Peptide-drug Conjugate Information

General Information of This Peptide-drug Conjugate (PDC)
PDC ID
PDC_00007
PDC Name
[177Lu]Lu-P17-079
PDC Status
Investigative
Indication
In total 1 Indication(s)
Metastatic castration-resistant prostate cancer
Structure
Peptide Name
PSMA-617
  Peptide Info 
Receptor Name
Glutamate carboxypeptidase 2 (FOLH1)
  Receptor Info 
Drug Name
Lutetium-177
  Drug Info 
Therapeutic Target
Human Deoxyribonucleic acid (hDNA)
  Target Info 
Linker Name
Phosphonic Acid Linker
  Linker Info 
Peptide Modified Type
The modification of binding with chemical molecules
Modified Segment
Urea
Formula
C56H81LuN12O28P2
#Ro5 Violations (Lipinski): 5 Molecular Weight 1609.211758
Lipid-water partition coefficient (xlogp) -9.3388
Hydrogen Bond Donor Count (hbonddonor) 17
Hydrogen Bond Acceptor Count (hbondacc) 25
Rotatable Bond Count (rotbonds) 42
Full List of Activity Data of This Peptide-drug Conjugate
Revealed Based on the Cell Line Data
Click To Hide/Show 5 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
4.50%
Administration Time 5 min
Administration Dosage 37 kBq
Evaluation Method Gamma counter assay
MOA of PDC
Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [177Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [177Lu]Lu-P17-079 ([177Lu]Lu-1) and [177Lu]Lu-P17-081 ([177Lu]Lu-2) were prepared. In vivo biodistribution studies of [177Lu]Lu-PSMA-617, [177Lu]Lu-1, and [177Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [177Lu]Lu-P17-079 ([177Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer.

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Description
As expected, the PSMA-targeting hetero-bivalent agents, [177Lu]Lu-1 and [177Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [177Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [177Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [177Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [177Lu]Lu-1 and [177Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [177Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [177Lu]Lu-2 showed a very similar uptake kinetics as that of [177Lu]Lu-PSMA-617, while [177Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [177Lu]Lu-1 and [177Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [177Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo.

   Click to Show/Hide
In Vitro Model Prostate carcinoma PC3-PIP PSMA-positive cell CVCL_0035
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
8%
Administration Time 15 min
Administration Dosage 37 kBq
Evaluation Method Gamma counter assay
MOA of PDC
Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [177Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [177Lu]Lu-P17-079 ([177Lu]Lu-1) and [177Lu]Lu-P17-081 ([177Lu]Lu-2) were prepared. In vivo biodistribution studies of [177Lu]Lu-PSMA-617, [177Lu]Lu-1, and [177Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [177Lu]Lu-P17-079 ([177Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer.

   Click to Show/Hide
Description
As expected, the PSMA-targeting hetero-bivalent agents, [177Lu]Lu-1 and [177Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [177Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [177Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [177Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [177Lu]Lu-1 and [177Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [177Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [177Lu]Lu-2 showed a very similar uptake kinetics as that of [177Lu]Lu-PSMA-617, while [177Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [177Lu]Lu-1 and [177Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [177Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo.

   Click to Show/Hide
In Vitro Model Prostate carcinoma PC3-PIP PSMA-positive cell CVCL_0035
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
14%
Administration Time 30 min
Administration Dosage 37 kBq
Evaluation Method Gamma counter assay
MOA of PDC
Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [177Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [177Lu]Lu-P17-079 ([177Lu]Lu-1) and [177Lu]Lu-P17-081 ([177Lu]Lu-2) were prepared. In vivo biodistribution studies of [177Lu]Lu-PSMA-617, [177Lu]Lu-1, and [177Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [177Lu]Lu-P17-079 ([177Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer.

   Click to Show/Hide
Description
As expected, the PSMA-targeting hetero-bivalent agents, [177Lu]Lu-1 and [177Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [177Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [177Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [177Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [177Lu]Lu-1 and [177Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [177Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [177Lu]Lu-2 showed a very similar uptake kinetics as that of [177Lu]Lu-PSMA-617, while [177Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [177Lu]Lu-1 and [177Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [177Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo.

   Click to Show/Hide
In Vitro Model Prostate carcinoma PC3-PIP PSMA-positive cell CVCL_0035
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
17%
Administration Time 60 min
Administration Dosage 37 kBq
Evaluation Method Gamma counter assay
MOA of PDC
Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [177Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [177Lu]Lu-P17-079 ([177Lu]Lu-1) and [177Lu]Lu-P17-081 ([177Lu]Lu-2) were prepared. In vivo biodistribution studies of [177Lu]Lu-PSMA-617, [177Lu]Lu-1, and [177Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [177Lu]Lu-P17-079 ([177Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer.

   Click to Show/Hide
Description
As expected, the PSMA-targeting hetero-bivalent agents, [177Lu]Lu-1 and [177Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [177Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [177Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [177Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [177Lu]Lu-1 and [177Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [177Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [177Lu]Lu-2 showed a very similar uptake kinetics as that of [177Lu]Lu-PSMA-617, while [177Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [177Lu]Lu-1 and [177Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [177Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo.

   Click to Show/Hide
In Vitro Model Prostate carcinoma PC3-PIP PSMA-positive cell CVCL_0035
Experiment 5 Reporting the Activity Data of This PDC [1]
Indication Metastatic castration-resistant prostate cancer
Efficacy Data Cell uptake rate
20%
Administration Time 120 min
Administration Dosage 37 kBq
Evaluation Method Gamma counter assay
MOA of PDC
Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [177Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [177Lu]Lu-P17-079 ([177Lu]Lu-1) and [177Lu]Lu-P17-081 ([177Lu]Lu-2) were prepared. In vivo biodistribution studies of [177Lu]Lu-PSMA-617, [177Lu]Lu-1, and [177Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [177Lu]Lu-P17-079 ([177Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer.

   Click to Show/Hide
Description
As expected, the PSMA-targeting hetero-bivalent agents, [177Lu]Lu-1 and [177Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [177Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [177Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [177Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [177Lu]Lu-1 and [177Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [177Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [177Lu]Lu-2 showed a very similar uptake kinetics as that of [177Lu]Lu-PSMA-617, while [177Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [177Lu]Lu-1 and [177Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [177Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo.

   Click to Show/Hide
In Vitro Model Prostate carcinoma PC3-PIP PSMA-positive cell CVCL_0035
References
Ref 1 Lu-177-Labeled Hetero-Bivalent Agents Targeting PSMA and Bone Metastases for Radionuclide Therapy. J Med Chem. 2023 Sep 14;66(17):12602-12613. doi: 10.1021/acs.jmedchem.3c01294. Epub 2023 Sep 5.