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Article ; Online: Radiolabeled Antibodies for Immune Checkpoint PET in Preclinical Research.

Boswinkel, Milou / Franssen, Gerben M / Heskamp, Sandra

Methods in molecular biology (Clifton, N.J.)

2023 Volume 2729, Page(s) 143–158

Abstract: Antibodies that block immune checkpoints, also called immune checkpoint inhibitors (ICI), have demonstrated impressive anti-tumor efficacy. The success of ICIs results from a complex interplay between cancer cells and their immune microenvironment. One ... ...

Abstract	Antibodies that block immune checkpoints, also called immune checkpoint inhibitors (ICI), have demonstrated impressive anti-tumor efficacy. The success of ICIs results from a complex interplay between cancer cells and their immune microenvironment. One of the predictors for ICI efficacy is the expression of the targeted immune checkpoint, such as programmed death ligand 1 (PD-L1). Immune checkpoints can be expressed on tumor cells and/or subsets of immune cells. PET imaging offers unique possibilities to study the dynamics of immune checkpoint expression in tumor and normal tissues in a longitudinal manner. In this chapter, we describe the methodology to use zirconium-89-labeled antibodies to assess the expression of immune checkpoint molecules in syngeneic murine tumor models by PET imaging.
MeSH term(s)	Humans ; Mice ; Animals ; Neoplasms/diagnostic imaging ; Positron-Emission Tomography/methods ; Immunoconjugates ; Tumor Microenvironment
Chemical Substances	Immunoconjugates
Language	English
Publishing date	2023-11-25
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3499-8_9
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Article ; Online: Liver and spleen predominantly mediate calciprotein particle clearance in a rat model of chronic kidney disease.

Zeper, Lara W / Bos, Caro / Leermakers, Pieter A / Franssen, Gerben M / Raavé, René / Hoenderop, Joost G J / de Baaij, Jeroen H F

American journal of physiology. Renal physiology

2024 Volume 326, Issue 4, Page(s) F622–F634

Abstract: Calciprotein particles (CPPs) provide an efficient mineral buffering system to prevent the complexation of phosphate and calcium in the circulation. However, in chronic kidney disease (CKD), the phosphate load exceeds the mineral buffering capacity, ... ...

Abstract	Calciprotein particles (CPPs) provide an efficient mineral buffering system to prevent the complexation of phosphate and calcium in the circulation. However, in chronic kidney disease (CKD), the phosphate load exceeds the mineral buffering capacity, resulting in the formation of crystalline CPP2 particles. CPP2 have been associated with cardiovascular events and mortality. Moreover, CPP2 have been demonstrated to induce calcification in vitro. In this study, we examined the fate of CPP2 in a rat model of CKD. Calcification was induced in Sprague-Dawley rats by 5/6 nephrectomy (5/6-Nx) combined with a high-phosphate diet. Control rats received sham surgery and high-phosphate diet. Twelve weeks after surgery, kidney failure was significantly induced in 5/6-Nx rats as determined by enhanced creatinine and urea plasma levels and abnormal kidney histological architecture. Subsequently, radioactive and fluorescent (FITC)-labeled CPP2 ([
MeSH term(s)	Rats ; Animals ; Spleen/metabolism ; Calcium/metabolism ; Fluorescein-5-isothiocyanate ; Tissue Distribution ; Rats, Sprague-Dawley ; Vascular Calcification/diagnostic imaging ; Vascular Calcification/etiology ; Minerals ; Liver/metabolism ; Phosphates ; Renal Insufficiency, Chronic/pathology
Chemical Substances	Calcium (SY7Q814VUP) ; Fluorescein-5-isothiocyanate (I223NX31W9) ; Minerals ; Phosphates
Language	English
Publishing date	2024-02-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00239.2023
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Article: Effect of

Hörmann, Anton Amadeus / Klingler, Maximilian / Rangger, Christine / Mair, Christian / Joosten, Lieke / Franssen, Gerben M / Laverman, Peter / von Guggenberg, Elisabeth

Pharmaceutics

2023 Volume 15, Issue 3

Abstract: The therapeutic potential of minigastrin (MG) analogs for the treatment of cholecystokinin-2 receptor (CCK2R)-expressing cancers is limited by poor in vivo stability or unfavorable accumulation in non-target tissues. Increased stability against metabolic ...

Abstract	The therapeutic potential of minigastrin (MG) analogs for the treatment of cholecystokinin-2 receptor (CCK2R)-expressing cancers is limited by poor in vivo stability or unfavorable accumulation in non-target tissues. Increased stability against metabolic degradation was achieved by modifying the C-terminal receptor-specific region. This modification led to significantly improved tumor targeting properties. In this study, further
Language	English
Publishing date	2023-02-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15030796
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Article ; Online: 89Zr-PSMA-617 PET/CT May Reveal Local Recurrence of Prostate Cancer Unidentified by 68Ga-PSMA-11 PET/CT.

Rosar, Florian / Bartholomä, Mark / Maus, Stephan / Privé, Bastiaan M / Khreish, Fadi / Franssen, Gerben M / Derks, Yvonne H W / Nagarajah, James / Ezziddin, Samer

Clinical nuclear medicine

2022 Volume 47, Issue 5, Page(s) 435–436

Abstract: Abstract: For localization of biochemical recurrence of prostate cancer, 68Ga-PSMA-11 PET/CT imaging was performed in a 66-year-old man with no suspicious findings at 1 hour p.i. Additional 89Zr-PSMA-617 PET/CT revealed a small local recurrence in the ... ...

Abstract	Abstract: For localization of biochemical recurrence of prostate cancer, 68Ga-PSMA-11 PET/CT imaging was performed in a 66-year-old man with no suspicious findings at 1 hour p.i. Additional 89Zr-PSMA-617 PET/CT revealed a small local recurrence in the prostate bed, facilitating consecutive local therapy. This interesting image points to the potential of PET/CT with 89Zr-labeled PSMA ligands, for example, 89Zr-PSMA-617, for identifying the source of biochemical recurrence despite otherwise negative imaging including conventional PSMA PET/CT.
MeSH term(s)	Aged ; Dipeptides ; Edetic Acid ; Gallium Isotopes ; Gallium Radioisotopes ; Heterocyclic Compounds, 1-Ring ; Humans ; Male ; Neoplasm Recurrence, Local/diagnostic imaging ; Positron Emission Tomography Computed Tomography/methods ; Prostate-Specific Antigen ; Prostatic Neoplasms/diagnostic imaging ; Radioisotopes ; Zirconium
Chemical Substances	Dipeptides ; Gallium Isotopes ; Gallium Radioisotopes ; Heterocyclic Compounds, 1-Ring ; PSMA-617 ; Radioisotopes ; gallium 68 PSMA-11 ; Edetic Acid (9G34HU7RV0) ; Zirconium (C6V6S92N3C) ; Prostate-Specific Antigen (EC 3.4.21.77) ; Zirconium-89 (NTM296JU95)
Language	English
Publishing date	2022-03-02
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	197628-x
ISSN	1536-0229 ; 0363-9762
ISSN (online)	1536-0229
ISSN	0363-9762
DOI	10.1097/RLU.0000000000004108
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Zs.A 1276: Show issues

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Article ; Online: Fibroblast Activation Protein-Targeting Minibody-IRDye700DX for Ablation of the Cancer-Associated Fibroblast with Photodynamic Therapy.

Smeets, Esther M M / Dorst, Daphne N / Franssen, Gerben M / van Essen, Merijn S / Frielink, Cathelijne / Stommel, Martijn W J / Trajkovic-Arsic, Marija / Cheung, Phyllis F / Siveke, Jens T / Wilson, Ian / Mascioni, Alessandro / Aarntzen, Erik H J G / van Lith, Sanne A M

Cells

2023 Volume 12, Issue 10

Abstract: Fibroblast activation protein (FAP), expressed on cancer-associated fibroblasts, is a target for diagnosis and therapy in multiple tumour types. Strategies to systemically deplete FAP-expressing cells show efficacy; however, these induce toxicities, as ... ...

Abstract	Fibroblast activation protein (FAP), expressed on cancer-associated fibroblasts, is a target for diagnosis and therapy in multiple tumour types. Strategies to systemically deplete FAP-expressing cells show efficacy; however, these induce toxicities, as FAP-expressing cells are found in normal tissues. FAP-targeted photodynamic therapy offers a solution, as it acts only locally and upon activation. Here, a FAP-binding minibody was conjugated to the chelator diethylenetriaminepentaacetic acid (DTPA) and the photosensitizer IRDye700DX (DTPA-700DX-MB). DTPA-700DX-MB showed efficient binding to FAP-overexpressing 3T3 murine fibroblasts (3T3-FAP) and induced the protein's dose-dependent cytotoxicity upon light exposure. Biodistribution of DTPA-700DX-MB in mice carrying either subcutaneous or orthotopic tumours of murine pancreatic ductal adenocarcinoma cells (PDAC299) showed maximal tumour uptake of
MeSH term(s)	Animals ; Mice ; Serine Endopeptidases/metabolism ; Cancer-Associated Fibroblasts/metabolism ; Tissue Distribution ; Membrane Proteins/metabolism ; Pancreatic Neoplasms/pathology ; Fibroblasts/metabolism ; Photochemotherapy ; Pentetic Acid/metabolism
Chemical Substances	Serine Endopeptidases (EC 3.4.21.-) ; Membrane Proteins ; Pentetic Acid (7A314HQM0I)
Language	English
Publishing date	2023-05-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12101420
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Article: Carbonic Anhydrase IX-Targeted α-Radionuclide Therapy with 225Ac Inhibits Tumor Growth in a Renal Cell Carcinoma Model.

Merkx, Robin I J / Rijpkema, Mark / Franssen, Gerben M / Kip, Annemarie / Smeets, Bart / Morgenstern, Alfred / Bruchertseifer, Frank / Yan, Eddie / Wheatcroft, Michael P / Oosterwijk, Egbert / Mulders, Peter F A / Heskamp, Sandra

Pharmaceuticals (Basel, Switzerland)

2022 Volume 15, Issue 5

Abstract: In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability of the humanized anti-CAIX antibody (hG250) labeled with either the α-emitter actinium-225 (225Ac) or the β--emitter lutetium-177 (177Lu) in mice. BALB/c ... ...

Abstract	In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability of the humanized anti-CAIX antibody (hG250) labeled with either the α-emitter actinium-225 (225Ac) or the β--emitter lutetium-177 (177Lu) in mice. BALB/c nude mice were grafted with human renal cell carcinoma SK-RC-52 cells and intravenously injected with 30 µg [225Ac] Ac-DOTA-hG250 (225Ac-hG250) or 30 µg [177Lu] Lu-DOTA-hG250 (177Lu-hG250), followed by ex vivo biodistribution studies. Therapeutic efficacy was evaluated in mice receiving 5, 15, and 25 kBq of 225Ac-hG250; 13 MBq of 177Lu-hG250; or no treatment. Tolerability was evaluated in non-tumor-bearing animals. High tumor uptake of both radioimmunoconjugates was observed and increased up to day 7 (212.8 ± 50.2 %IA/g vs. 101.0 ± 18.4 %IA/g for 225Ac-hG250 and 177Lu-hG250, respectively). Survival was significantly prolonged in mice treated with 15 kBq 225Ac-hG250, 25 kBq 225Ac-hG250, and 13 MBq 177Lu-hG250 compared to untreated control (p < 0.05). Non-tumor-bearing mice that received single-dose treatment with 15 or 25 kBq 225Ac-hG250 showed weight loss at the end of the experiment (day 126), and immunohistochemical analysis suggested radiation-induced nephrotoxicity. These results demonstrate the therapeutic potential of CAIX-targeted α-therapy in renal cell carcinoma. Future studies are required to find an optimal balance between therapeutic efficacy and toxicity.
Language	English
Publishing date	2022-05-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph15050570
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Article ; Online: [<sup>89</sup>Zr]Zr-PSMA-617 PET/CT in biochemical recurrence of prostate cancer: first clinical experience from a pilot study including biodistribution and dose estimates.

Rosar, Florian / Schaefer-Schuler, Andrea / Bartholomä, Mark / Maus, Stephan / Petto, Sven / Burgard, Caroline / Privé, Bastiaan M / Franssen, Gerben M / Derks, Yvonne H W / Nagarajah, James / Khreish, Fadi / Ezziddin, Samer

European journal of nuclear medicine and molecular imaging

2022 Volume 49, Issue 13, Page(s) 4736–4747

Abstract: Purpose: Prostate-specific membrane antigen (PSMA)-targeted PET/CT has become increasingly important in the management of prostate cancer, especially in localization of biochemical recurrence (BCR). PSMA-targeted PET/CT imaging with long-lived ... ...

Abstract	Purpose: Prostate-specific membrane antigen (PSMA)-targeted PET/CT has become increasingly important in the management of prostate cancer, especially in localization of biochemical recurrence (BCR). PSMA-targeted PET/CT imaging with long-lived radionuclides as <sup>89</sup>Zr (T<sub>1/2</sub> = 78.4 h) may improve diagnostics by allowing data acquisition on later time points. In this study, we present our first clinical experience including preliminary biodistribution and dosimetry data of [<sup>89</sup>Zr]Zr-PSMA-617 PET/CT in patients with BCR of prostate cancer. Methods: Seven patients with BCR of prostate cancer who revealed no (n = 4) or undetermined (n = 3) findings on [<sup>68</sup>Ga]Ga-PSMA-11 PET/CT imaging were referred to [<sup>89</sup>Zr]Zr-PSMA-617 PET/CT. PET/CT imaging was performed 1 h, 24 h, 48 h, and 72 h post injection (p.i.) of 111 ± 11 MBq [<sup>89</sup>Zr]Zr-PSMA-617 (mean ± standard deviation). Normal organ distribution and dosimetry were determined. Lesions visually considered as suggestive of prostate cancer were quantitatively analyzed. Results: Intense physiological uptake was observed in the salivary and lacrimal glands, liver, spleen, kidneys, intestine and urinary tract. The parotid gland received the highest absorbed dose (0.601 ± 0.185 mGy/MBq), followed by the kidneys (0.517 ± 0.125 mGy/MBq). The estimated overall effective dose for the administration of 111 MBq was 10.1 mSv (0.0913 ± 0.0118 mSv/MBq). In 6 patients, and in particular in 3 of 4 patients with negative [<sup>68</sup>Ga]Ga-PSMA-11 PET/CT, at least one prostate cancer lesion was detected in [<sup>89</sup>Zr]Zr-PSMA-617 PET/CT imaging at later time points. The majority of tumor lesions were first visible at 24 h p.i. with continuously increasing tumor-to-background ratio over time. All tumor lesions were detectable at 48 h and 72 h p.i. Conclusion: [<sup>89</sup>Zr]Zr-PSMA-617 PET/CT imaging is a promising new diagnostic tool with acceptable radiation exposure for patients with prostate cancer especially when [<sup>68</sup>Ga]Ga-PSMA-11 PET/CT imaging fails detecting recurrent disease. The long half-life of <sup>89</sup>Zr enables late time point imaging (up to 72 h in our study) with increased tracer uptake in tumor lesions and higher tumor-to-background ratios allowing identification of lesions non-visible on [<sup>68</sup>Ga]Ga-PSMA-11 PET/CT imaging.
MeSH term(s)	Male ; Humans ; Positron Emission Tomography Computed Tomography/methods ; Gallium Radioisotopes ; Tissue Distribution ; Pilot Projects ; Prostatic Neoplasms/diagnostic imaging ; Prostatic Neoplasms/pathology ; Radioisotopes
Chemical Substances	PSMA-617 ; Gallium Radioisotopes ; Radioisotopes
Language	English
Publishing date	2022-08-05
Publishing country	Germany
Document type	Journal Article
ZDB-ID	8236-3
ISSN	1619-7089 ; 0340-6997 ; 1619-7070
ISSN (online)	1619-7089
ISSN	0340-6997 ; 1619-7070
DOI	10.1007/s00259-022-05925-3
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Article ; Online: Theranostic PSMA ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer.

Derks, Yvonne H W / van Lith, Sanne A M / Amatdjais-Groenen, Helene I V / Wouters, Lieke W M / Kip, Annemarie / Franssen, Gerben M / Laverman, Peter / Löwik, Dennis W P M / Heskamp, Sandra / Rijpkema, Mark

European journal of nuclear medicine and molecular imaging

2022 Volume 49, Issue 7, Page(s) 2425–2435

Abstract: Introduction: The first generation ligands for prostate-specific membrane antigen (PSMA)-targeted radio- and fluorescence-guided surgery followed by adjuvant photodynamic therapy (PDT) have already shown the potential of this approach. Here, we ... ...

Abstract	Introduction: The first generation ligands for prostate-specific membrane antigen (PSMA)-targeted radio- and fluorescence-guided surgery followed by adjuvant photodynamic therapy (PDT) have already shown the potential of this approach. Here, we developed three new photosensitizer-based dual-labeled PSMA ligands by crucial modification of existing PSMA ligand backbone structures (PSMA-1007/PSMA-617) for multimodal imaging and targeted PDT of PCa. Methods: Various new PSMA ligands were synthesized using solid-phase chemistry and provided with a DOTA chelator for Results: In order to synthesize the new dual-labeled ligands, we modified the PSMA peptide linker by substitution of a glutamic acid into a lysine residue, providing a handle for conjugation of multiple functional moieties. Ligand optimization showed that the new backbone structure leads to high-affinity PSMA ligands (all IC Conclusion: The new high-affinity dual-labeled PSMA-targeting ligands with optimized backbone compositions showed increased tumor targeting and enabled multimodal image-guided PCa surgery combined with targeted photodynamic therapy.
MeSH term(s)	Animals ; Antigens, Surface/metabolism ; Cell Line, Tumor ; Glutamate Carboxypeptidase II/metabolism ; Humans ; Ligands ; Male ; Mice ; Mice, Nude ; Multimodal Imaging ; Photochemotherapy ; Photosensitizing Agents/therapeutic use ; Precision Medicine ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/therapy ; Tissue Distribution
Chemical Substances	Antigens, Surface ; Ligands ; Photosensitizing Agents ; Glutamate Carboxypeptidase II (EC 3.4.17.21)
Language	English
Publishing date	2022-01-14
Publishing country	Germany
Document type	Journal Article
ZDB-ID	8236-3
ISSN	1619-7089 ; 0340-6997 ; 1619-7070
ISSN (online)	1619-7089
ISSN	0340-6997 ; 1619-7070
DOI	10.1007/s00259-022-05685-0
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Zs.A 1227: Show issues

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Article ; Online: Combination of sunitinib and

Oosterwijk-Wakka, Jeannette C / de Weijert, Mirjam C A / Franssen, Gerben M / Kolev, Dimitar R / de Haan, Ton A F J / Boerman, Otto C / Mulders, Peter F A / Oosterwijk, Egbert

Neoplasia (New York, N.Y.)

2022 Volume 32, Page(s) 100826

Abstract: Sunitinib is an effective treatment for patients with metastatic Renal Cell Carcinoma (mRCC) but ultimately resistance occurs. The aim of this study was to investigate sunitinib resistance in RCCs and to develop therapeutic combination strategies with ... ...

Abstract	Sunitinib is an effective treatment for patients with metastatic Renal Cell Carcinoma (mRCC) but ultimately resistance occurs. The aim of this study was to investigate sunitinib resistance in RCCs and to develop therapeutic combination strategies with targeted radioimmunotherapy (RIT). We studied two RCC models, analyzed Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) and AXL/MET expression and performed therapy studies in Balb/c
MeSH term(s)	Animals ; Carcinoma, Renal Cell ; Cell Line, Tumor ; Kidney Neoplasms ; Mice ; Mice, Nude ; Radioimmunotherapy ; Sunitinib ; Vascular Endothelial Growth Factor A
Chemical Substances	Vascular Endothelial Growth Factor A ; Sunitinib (V99T50803M)
Language	English
Publishing date	2022-07-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1483840-0
ISSN	1476-5586 ; 1522-8002
ISSN (online)	1476-5586
ISSN	1522-8002
DOI	10.1016/j.neo.2022.100826
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Zs.A 5203: Show issues

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Article ; Online: Novel VHH-Based Tracers with Variable Plasma Half-Lives for Imaging of CAIX-Expressing Hypoxic Tumor Cells.

van Lith, Sanne A M / Huizing, Fokko J / Franssen, Gerben M / Hoeben, Bianca A W / Lok, Jasper / Doulkeridou, Sofia / Boerman, Otto C / Gotthardt, Martin / van Bergen En Henegouwen, Paul M P / Bussink, Johan / Heskamp, Sandra

Molecular pharmaceutics

2022 Volume 19, Issue 10, Page(s) 3511–3520

Abstract: Hypoxic areas are present in the majority of solid tumors, and hypoxia is associated with resistance to therapies and poor outcomes. A transmembrane protein that is upregulated by tumor cells that have adapted to hypoxic conditions is carbonic anhydrase ... ...

Abstract	Hypoxic areas are present in the majority of solid tumors, and hypoxia is associated with resistance to therapies and poor outcomes. A transmembrane protein that is upregulated by tumor cells that have adapted to hypoxic conditions is carbonic anhydrase IX (CAIX). Therefore, noninvasive imaging of CAIX could be of prognostic value, and it could steer treatment strategies. The aim of this study was to compare variants of CAIX-binding VHH B9, with and without a C-terminal albumin-binding domain with varying affinity (ABD
MeSH term(s)	Albumins/metabolism ; Animals ; Antibodies, Monoclonal/chemistry ; Antigens, Neoplasm/metabolism ; Carbonic Anhydrase IX/metabolism ; Cell Line, Tumor ; Half-Life ; Head and Neck Neoplasms/diagnostic imaging ; Humans ; Hypoxia ; Mice ; Pentetic Acid ; Tissue Distribution ; Tomography, Emission-Computed, Single-Photon
Chemical Substances	Albumins ; Antibodies, Monoclonal ; Antigens, Neoplasm ; Pentetic Acid (7A314HQM0I) ; Carbonic Anhydrase IX (EC 4.2.1.1)
Language	English
Publishing date	2022-01-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.1c00841
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