Peptide-drug Conjugate Information

General Information of This Peptide-drug Conjugate (PDC)
PDC ID
PDC_00008
PDC Name
[177Lu]Lu-P17-081
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
rac-(R)-2-(2-aminoacetamido)-3-(4-(2-(((R)-1-carboxy-2-phenylethyl)amino)-2-oxoethoxy)phenyl)propanoic acid
  Linker Info 
Peptide Modified Type
The modification of binding with chemical molecules
Modified Segment
Urea
Formula
C59H83LuN12O30P2
#Ro5 Violations (Lipinski): 5 Molecular Weight 1679.258758
Lipid-water partition coefficient (xlogp) -8.8972
Hydrogen Bond Donor Count (hbonddonor) 17
Hydrogen Bond Acceptor Count (hbondacc) 25
Rotatable Bond Count (rotbonds) 44
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
3.50%
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
5.50%
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
7.50%
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
8%
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
10%
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.