Research ArticleBasic Science Investigation

Albumin-Binding and Conventional PSMA Ligands in Combination with 161Tb: Biodistribution, Dosimetry, and Preclinical Therapy

Viviane J. Tschan, Sarah D. Busslinger, Peter Bernhardt, Pascal V. Grundler, Jan Rijn Zeevaart, Ulli Köster, Nicholas P. van der Meulen, Roger Schibli and Cristina Müller
Journal of Nuclear Medicine October 2023, 64 (10) 1625-1631; DOI: https://doi.org/10.2967/jnumed.123.265524

Abstract

The favorable decay characteristics of 161Tb attracted the interest of clinicians in using this novel radionuclide for radioligand therapy (RLT). 161Tb decays with a similar half-life to 177Lu, but beyond the emission of β−-particles and γ-rays, 161Tb also emits conversion and Auger electrons, which may be particularly effective to eliminate micrometastases. The aim of this study was to compare the dosimetry and therapeutic efficacy of 161Tb and 177Lu in tumor-bearing mice using SibuDAB and PSMA-I&T, which differ in their blood residence time and tumor uptake. Methods: [161Tb]Tb-SibuDAB and [161Tb]Tb-PSMA-I&T were evaluated in vitro and investigated in biodistribution, imaging, and therapy studies using PC-3 PIP tumor–bearing mice. The 177Lu-labeled counterparts served for dose calculations and comparison of therapeutic efficacy. The tolerability of RLT in mice was monitored on the basis of body mass, blood plasma parameters, blood cell counts, and the histology of relevant organs and tissues. Results: The prostate-specific membrane antigen (PSMA)–targeting radioligands, irrespective of whether labeled with 161Tb or 177Lu, showed similar in vitro data and comparable tissue distribution profiles. As a result of the albumin-binding properties, [161Tb]Tb/[177Lu]Lu-SibuDAB had an enhanced blood residence time and higher tumor uptake (62%–69% injected activity per gram at 24 h after injection) than [161Tb]Tb/[177Lu]Lu-PSMA-I&T (30%–35% injected activity per gram at 24 h after injection). [161Tb]Tb-SibuDAB inhibited tumor growth more effectively than [161Tb]Tb-PSMA-I&T, as can be ascribed to its 4-fold increased absorbed tumor dose. At any of the applied activities, the 161Tb-based radioligands were therapeutically more effective than their 177Lu-labeled counterparts, as agreed with the approximately 40% increased tumor dose of 161Tb compared with that of 177Lu. Under the given experimental conditions, no obvious adverse events were observed. Conclusion: The data of this study indicate the promising potential of 161Tb in combination with SibuDAB for RLT of prostate cancer. Future clinical studies using 161Tb-based RLT will shed light on a potential clinical benefit of 161Tb over 177Lu.

Radioligand therapy (RLT) using prostate-specific membrane antigen (PSMA)–targeting radioligands emerged as an effective means for the treatment of patients with metastatic castration-resistant prostate cancer (1–3). The positive outcome of a clinical phase III study (VISION; NCT0351166) using [177Lu]Lu-PSMA-617 (4) led to the approval of this radioligand (Pluvicto; Novartis) for the treatment of patients with PSMA-positive metastatic castration-resistant prostate cancer. [177Lu]Lu-PSMA-I&T, a similar radioligand, has also been used clinically for the treatment of metastatic castration-resistant prostate cancer (5–7).

Currently, several clinical trials are ongoing to investigate a potential benefit of 177Lu-based RLT in patients at an earlier disease stage (8–12). β−-particles have a relatively long tissue range (177Lu, 2 mm) and thus are suitable for the treatment of macrometastases; however, they are not effective enough to eliminate micrometastases, an ability that would be essential for these patients to achieve long-term disease control. RLT using an α-particle emitter may be an option to address this situation; however, severe side effects will prevent the use of 225Ac-based RLT in patients with a generally good prognosis (13,14).

161Tb has attracted the attention of clinicians and researchers alike. It shares similar chemical properties and physical decay characteristics (β−-particles and γ-ray emission) with 177Lu but coemits low-energy conversion and Auger electrons. Since Auger electrons have an ultrashort tissue range (<500 nm) and, hence, a high linear energy transfer (4–26 keV/μm), they may be particularly effective to eliminate single and clustered cancer cells (15,16). In our previous work, we demonstrated that 161Tb outperforms 177Lu in cell-based in vitro assays irrespective of the applied targeting concept (17–19). Preclinical therapy studies using [161Tb]Tb-PSMA-617 in xenografted mice showed a dose-dependent tumor growth delay and survival.

Currently, [161Tb]Tb-PSMA-I&T (VIOLET; NCT05521412 (20)) and [161Tb]Tb-PSMA-617 (REALITY; NCT04833517 (21) are applied to metastatic castration-resistant prostate cancer patients in phase I and II clinical studies and on a compassionate-use basis under the local regulatory framework (22).

At the Paul Scherrer Institute, we have developed several generations of albumin-binding PSMA ligands that are characterized by an enhanced blood circulation time and, as a result, higher tumor accumulation than for PSMA-617 or PSMA-I&T. [177Lu]Lu-PSMA-ALB-56, derivatized with a p-tolyl–based albumin binder, showed promising therapeutic efficacy in preclinical studies (23); however, the long blood residence time observed in patients affected the bone marrow dose unfavorably (24). [177Lu]Lu-SibuDAB, the S-isomer of [177Lu]Lu-Ibu-DAB-PSMA (25,26), was developed as an optimized PSMA ligand with moderate albumin-binding properties (27). The tolerability of this new class of ibuprofen-derivatized PSMA radioligands was in the same range as for conventional PSMA radioligands (26).

The goal of this study was to investigate SibuDAB in combination with 161Tb and assess the potential benefit of this novel RLT concept. We performed preclinical studies to evaluate [161Tb]Tb-SibuDAB and [161Tb]Tb-PSMA-I&T in comparison to their 177Lu-labeled counterparts with regard to dosimetry estimations and therapeutic efficacy.

MATERIALS AND METHODS

Detailed methods are presented as a supplemental data file (supplemental materials are available at http://jnm.snmjournals.org). This study was performed in agreement with national laws and the institutional internal guidelines on radiation safety.

Radioligand Preparation and In Vitro Characterization

SibuDAB (S-isomer of Ibu-DAB-PSMA (27)) and PSMA-I&T were labeled under standard conditions at molar activities of up to 50 MBq/nmol, with radiochemical purity of more than 98% (Supplemental Figs. 1 and 2). The radiolytic stability of [161Tb]Tb-SibuDAB and [161Tb]Tb/[177Lu]Lu-PSMA-I&T, their distribution coefficients (logD values), and cell uptake in PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor cells (provided by Martin Pomper, Johns Hopkins University School of Medicine) were determined as previously reported for [177Lu]Lu-SibuDAB (27). The in vitro albumin-binding capacity of the radioligands was determined according to an established protocol (28).

In Vivo Studies

All applicable international, national, or institutional guidelines for the care and use of laboratory animals were followed, and all animal experiments were performed according to the guidelines of Swiss Regulations for Animal Welfare. The preclinical studies were ethically approved by the Cantonal Committee of Animal Experimentation and permitted by the responsible cantonal authorities (license 75668).

Blood Clearance

The blood clearance of [161Tb]Tb-SibuDAB (25 MBq, 1 nmol per mouse) was determined as previously reported for [177Lu]Lu-SibuDAB using an immunocompetent mouse strain (FVB, Friend leukemia virus B) (27). The collected blood samples were measured to calculate the percentage injected activity (%IA) retained in the blood over 24 h, with the activity at t = 0 set as 100%.

Biodistribution Studies and Dosimetry Estimation

PC-3 PIP/flu tumor–bearing nude mice (BALB/c nude, Bagg Albino) were intravenously injected with the respective radioligand (5 MBq, 1 nmol per mouse). Tissues were collected, weighed, and counted for activity using a γ-counter. The decay-corrected results were listed as %IA per gram of tissue mass (%IA/g).

Dosimetry estimations were performed for tumors (assuming a sphere of 80 mm3) and kidneys on the basis of the time-integrated activity concentration using non–decay-corrected biodistribution data for the 177Lu-labeled PSMA ligands. The Monte Carlo code PENELOPE (penetration and energy loss of positrons and electrons) was used for determination of the energy deposits in the tissues (29).

Dual-Isotope SPECT/CT Imaging

Dual-isotope SPECT/CT was performed according to a previously established protocol using a small-animal SPECT/CT scanner (27). PC-3 PIP/flu tumor–bearing BALB/c nude mice were injected with a mixture of [161Tb]Tb-SibuDAB and [177Lu]Lu-SibuDAB or [161Tb]Tb-PSMA-I&T and [177Lu]Lu-PSMA-I&T (20 MBq, 1 nmol per mouse in total). The images were reconstructed on the basis of γ-lines of 161Tb or 177Lu or the combined γ-lines.

Therapy Study

PC-3 PIP tumor–bearing BALB/c nude mice were treated with either [161Tb]Tb-SibuDAB or [177Lu]Lu-SibuDAB (2, 5, or 10 MBq, 1 nmol per mouse) or with [161Tb]Tb-PSMA-I&T or [177Lu]Lu-PSMA-I&T (5 or 10 MBq, 1 nmol per mouse). Control mice received only vehicle (saline with 0.05% bovine serum albumin) (Supplemental Table 1). The body mass and tumor volume of the mice were monitored (27). The area under the curve of the relative tumor volume (AUCRTV) for each mouse in a group was calculated and expressed as the average value per group. The median survival of mice was determined as a measure of the radioligands’ therapeutic efficacy. Potential adverse events were determined on the basis of body mass, plasma parameters, blood cell counts, and analysis of histologic changes using a predefined scoring system (Supplemental Table 2).

Analysis and Statistical Methods

GraphPad Prism software (version 8) was used for data analysis, including determination of statistical significance (P < 0.05) and preparation of graphs.

RESULTS

In Vitro Characterization of Radioligands

The radioligands (25 MBq/nmol) were stable over 4 h in saline at room temperature (>95% of intact radioligand). The logD values of [161Tb]Tb-SibuDAB (−2.5 ± 0.1) and [161Tb]Tb-PSMA-I&T (<−4) were similar to those of [177Lu]Lu-SibuDAB (−2.3 ± 0.1 (27)) and [177Lu]Lu-PSMA-I&T (<−4), respectively.

PC-3 PIP tumor cell uptake and internalization of [161Tb]Tb-SibuDAB (54% ± 1% and 18% ± 2%, respectively) and [161Tb]Tb-PSMA-I&T (42% ± 6% and 11% ± 2%, respectively) were in the same range as for their respective 177Lu-labeled counterparts (Fig. 1A). Negligible uptake of the radioligands (<1%) was observed in PC-3 flu cells.

FIGURE 1.
FIGURE 1.

(A) Cell uptake and internalization of [161Tb]Tb/[177Lu]Lu-SibuDAB and [161Tb]Tb/[177Lu]Lu-PSMA-I&T in PC-3 PIP cells after 4 h of incubation (average ± SD). (B and C) In vitro albumin-binding curves of [161Tb]Tb/[177Lu]Lu-SibuDAB and [161Tb]Tb/[177Lu]Lu-PSMA-I&T in mouse (B) and human (C) blood plasma. Dashed line indicates half-maximum (i.e., 50%) binding. HSA = human serum albumin; Int. = internalization; MSA = mouse serum albumin; Up. = uptake. *Data were previously published (27). †Data were previously published (28).

The protein-bound fraction of [161Tb]Tb-SibuDAB and [177Lu]Lu-SibuDAB (28) was approximately 90% in undiluted mouse and human blood plasma (Figs. 1B and 1C) but much lower for [161Tb]Tb-PSMA-I&T and [177Lu]Lu-PSMA-I&T (50%–60%) (Figs. 1B and 1C). Affinity curves determined using variable serum albumin-to-radioligand molar ratios confirmed the strong plasma protein binding of SibuDAB as compared with only moderate binding of PSMA-I&T irrespective of the used radionuclide in both mouse and human plasma (Figs. 1B and 1C).

Blood Clearance and Biodistribution Data

Equal blood clearance curves were obtained for [161Tb]Tb-SibuDAB as previously determined for [177Lu]Lu-SibuDAB (27) in immunocompetent mice without tumors (P > 0.05; Fig. 2A).

FIGURE 2.
FIGURE 2.

(A) Blood clearance of [161Tb]Tb-SibuDAB and [177Lu]Lu-SibuDAB over 24 h after injection. (B) Decay-corrected biodistribution data 4 and 24 h after injection of [161Tb]Tb-SibuDAB and [161Tb]Tb-PSMA-I&T. PC-3 flu = PSMA-negative tumor xenografts; PC-3 PIP = PSMA-positive tumor xenograft. *Data were previously published (27).

The blood retention of [161Tb]Tb-SibuDAB in tumor-bearing BALB/c nude mice (6.5 ± 3.7 %IA/g and 0.32 ± 0.05 %IA/g at 4 and 24 h after injection, respectively) was considerably enhanced as compared with that of [161Tb]Tb-PSMA-I&T (<0.1%IA/g at 4 h after injection). As a result, the tumor uptake of [161Tb]Tb-SibuDAB was almost twice as high (75 ± 5 %IA/g) as for [161Tb]Tb-PSMA-I&T (42 ± 14 %IA/g) at 4 h after injection (Fig. 2B; Supplemental Tables 3 and 4). Kidney retention of [161Tb]Tb-SibuDAB (16 ± 1 %IA/g) was in a similar range to that for [161Tb]Tb-PSMA-I&T (18 ± 3 %IA/g) at this same time point. At the 24-h time point, less than 7 %IA/g was retained in the kidneys for both radioligands. Uptake in the tumors and kidneys at 4 and 24 h after injection of the 161Tb-based PSMA ligands did not significantly differ from that for the 177Lu-based counterparts (P > 0.05; Supplemental Tables 3 and 4). At 4 h after injection of any of the radioligands, activity retention was already less than 2% in nontargeted tissues such as the liver, spleen, and bone (Fig. 2B).

Dual-Isotope SPECT Imaging Studies

The SPECT images reconstructed on the basis of the γ-lines of 161Tb or 177Lu showed equal distribution in the blood, tumor, and kidneys of the same mouse, irrespective of the used radionuclide (Fig. 3). At 1 h after injection of [161Tb]Tb-SibuDAB/[177Lu]Lu-SibuDAB, blood retention was increased as compared with that of [161Tb]Tb-PSMA-I&T/[177Lu]Lu-PSMA-I&T, whereas kidney retention appeared somewhat lower for the former. At the 4-h time point, the differences between radiolabeled SibuDAB and PSMA-I&T were less pronounced (Fig. 3).

FIGURE 3.
FIGURE 3.

Dual-isotope SPECT/CT images of mice bearing PC-3 PIP (right shoulder) and PC-3 flu (left shoulder) tumor xenografts 1 and 4 h after injection of 1:1 mixture (20 MBq per mouse) of [161Tb]Tb-SibuDAB and [177Lu]Lu-SibuDAB (A) or [161Tb]Tb-PSMA-I&T and [177Lu]Lu-PSMA-I&T (B). Image reconstruction was based on γ-lines of 161Tb (red), 177Lu (green), or both (red/green overlay). Bl = bladder; Ki = kidneys; PC-3 flu = PSMA-negative tumor xenograft; PC-3 PIP = PSMA-positive tumor xenograft.

Dosimetry Estimations

Dosimetry data were calculated using extended biodistribution data acquired with the 177Lu-based radioligands (Supplemental Tables 5 and 6), assuming equal distribution profiles for the 161Tb- and 177Lu-labeled counterparts (Figs. 2A and 3; Supplemental Tables 3 and 4). The mean absorbed PC-3 PIP tumor dose of [161Tb]Tb-SibuDAB (10.8 ± 1.6 Gy/MBq) was about 40% higher than for [177Lu]Lu-SibuDAB (7.7 ± 1.1 Gy/MBq), and the same held true for [161Tb]Tb-PSMA-I&T (2.9 ± 0.3 Gy/MBq) as compared with [177Lu]Lu-PSMA-I&T (2.1 ± 0.2 Gy/MBq). The mean absorbed kidney dose was 0.44 ± 0.04 Gy/MBq and 0.59 ± 0.04 Gy/MBq for the respective 161Tb-labeled ligands and 0.32 ± 0.03 Gy/MBq and 0.43 ± 0.03 Gy/MBq for the 177Lu-labeled counterparts. [161Tb]Tb/[177Lu]Lu-SibuDAB demonstrated an approximately 5-fold higher tumor-to-kidney dose ratio (∼24.5) than [161Tb]Tb/[177Lu]Lu-PSMA-I&T (∼4.8) (Supplemental Table 7).

Therapeutic Efficacy of Radioligands

In control mice, the tumors grew rapidly over time, with all mice reaching a predefined endpoint between days 14 and 28 (median survival, 18 d). 161Tb-labeled PSMA ligands were consistently more effective at delaying tumor growth than the respective 177Lu-labeled counterparts, irrespective of whether SibuDAB or PSMA-I&T was used (Fig. 4; Table 1). The increased therapeutic efficacy of [161Tb]Tb-SibuDAB over [177Lu]Lu-SibuDAB was most visible in mice that received 2 MBq, as demonstrated by a median survival of 32.5 versus 23 d, respectively. All mice treated with 5 MBq of [161Tb]Tb-SibuDAB survived until study end, whereas 1 of 6 mice treated with 5 MBq [177Lu]Lu-SibuDAB reached an endpoint on day 49. Treatment of the mice with 10 MBq of [161Tb]Tb-SibuDAB resulted in complete tumor regression over the 2-mo observation period, whereas tumor regrowth was observed in 1 case approximately 6 wk after treatment with 10 MBq of [177Lu]Lu-SibuDAB (Figs. 4A and 4C).

FIGURE 4.
FIGURE 4.

(A and B) Relative tumor growth curves shown until first mouse of respective group reached endpoint. (C and D) Kaplan–Meier plot (vertical offset was applied to improve readability). Mice received vehicle or were treated with [161Tb]Tb-SibuDAB or [177Lu]Lu-SibuDAB (A and C) or with [161Tb]Tb-PSMA-I&T or [177Lu]Lu-PSMA-I&T (B and D). (Data of control group and mice treated with 5 MBq and 10 MBq of [177Lu]Lu-SibuDAB were previously published (27,28).)

View this table:
TABLE 1.

Parameters Indicative of Efficacy of Treatment

When the application was 5 MBq per mouse, 3 of 6 mice treated with [161Tb]Tb-PSMA-I&T were alive at study end (median survival, 43.5 d), whereas all mice treated with [177Lu]Lu-PSMA-I&T reached an endpoint by day 41 (median survival, 28 d). When the application was 10 MBq, 4 of 6 mice injected with [161Tb]Tb-PSMA-I&T were alive at study end, whereas only 1 of 6 mice in the group that received [177Lu]Lu-PSMA-I&T was alive at study end (Figs. 4B and 4D).

The therapeutic efficacy was quantitatively expressed as the average of the AUCRTV for mice in each group (Table 1). These values were 1.3-fold and 1.7-fold smaller for mice injected with 2 MBq or 5 MBq, respectively, of [161Tb]Tb-SibuDAB than for mice treated ith equal activities of [177Lu]Lu-SibuDAB. The AUCRTV was 2.4- and 2.2-fold lower for mice that received 5 or 10 MBq of [161Tb]Tb-PSMA-I&T, respectively, than for mice treated with equal activities of [177Lu]Lu-PSMA-I&T.

Analysis of Potential Adverse Events During Therapy

The body mass of mice with effective tumor shrinkage increased over time, with the average body mass of mice treated with 10 MBq of radioligand being in the same range on the day of euthanasia as for untreated, non–tumor-bearing control mice of the same age (P > 0.05; Supplemental Fig. 3). In contrast, rapid tumor growth was associated with body mass loss, which was observed for PC-3 PIP tumor–bearing mice that received only vehicle and for mice treated with the lowest activity.

Blood urea nitrogen, albumin, alkaline phosphatase, and total bilirubin in blood plasma were in the same range for mice treated with 10 MBq of radioligands and non–tumor-bearing control mice. The same held true for blood cell counts (P > 0.05; Fig. 5; Supplemental Tables 8 and 9). The leukocyte, erythrocyte, and thrombocyte counts were in the reference range irrespective of the applied treatment. Histopathologic analysis of the kidneys, liver, salivary glands, spleen, and bone marrow did not indicate any changes after RLT (Supplemental Table 10).

FIGURE 5.
FIGURE 5.

(A) Blood plasma parameters: blood urea nitrogen, albumin, and alkaline phosphatase. (B) Blood cell counts of leukocytes, erythrocytes, and thrombocytes. *Data were previously published (28).

DISCUSSION

Several preclinical studies demonstrated the superiority of 161Tb over 177Lu (17,18,30), which was supported by dose calculations that consistently proposed the benefit of the coemitted conversion and Auger electrons by 161Tb (15,16,31). The fact that 161Tb can be produced in large quantities, in analogy to 177Lu (32), and the commercial interest of companies to produce 161Tb make this radionuclide particularly attractive for clinical translation.

In agreement with our previous study performed with [161Tb]Tb-PSMA-617 and [177Lu]Lu-PSMA-617 (18), the in vitro properties and tissue distribution profiles of [161Tb]Tb-SibuDAB and [161Tb]Tb-PSMA-I&T were similar to their respective 177Lu-labeled counterparts. Dosimetry estimations were thus based on data obtained with [177Lu]Lu-SibuDAB and [177Lu]Lu-PSMA-I&T. Estimation of the radiation dose of [161Tb]Tb-SibuDAB and [161Tb]Tb-PSMA-I&T would most likely be feasible also for clinical data currently being acquired for [177Lu]Lu-SibuDAB and already published for [177Lu]Lu-PSMA-I&T (33). 161Tb delivers a slightly higher dose to the tissue than 177Lu because of the 15% increased β−-energy (average β− energy, 154 vs. 134 keV). More importantly, the coemission of conversion and Auger electrons contributes substantially to the enhanced dose of 161Tb depending on the sphere radius assumed for the tumor size (15). In the current study, the absorbed tumor dose estimated for the 161Tb-based PSMA ligands was 40% higher than that of the 177Lu-based counterparts. As a result, and in agreement with previous studies using other targeting agents (17,30), our data showed consistently enhanced antitumor efficacy and prolonged survival in mice treated with the 161Tb-labeled versions of SibuDAB and PSMA-I&T as compared with mice that received their 177Lu-labeled counterparts.

Because the albumin-binding properties of SibuDAB enhanced tumor uptake considerably, [161Tb]Tb-SibuDAB demonstrated an approximately 4-fold higher absorbed tumor dose than [161Tb]Tb-PSMA-I&T. [161Tb]Tb-SibuDAB, applied at the same activity as [161Tb]Tb-PSMA-I&T, thus showed better therapeutic efficacy as demonstrated by the 2.5- to 5-fold enhanced tumor growth inhibition quantified on the basis of the AUCRTV. According to dosimetry calculations, a complete tumor response could most likely also be achieved with approximately 20 MBq of [161Tb]Tb-PSMA-I&T or approximately 25 MBq of [177Lu]Lu-PSMA-I&T applied under the given experimental conditions.

Since the absorbed kidney dose was similar for both radioligands, [161Tb]Tb-SibuDAB showed a more favorable tumor-to-kidney dose ratio than [161Tb]Tb-PSMA-I&T. Assuming 23 Gy as the kidney dose limit (34), 4–5 therapy cycles of 10 MBq of [161Tb]Tb-SibuDAB or [161Tb]Tb-PSMA-I&T could be safely applied; thus, no kidney toxicity was observed in our study. In agreement with other reported preclinical studies (35), kidney uptake was considerably higher for [161Tb]Tb/[177Lu]Lu-PSMA-I&T than for [161Tb]Tb/[177Lu]Lu-PSMA-617 tested in the same tumor mouse model (18). In patients, renal retention of [177Lu]Lu-PSMA-I&T and [177Lu]Lu-PSMA-617 was more similar (36) and radionephrotoxicity was only rarely reported in the literature (37,38). Regarding other organs and tissues, the applied RLT in our study was well tolerated in mice, irrespective of the ligand and radionuclide applied. It is noteworthy, however, that salivary gland toxicity cannot be investigated in mice and therefore has to be carefully assessed in clinical studies conducted with 161Tb-based RLT.

Because mice seem to be less susceptible to undesired effects of RLT than humans, much higher activities would probably be necessary to observe hematotoxicity (39,40). Indeed, previous experiments showed that [177Lu]Lu-(R/S)-Ibu-DAB-PSMA (30 MBq per mouse) was well tolerated in immunocompetent mice over the first month after treatment (26).

Potential limitations of our study relate to the fact that an extrapolation from mice to men may not be easily feasible and that bone marrow dose calculations can hardly be performed for mice. It is likely, however, that bone marrow represents the dose-limiting organ for application of albumin-binding PSMA radioligands. Investigations of the tissue distribution profile of [161Tb]Tb/[177Lu]Lu-SibuDAB thus remain to be assessed in patients, and the favorable preclinical findings of using 161Tb remain to be confirmed clinically. As the proposed benefit of using 161Tb over 177Lu refers mainly to the elimination of single cancer cells and micrometastases, 161Tb-based radioligands should be tested in a follow-up study using mouse models of metastasized disease.

CONCLUSION

The superior therapeutic efficacy of 161Tb over 177Lu in combination with PSMA ligands agreed with the increased estimated absorbed tumor dose. The data of this study indicate particularly promising potential for [161Tb]Tb-SibuDAB in the RLT of prostate cancer patients. Generally, the clinical translation of 161Tb-based RLT appears promising, yet the therapeutic window for each of these radioligands must be carefully assessed.

DISCLOSURE

Viviane Tschan was funded by an iDoc grant from the Personalized Medicine and Related Technology program (PHRT-301; principal investigator, Cristina Müller). The research was supported by the Swiss Cancer Research Foundation (KFS-4678-02-2019-R; principal investigator, Cristina Müller) and by the Swiss National Science Foundation (310030_188978; principal investigator, Cristina Müller). Peter Bernhardt received grants from the Swedish Cancer Society, the Swedish Research Council, the King Gustav V Jubilee Clinic Cancer Research Foundation, and the Swedish state under the agreement between the Swedish government and the county councils (an ALF agreement). The project was further supported by ITM Isotope Technologies Munich SE, Germany, which delivered free 177Lu for all the performed studies. The following is a competing financial interest: patent applications on albumin-binding PSMA ligands have been filed by ITM Isotope Technologies Munich SE, Germany, in which Roger Schibli and Cristina Müller are listed as coinventors. No other potential conflict of interest relevant to this article was reported.

KEY POINTS

QUESTIONS: How effective is the therapeutic application of 161Tb in combination with albumin-binding and conventional PSMA ligands in comparison to their respective 177Lu-labeled analogs?

PERTINENT FINDINGS: These preclinical therapy studies confirmed the benefit of 161Tb-based RLT over 177Lu-based RLT in PSMA-positive tumor-bearing mice. It was also shown that [161Tb]Tb-SibuDAB was more powerful than [161Tb]Tb-PSMA-I&T because of its increased tumor uptake and, hence, absorbed tumor dose.

IMPLICATIONS FOR PATIENT CARE: These preclinical data set the basis for future clinical translation of 161Tb-based RLT using albumin-binding and conventional PSMA radioligands.

ACKNOWLEDGMENTS

We thank Luisa M. Deberle, Anna E. Becker, Susan Cohrs, Fan Sozzi-Guo, Colin Hillhouse, and Rebekka Mayer for technical assistance with the experiments at Paul Scherrer Institute, Switzerland.

Footnotes

  • Published online Jul. 13, 2023.

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  • Received for publication January 28, 2023.
  • Revision received May 31, 2023.
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