Welcome to Mediso

Please select your region:

North America

Please select your language:


Evaluation of Candidate Theranostics for 227Th/89Zr Paired Radioimmunotherapy of Lymphoma


Diane S. Abou et al, Journal of Nuclear Medicine, 2023


Radiotheranostic agents provide a unique ability to detect, characterize, treat, and monitor sites of disease with exceptional specificity. A persistent challenge for clinical theranostics is the development of suitably matched therapeutic and diagnostic agents that provide correlating pharmacokinetic data to guide therapeutic application. Ideally, this goal is realized in the form of a targeted agent that can be labelled with radionuclides for either imaging or therapy without other chemical changes.

227Th is a promising radioisotope for targeted α-particle therapy. It produces 5 α-particles through its decay, with the clinically approved 223Ra as its first daughter. There is an ample supply of 227Th, allowing for clinical use; however, the chemical challenges of chelating this large tetravalent f-block cation are considerable. Radiometals must be stably bound to a molecularly specific vector (a small molecule, peptide, or antibody) to achieve localized uptake. The extended biologic residency time and longer radiologic half-life (t½) of isotopes used for antibody-based agents add a requirement for greater stability.

Using the CD20-targeting antibody ofatumumab, evaluation chelation of 227Th4+ for α-particle–emitting and radiotheranostic applications was performed. 227Th-labeled ofatumumab-chelator constructs were synthesized and showed moderate in vitro stability. In this work, 4 antibody-chelator conjugates for in vitro and in vivo stability using ofatumumab, a human anti-CD20 antibody were evaluated. The most stable 227Th chelator conjugate, L804, was evaluated in vivo for tumour-targeting capability. 227Th-L804-ofatumumab coordinated 227Th rapidly and efficiently at high yields, and demonstrated extended stability. An 89Zr-L804- theranostic analogue was compared. In vivo tumour targeting confirmed the utility of this chelator, and the diagnostic analogue, 89Zr-L804-ofatumumab, showed organ distribution matching that of 227Th to delineate SU-DHL-6 tumours.

Commercially available and novel chelators for 227Th showed a range of performances. The L804 chelator can be used with potent radiotheranostic capabilities for 89Zr/227Th quantitative imaging and α-particle therapy.

Results from nanoScan® PET/CT

PET/CT of the SU-DHL-6 tumor–bearing animals was performed on the Nanoscan (Mediso) on day 7. A CT acquisition of 720°, 70 kV/980 μA of 90 ms, and 4× binning was reconstructed by filtered backprojection to produce isotropic 124-μm voxels (122 × 122 × 97 mm). PET data (400–600 keV, 5-ns timing) were reconstructed using the iterative, 3-dimensional TeraTomo algorithm (4 iterations and 6 subsets; Mediso Medical Imaging Systems). Decay, attenuation, and scatter corrections were applied to quantify injected activity.

The 227Th-L804 conjugate was selected as the lead agent for further evaluation. The tumour-targeting ability of 227Th-L804-ofatumumab in CD20–positive Raji tumours was investigated. Mice were randomized to receive 227Th-L804-ofatumumab, control 227Th-L804-IgG, or 227Th-L804-ofatumumab preceded by unmodified ofatumumab. The early blood signal for the unblocked group (21.6 ± 1.9 %IA/g) decreased with time to 7.5 ± 1.8 %IA/g at 7 d. Control IgG uptake was significantly greater in the spleen over the course of the experiment, whereas 227Th tumor uptake was significantly higher for the targeted construct at all time points (to control IgG, P < 0.01) and to blocked group at 7 d (P < 0.05). Peak tumour uptake at day 3 for 227Th-L804-ofatumumab achieved 20 ± 1 %IA/g (Fig. 4).

Figure 4. Organ distribution of 227Th-L804-ofatumamab and 227Th-L804-IgG and blocking with ofatumumab using Raji tumour–bearing mice (R2G2, female), reporting 227Th only (%IA/g) at 24 h, 3 d, and 7 d after injection. GI = gastrointestinal tract.

The pharmacokinetics of 227Th- and 89Zr-L804-ofatumumab and conventional 89Zr-DFO-ofatumumab was compared (Fig. 5). Small but statistically significant differences were observed between 227Th- and 89Zr-L804-ofatumumab for blood, heart, lung, and cecal tissues at 1 d (Fig. 5A). At 14 d, no differences were detected (Fig. 5B). Together, these data demonstrate that use of different chelators (DFO and L804) alters radiopharmaceutical distribution to a greater degree than does exchange of radiometals.

Figure 5. Pharmacokinetic comparison of 227Th-L804-, 89Zr-L804-, and 89Zr-DFO-ofatumumab in naïve female mice at 1 d (A) and 14 d (B) after injection. Significant differences were observed for blood, heart, and lung accumulation of 227Th-L804- vs. 89Zr-L804-ofatumumab at 1 d (P < 0.05). At 14 d, no differences were seen between 227Th-L804- and 89Zr-L804-ofatumumab. 89Zr bone uptake was greater for DFO (7.3 ± 1.1 %IA/g) than for L804 (89Zr, 3.7 ± 0.5 %IA/g; 227Th, 3.0 ± 0.4 %IA/g [P < 0.001]). p.i. = postinjection.

The theranostic capability of L804-ofatumumab for 89Zr PET was tested in CD20–positive SU-DHL-6 xenografts (Fig. 6). Recapitulating Raji accumulation of 227Th-L804-ofatumumab, we observed high-contrast delineation with 89Zr-L804-ofatumumab and a low skeletal signal.

Figure 6. (A) Representative PET images of SU-DHL-6 tumour–bearing animal with 89Zr-L804-ofatumumab, with or without blocking. (B) PET/CT at 7 d, without blocking. On right are cross-sectional images of cervical lymph nodes, brachial lymph nodes, and tumour, from top to bottom.

To confirm specificity, blocking antibody was administered to a representative animal; the result was decreased tumour uptake (Supplemental Fig. 11).

Supplemental Figure 11. Biodistribution of 89Zr-L804-Ofatumumab in SU-DHL-6 Tumor bearing Mice. A) Organ distribution at 7 d p.i. of 89Zr-L804-ofatumumab for SU-DHL-6 xenografted Nu/Nu mice; B) quantitation of SU-DHL-6 uptake to 7 d.

  • Commercially available and novel chelators for 227Th showed a range of performances.
  • L804 chelator is the most stable and versatile chelator of those tested, providing facile coordination of 227Th and 89Zr and can be used with potent radiotheranostic capabilities for 227Th/89Zr quantitative imaging and α-particle therapy.
  • Stable chelation of 227Th was demonstrated and applied for tumour-targeted delivery across 2 lymphoma models.
  • Obtained data support the further development of 227Th/89Zr antibody theranostics using this chemically identical precursor.

Full article on jnm.snmjournals.org







How can we help you?

Don't hesitate to contact us for technical information or to find out more about our products and services.

Get in touch