Table 1.
Overview of therapeutic and/or theranostic studies with α-particle emitting radiopharmaceuticals in ovarian cancer.
| Target | Radioligand | Development stage | Cell line/patient population | Reported radiotoxicity or dosimetry | Summary of (therapeutic) study results | Ref. |
|---|---|---|---|---|---|---|
| TAG-72 | [225Ac]Ac-DOTA-huCC49 | Preclinical in vivo: s.c. xenograft | OVCAR-3 | NR | [225Ac]Ac-DOTA-huCC49 significantly reduced tumor growth in a dose-dependent manner (1.85, 3.7, and 7.4 kBq), with the 7.4 kBq dose extending survival > 3-fold compared to controls. 1.85 kBq followed by 5 weekly doses of 0.70 kBq for a total of 5.4 kBq extended survival almost 3-fold compared with controls. | 28 |
| B7-H3 | [212Pb]Pb-TCMC-376.96 & -TCMC-F3-C25 | Preclinical in vitro | ES-2 & A2780cp20 | NR | Synergistic effect of carboplatin and 2.7 or 21 kBq/mL [212Pb]Pb-TCMC-376.96 on clonogenic survival. | 36 |
| Preclinical in vivo: i.p. xenograft | NR | 0.35-0.51 MBq [212Pb]Pb-TCMC-376.96 treatment significantly prolonged survival (2 - 3 fold) of mice with i.p. tumor xenografts relative to controls. High retention in spleen and liver. No additive effect of carboplatin. | ||||
| FR1α | [211At]At-m-MeATE-farletuzumab (& [211At]At-MX35) | Preclinical in vitro | OVCAR-3 | NR | TFF after i.p. [211At]At-farletuzumab was 91%. Biodistributions revealed accumulation of unlabeled astatine-211 in throat (incl. thyroid) and stomach. | 43 |
| Preclinical in vivo: i.p. xenograft | OVCAR-3 | AD to the nucleus from peritoneal liquid and cell membrane was 7.6 Gy and 9.6 Gy, respectively. | TFF of control groups ranged from 9% to 14%. TFF after [211At]At-farletuzumab was 91%. | |||
| HER2 | [212Pb]Pb-TCMC-trastuzumab | Clinical: phase 1 trial | 3 patients with HER2+ ovarian malignancies and disease progression | No evident short- or long-term toxicity upon follow-up over > 6 months | First-in-human experience with i.p. infusion of [212Pb]Pb-TCMC-trastuzumab (7.4 MBq/m2). No redistribution out of peritoneal cavity. | 46 |
| Clinical: phase 1 trial | 18 patients with HER2+ peritoneal metastases | No late toxicity (renal, liver, cardiac or other) < 1 year after treatment | I.p. [212Pb]Pb-TCMC-trastuzumab up to 27 MBq/m² appears safe for patients with peritoneal carcinomatosis who have failed standard therapies. Serum TAG-72 levels better correlated to imaging changes in OC patients than the tumor marker, CA125. | 47 | ||
| [214Pb]Pb- & [214Bi]Bi-TCMC-trastuzumab | Preclinical in vitro | SKOV-3 & OVCAR-3 | NR | 0.37 MBq/well reduced clonogenic survival more than 4-fold. | 48 | |
| Preclinical in vivo: i.p. xenograft | SKOV-3 | NR | Fractionation (2 x 0.74 MBq) was more efficient compared to single i.p. administration (0.74 MBq) in reducing tumor mass (> 5 fold for both treatment schedules). | |||
| Preclinical in vivo: s.c. xenograft | SKOV-3 | NR | Sustained tumor retention of the Ab until 120 h p.i. (~25% IA/g). Blood clearance within 120 h. | |||
| [211At]At-SAGMB-2Rs15d, -SAB-2Rs15d & -MSB-2Rs15d | Preclinical in vitro | SKOV-3 | NR | Highest specific binding for [211At]At-SAGMB-2Rs15d (~66%) and [211At]At-MSB-2Rs15d (~77%) after 1 h incubation. | 54 | |
| Preclinical in vivo: s.c. xenograft | SKOV-3 | Highest AD to tumor (2 Gy/MBq) and kidneys (7.7 Gy/MBq) for [211At]At-SAGMB-2Rs15d was also associated with best therapeutic window. Astatinated sdAbs with m-MeATE or MSB reagents indicated the presence of released astatine-211 in lungs/stomach. | Comparable tumor uptake in all radioconjugates (> 8% IA/g at 1 h). [211At]At-SAGMB-2Rs15d showed minor uptake in normal tissues. Astatinated sdAbs consisting of m-MeATE or MSB reagents revealed elevated uptake in lungs and stomach, indicating free astatine-211. α-camera imaging revealed a homogeneous tumor activity distribution. Fast washout into urine (~3 h p.i.). | |||
| [213Bi]Bi-DTPA-2Rs15d | Preclinical in vitro | SKOV-3 | NR | Clonogenic ability, cell growth rates and cellular apoptosis were significantly impacted upon treatment with [213Bi]Bi-DTPA-2Rs15d. | 56 | |
| Preclinical in vivo: s.c. xenograft | SKOV-3 | An activity escalation study up to 2 - 11 MBq induced signs of toxicity in kidneys and spleen. Co-infusion of gelofusine significantly reduced kidney uptake. | Administration of [213Bi]Bi-DTPA-2Rs15d alone and in combination with trastuzumab resulted in a significant increase in median survival. | |||
| [225Ac]Ac-DOTA-2Rs15d | Preclinical in vitro | SKOV-3 | NR | There was no treatment-specific effect on colony formation and DSB formation in vitro. | 57 | |
| Preclinical in vivo: s.c. & i.p. xenograft | SKOV-3 | Mild to serious tubulopathy in mice treated with [225Ac]Ac-DOTA-2Rs15d resulting in AD ~9.8 - 29.5 Gy (inflammatory lesions and tubular dilation). | Dose fractionation (3 x 85 kBq) was more efficient compared to a single dose to prolong survival (~factor 3 compared to controls). | |||
| Mesothelin | [227Th]Th-BAY 2287411 | Preclinical in vitro | OVCAR-3 and ST103 | NR | [227Th]Th-BAY 2287411 induces significant cytoxicity by causing DNA DSB, G2-M cycle arrest and ROS production. | 71 |
| Preclinical in vivo: xenograft and PDX models | OVCAR-3 and ST103 | NR | Strong correlation between MSLN expression levels and tumor uptake. Tumor accumulation close to 100% IA/g at 672 h in the ST103 model. Complete tumor remission with single dose of 500 kBq/kg of [227Th]Th-BAY 2287411 in ST103 and near-complete tumor response with 250 kBq/kg for OVCAR-3 in vivo. | |||
| [227Th]Th-BAY 2287411 | Preclinical in vitro | OVCAR-3/8 | NR | ATRi and PARPi potentiate [227Th]Th-BAY 2287411 therapy by suppressing DNA damage repair. | 73 | |
| Preclinical in vivo: s.c. xenograft | OVCAR-3/8 | NR | Enhanced therapeutic efficacy of [227Th]Th-BAY 2287411 in combination with ATRi or PARPi in OVCAR-3 and OVCAR-8 | |||
| NaPi2b | [213Bi]Bi-MX35 | Preclinical in vivo: i.p. xenograft | OVCAR-3 | No significant differences in platelet or WBC count at 6 and 14 days post treatment. Tumor AD between ~ 11.3 Gy and 27 Gy for 3 and 9 MBq, respectively. | 78% of mice were in remission (no macroscopic or microscopic tumors) after single i.p. administration of 9 MBq [213Bi]Bi-MX35 | 81 |
| [211At]At-MX35-F(ab′)2 | Preclinical in vivo: s.c. xenograft | OVCAR-3 | Bone marrow recovery was noted for the low-activity groups, whereas for high-activity groups the reduction was close to acute myelotoxicity. Decreased hematocrit was seen at a late interval (34 - 59 weeks after therapy). | Complete remission is achievable for < 50 mm3 tumors. Complete remission (TFF, 100 %) was found for tumor AD of 12.4 and 16.4 Gy. | 83 | |
| [211At]At-MX35-F(ab′)2 | Clinical: phase 1 trial | 6 patients in clinical remission from recurrence | No acute or deterministic radiation toxicities up to 297 MBq. The urinary bladder, thyroid, and kidneys (1.9, 1.8, and 1.7 mGy per MBq/L) received the highest AD. | Absolute activity in the blood peaked at ~12 h (~3% of infusate activity). | 110 | |
| [211At]At-MX35-F(ab′)2 | Clinical: phase 1 trial | 12 patients with relapsed epithelial ovarian cancer | Escalation to 355 MBq without dose-limiting toxicities in patients (median follow-up time: 42 months). No decreased tolerance to relapse therapy, | Overall median survival was 35 months, with a 1-, 2-, 5-, and 10-year survival of 100%, 83%, 50%, and 25%, respectively. Lower SA is associated with a lower single-cell dose, whereas a high SA may result in a lower central AD in microtumors. Individual differences in AD to possible microtumors were due to variations in administered activity and the SA. | 85 |
%IA/g: % injected activity/gram of tissue; Ab: antibody; AD: absorbed dose; ATRi: ataxia telangiectasia and Rad3-related protein inhibitor; DSB: double-strand break; i.p.: intraperitoneal; KO: knock-out; sdAb: single-domain antibody fragments; NR: not reported; PARPi: poly (ADP-ribose) polymerase inhibitor; PDX: patient-derived xenograft; p.i.: post-injection; ROS: reactive oxygen species; SA: specific activity; s.c.: subcutaneous; TFF: tumor free fraction.