[177Lu]Pertuzumab: Experimental Therapy of HER-2–Expressing Xenografts

Persson, Mikael; Gedda, Lars; Lundqvist, Hans; Tolmachev, Vladimir; Nordgren, Hans; Malmström, Per‐Uno; Carlsson, Jörgen

doi:10.1158/0008-5472.can-06-2363

Cited by 51 publications

(28 citation statements)

References 21 publications

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“…As such effects may occur only in the long-term, such as 120-145 days after injection in the present study, the absence of previous observation of oncogenic effects could be related to excessively short follow-up times, not extending beyond a few weeks in the majority of previous studies. As an example, the maximum follow-up time was respectively 77 and 102 days in two studies performed with antibodies labeled with lutetium-177 [6,7]. However, in one study performed with a 177 Lu-labeled anti-Lewis Y antibody the maximum follow-up time was 150 days after injection of an activity of 12.95 MBq, comparable to that of the present study, and no oncogenic effect was observed [8].…”

supporting

confidence: 78%

The best radionuclide for radioimmunotherapy of small tumors: beta- or alpha-emitter?

Barbet

Chatal

2010

Eur J Nucl Med Mol Imaging

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supporting

confidence: 78%

The best radionuclide for radioimmunotherapy of small tumors: beta- or alpha-emitter?

Barbet

Chatal

2010

Eur J Nucl Med Mol Imaging

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“…Antibodies have been extensively investigated for therapeutic targeting of radionuclides [57]. Recently, Carlsson and co-workers used the HER2-binding antibody pertuzumab, also labeled with 177 Lu and using the same SKOV-3 tumor model and therapeutic protocol as used for the Affibody-ABD fusion protein described above [58]. Very encouraging results were obtained, but in contrast to the Affibody experiment, with no curative effect.…”

Section: Targeting Payloadsmentioning

confidence: 99%

Affibody molecules: Engineered proteins for therapeutic, diagnostic and biotechnological applications

et al. 2010

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a b s t r a c tAffibody molecules are a class of engineered affinity proteins with proven potential for therapeutic, diagnostic and biotechnological applications. Affibody molecules are small (6.5 kDa) single domain proteins that can be isolated for high affinity and specificity to any given protein target. Fifteen years after its discovery, the Affibody technology is gaining use in many groups as a tool for creating molecular specificity wherever a small, engineering compatible tool is warranted. Here we summarize recent results using this technology, propose an Affibody nomenclature and give an overview of different HER2-specific Affibody molecules. Cumulative evidence suggests that the three helical scaffold domain used as basis for these molecules is highly suited to create a molecular affinity handle for vastly different applications.

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“…Delivery of a higher radiation dose to the tumors can be achieved using radiolabeled antibodies. However, the absorbed dose in the red bone marrow usually becomes a limitation because of the prolonged blood circulation of full-length antibodies (27). In contrast, the blood retention half-life of 64 Cu-NOTA-FVIIai was estimated to be 1.6 h based on the in vivo PET data.…”

Section: Dosimetrymentioning

confidence: 99%

PET Imaging of Tissue Factor in Pancreatic Cancer Using ⁶⁴Cu-Labeled Active Site–Inhibited Factor VII

et al. 2016

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Tissue factor (TF) is the main initiator of the extrinsic coagulation cascade. However, TF also plays an important role in cancer. TF expression has been reported in 53%-89% of all pancreatic adenocarcinomas, and the expression level of TF has in clinical studies correlated with advanced stage, increased microvessel density, metastasis, and poor overall survival. Imaging of TF expression is of clinical relevance as a prognostic biomarker and as a companion diagnostic for TF-directed therapies currently under clinical development. Factor VII (FVII) is the natural ligand to TF. The purpose of this study was to investigate the possibility of using active siteinhibited FVII (FVIIai) labeled with 64 Cu for PET imaging of TF expression. Methods: FVIIai was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCNBn-NOTA) and labeled with 64 Cu ( 64 Cu-NOTA-FVIIai). Longitudinal in vivo PET imaging was performed at 1, 4, 15, and 36 h after injection of 64 Cu-NOTA-FVIIai in mice with pancreatic adenocarcinomas (BxPC-3). The specificity of TF imaging with 64 Cu-NOTAFVIIai was investigated in subcutaneous pancreatic tumor models with different levels of TF expression and in a competition experiment. In addition, imaging of orthotopic pancreatic tumors was performed using 64 Cu-NOTA-FVIIai and PET/MRI. In vivo imaging data were supported by ex vivo biodistribution, flow cytometry, and immunohistochemistry. Results: Longitudinal PET imaging with 64 Cu-NOTA-FVIIai showed a tumor uptake of 2.3 ± 0.2, 3.7 ± 0.3, 3.4 ± 0.3, and 2.4 ± 0.3 percentage injected dose per gram at 1, 4, 15, and 36 h after injection, respectively. An increase in tumor-tonormal-tissue contrast was observed over the imaging time course. Competition with unlabeled FVIIai significantly (P , 0.001) reduced the tumor uptake. The tumor uptake observed in models with different TF expression levels was significantly different from each other (P , 0.001) and was in agreement with the TF level evaluated by TF immunohistochemistry staining. Orthotopic tumors were clearly visible on the PET/MR images, and the uptake of 64 Cu-NOTA-FVIIai was colocalized with viable tumor tissue. Conclusion: 64 Cu-NOTA-FVIIai is well suited for PET imaging of tumor TF expression, and imaging is capable of distinguishing the TF expression level of various pancreatic tumor models. Ti ssue factor (TF) is a 47-kDa glycosylated transmembrane protein consisting of a large extracellular domain and a short cytoplasmic domain. TF acts as the initiator of the extrinsic coagulation cascade. The zymogen factor VII (FVII) is the natural ligand to TF and gets activated to FVIIa on binding to TF. The TF-FVIIa complex further activates factor IX and factor X, eventually leading to fibrin deposition, platelet aggregation, and formation of a thrombus (1).In addition to its role in the coagulation cascade, TF is associated with cancer (1-3). TF expression has been found in all solid tumors, and its expression has been linked to mutation of the K-ras oncogene, loss...

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[177Lu]Pertuzumab: Experimental Therapy of HER-2–Expressing Xenografts

Cited by 51 publications

References 21 publications

The best radionuclide for radioimmunotherapy of small tumors: beta- or alpha-emitter?

The best radionuclide for radioimmunotherapy of small tumors: beta- or alpha-emitter?

Affibody molecules: Engineered proteins for therapeutic, diagnostic and biotechnological applications

PET Imaging of Tissue Factor in Pancreatic Cancer Using ⁶⁴Cu-Labeled Active Site–Inhibited Factor VII

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[177Lu]Pertuzumab: Experimental Therapy of HER-2–Expressing Xenografts

Cited by 51 publications

References 21 publications

The best radionuclide for radioimmunotherapy of small tumors: beta- or alpha-emitter?

The best radionuclide for radioimmunotherapy of small tumors: beta- or alpha-emitter?

Affibody molecules: Engineered proteins for therapeutic, diagnostic and biotechnological applications

PET Imaging of Tissue Factor in Pancreatic Cancer Using 64Cu-Labeled Active Site–Inhibited Factor VII

Contact Info

Product

Resources

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PET Imaging of Tissue Factor in Pancreatic Cancer Using ⁶⁴Cu-Labeled Active Site–Inhibited Factor VII