Table 2.
Overview of therapeutic and/or theranostic studies with electron-emitting radiopharmaceuticals in ovarian cancer.
| Target | Radioligand | Development stage | Cell line | Reported radiotoxicity or dosimetry | Summary of (therapeutic) study results | Ref. |
|---|---|---|---|---|---|---|
| YKL40 | [111In]In & [177Lu]Lu-DTPA-YKL40/c41 or /c24 | Preclinical in vivo: s.c. xenograft | CA5171 & ES-2 | Significant body weight loss and hematuria. No toxic features in liver, spleen, lungs and kidneys H&E sections. | Significant tumor volume reduction with 7.4 to 22.2 MBq of [177Lu]Lu-DTPA-YKL40/c41. Higher therapeutic effect for lutetium-177 vs. indium-111. | 29 |
| HER2 | [177Lu]Lu-DOTA-trastuzumab | Preclinical in vivo: i.p. xenograft | SKOV-3 & OVCAR-3 | Exposure of Gd-NPs to lutetium-177 increased the AE yield but not the AD. | 5 MBq of [177Lu]Lu-DOTA-trastuzumab in combination with 2 x 5 mg Gd-NPs resulted in the highest tumor mass reduction. | 155 |
| [177Lu]Lu-DOTA-pertuzumab | Preclinical in vitro | SKOV-3 | NR | Specific binding up to 24% in SKOV3 cells with 65 - 70% internalization. | 49 | |
| 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. | |||
| [177Lu]Lu & [111In]In-DTPA-2Rs15d | Preclinical in vivo: s.c. xenograft | SKOV-3 | Equivalent AD in the tumor and kidneys (0.9 Gy/Mbq), 5x lower than [177Lu]Lu-DTPA-trastuzumab. No radiotoxicity was observed. | Highest tumor uptake was observed at 1 h p.i. ~6.5% IA/g vs. kidney 10.4% IA/g. Significantly longer event-free survival for 177Lu-treated mice (> day 125) vs. controls (day 33 - 75). | 53 | |
| [131I]I-SGMIB-2Rs15d | Preclinical in vitro | SKOV-3 | NR | The cell-associated fraction remained stable over 24 h with an internalized fraction up to 50%. | 55 | |
| Preclinical in vivo: i.p. xenograft | SKOV-3 | Highest AD to tumor (11.9 Gy) vs. kidneys receiving 9.4 Gy. Effective dose in humans was estimated at 0.0273 mSv/MBq. No radiotoxicity was observed. | Fast renal clearance was observed (< 0.5% IA/cc after 4 h) with relatively low tumor uptake (~2% IA/cc). [131I]I-SGMIB-2Rs15d treatment prolonged survival by 36% but with high inter-animal variability. | |||
| Iso-[131I]I-SGMIB-VHH_1028 | Preclinical in vivo: s.c. xenograft | SKOV-3 | Tumors received a 2.9 higher cumulative AD compared to [131I]I-SGMIB-2Rs15d, resulting in an 0.148 mSv/MBq effective dose in humans. | A single administration between 10 - 56 MBq significantly delayed tumor growth compared to control but not between different activity levels. | 60 | |
| L1CAM | [177Lu]Lu-DOTA-chCE7 | Preclinical in vitro | IGROV-1 | NR | [177Lu]Lu-DOTA-chCE7 in combination with paclitaxel (24 h prior to radioligand) significantly decreased cell viability and increased radiosensitivity in vitro in a synergistic manner. | 66 |
| Preclinical in vivo: s.c. xenograft | IGROV-1 | NR | In vivo combination therapy of [177Lu]Lu-DOTA-chCE7 and paclitaxel (24 h after radioligand) resulted in ~2-fold prolonged overall survival compared to monotherapy. Paclitaxel did not influence radioligand biodistribution 72 h p.i. | |||
| [161Tb]Tb-DOTA-chCE7 & [177Lu]Lu-DOTA-chCE7 | Preclinical in vivo: s.c. xenograft | IGROV-1 | Higher acute radiotoxicity for 161Tb-labeled chCE7 (MTD: 10 MBq) compared to lutetium-177 (MTD: 12 MBq). | [177Lu]Lu- and [161Tb]Tb-DOTA-chCE7 showed comparable high tumor uptake (37.8 - 39.0% IA/g, day 6) with low uptake in healthy organs. For equitoxic doses, tumor growth inhibition was better by 82.6% for the 161Tb- vs. 177Lu-labeled ligand. | 68 | |
| [177Lu]Lu-DOTA-chCE7 | Preclinical in vitro | SKOV-3 extracted from ascitic fluid + IGROV-1 | NR | Administration of protein kinase inhibitor MK1775 after or together with [177Lu]Lu-DOTA-chCE7 administration (0.05 - 5 MBq/mL) increased radiosensitivity and apoptosis in vitro. | 67 | |
| Preclinical in vivo: s.c. xenograft | SKOV-3 extracted from ascitic fluid | NR | MK1775 showed no additive effect on therapeutic efficacy of 6 MBq [177Lu]Lu-DOTA-chCE7 in vivo. | |||
| MISRII | [177Lu]Lu-DOTA-16F12, [213Bi]Bi-DTPA-16F12, [89Zr]Zr-DFOM-16F12 | Preclinical in vivo: i.p. xenograft | AN3-CA | Hematologic toxicity was more pronounced with [177Lu]Lu-16F12 than with [213Bi]Bi-16F12 for i.p. injections | I.p. treatment with [177Lu]Lu-16F12 was slightly more efficient in delaying tumor growth than [213Bi]Bi-16F12. Conversely, bismuth-213 was significantly more efficient than lutetium-177 when the peritoneal cavity is washed to remove unbound radioactivity. | 77 |
| Integrin αVβ3 | [64Cu]Cu-cyclam-RAFT-c(-RGDfK-)4 | Preclinical in vivo: s.c. & i.p. xenograft | OVCAR-3 & IGROV-1 | Kidney was dose-limiting organ (24.6 Gy). Only minor and recoverable hematological toxicity was observed until 60 days p.i. | [64Cu]Cu-RaftRGD showed an inverse relationship between uptake/therapeutic efficacy and tumor size. Intratumoral heterogeneity linked regions of RaftRGD uptake to sites of αVβ3-positive cancerous cells, angiogenesis and hypoxia. | 62 |
| PARP1 | [125I]I-KX1, [123I]I-KX1 & [131I]I-KX1 | Preclinical in vitro | OVCAR-8-wt, OVCAR-8-PARP1 KO, SKOV-3, SNU251, UWB1.289-BRCA1mut & restored | Leftward shift in dose-response curves for [125I]I-KX1, compared to [131I]I-KX1 in HRD cells. This shift was PARP1-specific. Average RBE ~3 with lowest value in BRCA1 mutant ovarian cancers. | [125I]I-KX1 caused a dose-dependent increase in γH2AX foci that was PARP-1 specific at 0.925-3.7 MBq/mL. | 89 |
| Preclinical in vivo: s.c. xenograft | OVCAR-8 | NR | [125I]I-KX1 increased expression of yH2AX (ns) in patient tumor slices. | |||
| [77Br]Br-RD1 & [76Br]Br-RD1 | Preclinical in vitro | murine ID8, OVCAR-8-wt & PARP1 KO, UWB1.289, UWB1.289-BRCA1mut & restored | NR | PARP-expression dependence of [77Br]Br-RD1 radiotoxicity is driven by differences in specific binding site expression, in which the loss of PARP1 did not change the radiosensitivity of the cancer cell line. [77Br]Br-RD1 cytotoxicity was independent of BRCA1 gene expression. | 90 | |
| Preclinical in vivo: healthy mice | - | Bone marrow was the dose-limiting organ, limiting the clinical IA at ~110 GBq. | A clear discrepancy was noted between in vivo and ex vivo biodistribution, related to heterogeneous uptake and blood/enteric content. |
%IA/g: % injected activity/gram of tissue; AD: absorbed dose; HRD: homologous recombination DNA repair deficiency; H&E: hematoxylin & eosin; i.p.: intraperitoneal; KO: knock-out; MTD: maximal tolerated dose; NPs: nanoparticles; NR: not reported; ns: not significant; OS: overall survival; PARP: poly (ADP-ribose) polymerase; p.i.: post-injection; s.c.: subcutaneous; wt: wild-type.