ²²⁷Th, thorium-227; TTCs, targeted thorium-227 conjugates, Zr, zirconium.

FIG. 3.

Evaluation of MSLN-TTC in a lung/bone orthotopic model using the luciferase transfected human lung mesothelioma cell line NCI-H226. (A) BLI of athymic mice bearing orthotopic bone/lung metastatic xenograft tumors generated by inoculation of luciferase-transfected lung cancer NCI-H226 cells. Animals were treated with either vehicle (n = 7), MSLN-TTC 250 kBq/kg (n = 7) or MSLN-TTC 500 kBq/kg (n = 7). Representative images of 1 animal from each of the treatment group at the end of the study (day 32) are shown. (B) Total tumor burden observed by BLI is shown as a sum of average radiance of tibia and lungs (photons/s/cm²/steradian). Higher dose of MSLN-TTC decreased total tumor burden on the study day 32. Each treatment group consisted of 7 animals. (C) Tumor burden in the tibia was evaluated by BLI. Animals were treated with either vehicle (n = 7), MSLN-TTC 250 kBq/kg (n = 7), or MSLN-TTC 500 kBq/kg (n = 7). Group means are shown. Higher dose of MSLN-TTC decreased tibia tumor burden on the study day 32. (D) Relative weight of the lungs (median ± IQR25% ± min/max). MSLN-TTC decreased relative lung weight in a dose-dependent manner compared with the vehicle group indicating antitumor effect in the lungs. Outliers are marked with floating dots, but they were not removed in the statistical analysis. Statistical analysis was performed using analysis of variance. As statistical differences were observed (p = 2.3115e-05), the pairwise comparison was performed using Tukey's Honest Significant Difference test. **p-value <0.01; ***p-value <0.001. BLI, bioluminescence imaging; COMP, comparison group; MSLN-TTC, mesothelin-targeted thorium-227 conjugate.

FIG. 4.

PET imaging of LNCaP tumor-bearing mice using Zr-HOPO-PSMA. LNCaP tumor-bearing mice were injected with Zr-HOPO-PSMA and subjected to PET scans at 24–168 h postinjection. Maximal intensity projections of PET imaging at 24, 48, 72, 96, and 168 h after the Zr-HOPO-PSMA injection are shown. HOPO, hydroxypyridinone; PET, positron emission tomography; PSMA, prostate-specific membrane antigen; Zr, zirconium-89.