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4. Generic semi-automated radiofluorination strategy for single domain antibodies: [18F]FB-labelled single domain antibodies for PET imaging of fibroblast activation protein-α or folate receptor-α overexpression in cancer

Author

Dierick, Herlinde, Navarro, Laurent, Ceuppens, Hannelore, Ertveldt, Thomas, Pombo Antunes, Ana Rita, Keyaerts, Marleen, Devoogdt, Nick, Breckpot, Karine, D’Huyvetter, Matthias, Lahoutte, Tony, Caveliers, Vicky, and Bridoux, Jessica

Published
2024
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5. Efficient α and β− radionuclide therapy targeting fibroblast activation protein-α in an aggressive preclinical mouse tumour model.

Author

Ceuppens, Hannelore, Pombo Antunes, Ana Rita, Navarro, Laurent, Ertveldt, Thomas, Berdal, Marion, Nagachinta, Surasa, De Ridder, Kirsten, Lahoutte, Tony, Keyaerts, Marleen, Devoogdt, Nick, Goyvaerts, Cleo, D'Huyvetter, Matthias, and Breckpot, Karine

Subjects
PROGRAMMED death-ligand 1, IMMUNE checkpoint proteins, MEDICAL sciences, TREATMENT effectiveness, LABORATORY mice
Abstract

Purpose: Targeted radionuclide therapy (TRT) is a cancer treatment with relative therapeutic efficacy across various cancer types. We studied the therapeutic potential of TRT using fibroblast activation protein-α (FAP) targeting sdAbs (4AH29) labelled with 225Ac or 131I in immunocompetent mice in a human FAP (hFAP) expressing lung cancer mouse model. We further explored the combination of TRT with programmed cell death ligand 1 (PD-L1) immune checkpoint blockade (ICB). Methods: We studied the biodistribution and tumour uptake of [131I]I-GMIB-4AH29 and [225Ac]Ac-DOTA-4AH29 by ex vivo γ-counting. Therapeutic efficacy of [131I]I-GMIB-4AH29 and [225Ac]Ac-DOTA-4AH29 was evaluated in an immunocompetent mouse model. Flow cytometry analysis of tumours from [225Ac]Ac-DOTA-4AH29 treated mice was performed. Treatment with [225Ac]Ac-DOTA-4AH29 was repeated in combination with PD-L1 ICB. Results: The biodistribution showed high tumour uptake of [131I]I-GMIB-4AH29 with 3.5 ± 0.5% IA/g 1 h post-injection (p.i.) decreasing to 0.9 ± 0.1% IA/g after 24 h. Tumour uptake of [225Ac]Ac-DOTA-4AH29 was also relevant with 2.1 ± 0.5% IA/g 1 h p.i. with a less steep decrease to 1.7 ± 0.2% IA/g after 24 h. Survival was significantly improved after treatment with low and high doses [131I]I-GMIB-4AH29 or [225Ac]Ac-DOTA-4AH29 compared to vehicle solution. Moreover, we observed significantly higher PD-L1 expression in tumours of mice treated with [225Ac]Ac-DOTA-4AH29 compared to vehicle solution. Therefore, we combined high dose [225Ac]Ac-DOTA-4AH29 with PD-L1 ICB showing therapeutic synergy. Conclusion: [225Ac]Ac-DOTA-4AH29 and [131I]I-GMIB-4AH29 exhibit high and persistent tumour targeting, translating into prolonged survival in mice bearing aggressive tumours. Moreover, we demonstrate that the combination of PD-L1 ICB with [225Ac]Ac-DOTA-4AH29 TRT enhances its therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Published
2025
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6. Automated radiofluorination of HER2 single domain antibody: the road towards the clinical translation of [18F]FB-HER2 sdAb.

Author

Dierick, Herlinde, Navarro, Laurent, Van den Block, Sonja, Saliën, Jelena, Lahoutte, Tony, Caveliers, Vicky, and Bridoux, Jessica

Subjects
POSITRON emission tomography, COMPUTED tomography, PRODUCTION methods, DECISION making, CLINICAL trials
Abstract

Background: With the next generation of Human Epidermal Growth Factor Receptor 2 (HER2) -targeting therapies, such as antibody–drug conjugates, showing benefit in "HER2 low" and even "HER2 ultralow" patients, the need for novel methods to quantify HER2 expression accurately becomes even more important for clinical decision making. A HER2 PET/CT imaging assessment could evaluate HER2 positive disease locations while improving patient care, reducing the need for invasive biopsies. A single-domain antibody (sdAb)-based PET tracer could combine the high specificity of sdAbs with short-lived radionuclides such as fluorine-18 (18F) and gallium-68 (68Ga). SdAb-based PET tracers have clinically been used via a 68Ga-chelator approach. However, the distribution of 68Ga-labelled pharmaceuticals to peripheral PET centres is more challenging to organize due to the short half-life of 68Ga, most certainly when the available activity is limited by a generator. Cyclotron produced 68Ga has removed this limitation. Distribution of 18F-labelled pharmaceuticals remains less challenging due to its slightly longer half-life, and radiofluorination of sdAbs via N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) has shown to be a promising strategy for developing sdAb-based PET tracers. Although [18F]SFB automation has been reported, automating protein conjugation proves challenging. Herein we report the fully automated, cartridge-based production of [18F]FB-HER2 sdAb on a single synthesis module. Results: [18F]FB-HER2 sdAb (> 6 GBq) was obtained after a fully automated production (95 min), with a RCP > 95%, apparent molar activity > 20 GBq/µmol and decay-corrected radiochemical yield (RCY d.c.) of 14 ± 2% (n = 4). Further upscaling amounted to production batches of 16 GBq with an apparent molar activity > 40 GBq/µmol and RCY d.c. of 8 ± 1% (n = 4). Ex vivo biodistribution and PET imaging showed specific HER2-positive tumour targeting and low kidney retention. Conclusion: The [18F]FB-HER2 sdAb tracer was produced with clinically relevant activities using a fully automated production method. The automated production method was designed to ease the translation to the clinic and has the potential to be used not only in mono-centre but also multi-centre clinical trials with one central production site. [18F]FB-HER2 sdAb showed a favourable biodistribution pattern and could be a valuable alternative to 68Ga-labelled sdAb-based PET tracers in the clinic. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Generic semi-automated radiofluorination strategy for single domain antibodies: [18F]FB-labelled single domain antibodies for PET imaging of fibroblast activation protein-α or folate receptor-α overexpression in cancer.

Author

Dierick, Herlinde, Navarro, Laurent, Ceuppens, Hannelore, Ertveldt, Thomas, Pombo Antunes, Ana Rita, Keyaerts, Marleen, Devoogdt, Nick, Breckpot, Karine, D'Huyvetter, Matthias, Lahoutte, Tony, Caveliers, Vicky, and Bridoux, Jessica

Subjects
POSITRON emission tomography, FIBROBLASTS, TUMOR markers, FOLIC acid, GENETIC overexpression, BREAST, IMMUNOGLOBULINS, MOLECULAR pathology
Abstract

Background: Radiofluorination of single domain antibodies (sdAbs) via N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) has shown to be a promising strategy in the development of sdAb-based PET tracers. While automation of the prosthetic group (PG) [18F]SFB production, has been successfully reported, no practical method for large scale sdAb labelling has been reported. Therefore, we optimized and automated the PG production, enabling a subsequently efficient manual conjugation reaction to an anti-fibroblast activation protein (FAP)-α sdAb (4AH29) and an anti-folate receptor (FR)-α sdAb (2BD42). Both the alpha isoform of FAP and the FR are established tumour markers. FAP-α is known to be overexpressed mainly by cancer-associated fibroblasts in breast, ovarian, and other cancers, while its expression in normal tissues is low or undetectable. FR-α has an elevated expression in epithelial cancers, such as ovarian, brain and lung cancers. Non-invasive imaging techniques, such as PET-imaging, using tracers targeting specific tumour markers can provide molecular information over both the tumour and its environment, which aides in the diagnosis, therapy selection and assessment of the cancer treatment. Results: [18F]SFB was synthesized using a fully automated three-step, one-pot reaction. The total procedure time was 54 min and results in [18F]SFB with a RCP > 90% and a RCY d.c. of 44 ± 4% (n = 13). The manual conjugation reaction after purification produced [18F]FB-sdAbs with a RCP > 95%, an end of synthesis activity > 600 MBq and an apparent molar activity > 10 GBq/µmol. Overall RCY d.c., corrected to the trapping of [18F]F− on the QMA, were 9% (n = 1) and 5 ± 2% (n = 3) for [18F]FB-2BD42 and [18F]FB-4AH29, respectively. Conclusion: [18F]SFB synthesis was successfully automated and upscaled on a Trasis AllInOne module. The anti-hFAP-α and anti-hFR-α sdAbs were radiofluorinated, yielding similar RCYs d.c. and RCPs, showing the potential of this method as a generic radiofluorination strategy for sdAbs. The radiofluorinated sdAbs showed a favourable biodistribution pattern and are attractive for further characterization as new PET tracers for FAP-α and FR-α imaging. [ABSTRACT FROM AUTHOR]

Published
2024
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25. Phase I Study of [68Ga]Ga-Anti-CD206-sdAb for PET/CT Assessment of Protumorigenic Macrophage Presence in Solid Tumors (MMR Phase I).

Author

Gondry, Odrade, Xavier, Catarina, Raes, Laurens, Heemskerk, Johannes, Devoogdt, Nick, Everaert, Hendrik, Breckpot, Karine, Lecocq, Quentin, Decoster, Lore, Fontaine, Christel, Schallier, Denis, Aspeslagh, Sandrine, Vaneycken, Ilse, Raes, Geert, Van Ginderachter, Jo A., Lahoutte, Tony, Caveliers, Vicky, and Keyaerts, Marleen

Published
2023
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38. Repeatability of 68GaNOTA-anti-HER2 sdAb in 20 breast cancer patients

Author

Gondry, Odrade, Xavier, Catarina, De Geeter, Frank, Al Dabssi, Omar, Glorieus, Katrien, Aspeslagh, Sandrine, Joris, Sofie, Fontaine, Christel, Verfaillie, Guy, De Grève, Jacques, Vanhoeij, Marian, Luyten, Ine, Heemskerk, Johannes, Bourgeois, Sophie, Raes, Laurens Albert J, Devoogdt, Nick, Vaneycken, Ilse, Cousaert, Julie, Caveliers, Vicky, Everaert, Hendrik, Lahoutte, Tony, Keyaerts, Marleen, Nuclear Medicine, Supporting clinical sciences, Faculty of Medicine and Pharmacy, Medical Imaging, Surgery, Laboratory for Medical and Molecular Oncology, Clinical sciences, Medical Oncology, and Medical Genetics

Abstract

Introduction The human epidermal growth factor receptor 2 (HER2) status is important for HER2 targeting therapies. T his information is obtained through immunohistochemistry (IHC) or in situ hybridisation (ISH), which necessitates tissue sampling, and may miss tumor heterogeneity as not every lesion consists of the same cells, nor expresses the same levels of HER2. To assess multiple lesions, whole-body imaging using PET/CT imaging might be a solution. A 68Ga-labeled, NOTA-coupled, single-domain antibody (sdAb) targeting the HER2 receptor has been developed (1). Methods In this phase II trial, 20 patients (pts) with locally advanced or metastatic breast carcinoma (BC) were included. Pts were injected intravenously with a typical dose of 100 ug and an activity range of 98-168 MBq 68GaNOTA-anti-HER2 sdAb, followed by PET/CT (Siemens Biograph Vision, 120 s per bed position and 40 s for the legs) at 90 min post injection (pi). A 2nd tracer injection, followed by PET/CT with identical parameters, was done within 8 days. In both image data sets, up to 5 lesions (minimal diameter 12mm, for lymph nodes in the short axis) per pt were selected with no more than 2 per organ system. Peak Standard Uptake Values (SUVpeak) of selected lesions were measured on both scans with Siemens' Syngo.via VB40 and compared with student t-test and Bland-Altman Plots for differences. Results/Discussion Out of 20 pts included with BC (6 HER2+, 14 HER2-) with a mean age of 58.6 y (37-81), three were scanned only once: one owing to the COVID-19 pandemic and two due to withdrawal of consent. An example of repeated tracer injection and subsequent imaging is shown in fig. 1. No safety concerns were identified in these 20 patients, confirming the excellent safety of this imaging tracer. For repeatability analysis, 50 lesions were delineated by a study team member on both scans in 17 pts. No significant differences between the two measurements were found (p:0.40). The repeatability coefficient (RC) was 38.2%. The mean absolute percentagedifference (MAPD), which is the mean of 1100x(SUV2- all subjects, was 13.6%, comparable to repeated values reported for 18F-FDG (2). Bland-Altman plot with the relative difference is shown in Fig. 2. Independent uptake analysis of all lesions by a central image reviewer, blinded to the HER2 status of the patient is ongoing. Conclusions This study confirms that on PET/CT imaging in patients with breast carcinoma, SUVpeak is a highly repeatable metric for quantifying 68GaNOTA-anti-HER2 sdAb uptake in subsequent scans. lts repeatability is similar to that reported for other routinely used tracers, such as FDG. Additional studies to define the potential clinical benefit of this technique are currently ongoing.

Published
2022

39. Assessment of repeatability and uptake quantification of (68)GaNOTA-anti-HER2 sdAb PET/CT in patients with locally advanced or metastatic breast cancer

Author

Gondry, Odrade, Xavier, Catarina, Waelput, Wim, Al Dabssi, Omar, Vanhoeij, Marian, Aspeslagh, Sandrine, Joris, Sofie, Fontaine, Christel, Verfaillie, Guy, De Grève, Jacques, Glorieus, Katrien, Luyten, Ine, Frederik, Vandenbroucke, Bourgeois, Sophie, Thyparambil, Sheeno, Devoogdt, Nick, Vaneycken, Ilse, Cousaert, Julie, Caveliers, Vicky, Everaert, Hendrik, Lahoutte, Tony, Keyaerts, Marleen, Raes, Laurens Albert J, Nuclear Medicine, Supporting clinical sciences, Faculty of Medicine and Pharmacy, Medical Imaging, Experimental Pathology, Pathology, Surgical clinical sciences, Clinical sciences, Surgery, Laboratory for Medical and Molecular Oncology, Medical Oncology, Medical Genetics, Medicine and Pharmacy academic/administration, and Radiology

Abstract

Background: Human epidermal growth factor receptor 2 (HER2) status is an important predictive biomarker in breast cancer (BC). Tumor heterogeneity has been described, with changes in HER2 expression levels between lesions and over the disease course. HER2 expression is assessed on tissue biopsies, at primary diagnosis and in metastatic lesions. A whole-body imaging technique such as PET/CT could help understand expression levels in different lesions. A 68Ga-labeled single domain antibody (sdAb) targeting the HER2 receptor has been developed and proven safe (Keyaerts et al., 2016). Imaging is performed at 90 min post-injection (pi). We report results of a phase II trial to assess the repeatability of the technique in 20 patients and the correlation of tracer uptake with HER2 tissue expression of the lesions present at the time of imaging. Methods: Twenty patients (pts) with a locally advanced or metastatic BC with at least one lesion of minimum 12 mm were included. Pts were injected intravenously with a typical protein mass of 100 µg and a radioactive dose ranging from 98-168 MBq 68GaNOTA-anti-HER2 sdAb. PET/CT images were obtained at 90 min pi. A second tracer injection followed by PET/CT was done with a maximal interval of 8 days. To assess repeatability, up to 5 lesions per pt were selected, with no more than 2 in a single organ. Peak Standard Uptake Values (SUVpeak) of the lesions were measured on both scans and compared with a t-test and Bland-Altman Plots. Images were compared to other available medical or imaging data and interpreted considering the subject’s disease course. Serum and plasma samples were collected before injection and between 60 and 365 days pi and stored for future detection of anti-drug antibodies (ADA) and liquid biopsies analysis for the presence of HER2 amplification. Tissue samples were assessed by central labs using mass spectrometry, immunohistochemistry and in fluorescence situ hybridization. Results: Twenty women with BC (6 HER2+, 14 HER2-) with a mean age of 58.6 y (37-81) were included. Three pts were scanned only once (2 due to withdrawal of consent, 1 due to covid pandemic). Repeatability of the technique was visually scored as excellent. For quantification, 50 lesions were compared on both scans in 17 pts without significant differences between the two measurements (p=0.40). The repeatability coefficient (RC) was 38.2%. The mean absolute percentage difference (MAPD) was 13.6%, comparable to repeat values reported for 18F-FDG. In 3 out of 6 HER2-positive (HER2+) patients, lesions showed high uptake, even better visible than using 18F-FDG in 2 of them. In 2 HER2+ subjects with a negative scan, lesions were confirmed to be true negatives: one patient did not relapse from BC but had tuberculosis; the other was confirmed to have a radiopneumonitis after radiotherapy and no relapse. In 1 HER2+ patient, the uptake was unexpectedly low. However, the HER2 status was also not reconfirmed in the metastatic setting for this subject. In 1 HER2-negative patient, the tumor HER2 status was changed from negative to positive based on a subsequent image-guided biopsy performed in this study. High tracer uptake was also seen in many of the patients presenting with HER2-low BC (IHC 1+ or 2+), indicating the potential of the tracer to detect low-level HER2 expression. Additional correlation to centrally performed tissue and blood analysis is ongoing. Conclusion: 68GaNOTA-Anti-HER2 PET/CT shows high uptake in HER2-expressing BC lesions but also in HER2-low lesions. The technique shows good repeatability and, in some cases, even better sensitivity than 18F-FDG PET/CT. Specificity was confirmed in relapse-free lesions such as tuberculosis and radiopneumonitis. Its sensitivity makes it a promising technique to assess HER2+ and HER2-low lesions in BC patients.

Published
2022

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