Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [<sup>68</sup>Ga]ABY-025 Affibody PET/CT

Sørensen, Jens Nørkær; Velikyan, Irina; Sandberg, Dan; Wennborg, Anders; Feldwisch, Joachim; Tolmachev, Vladimir; Orlova, Anna; Sandström, Mattias; Lubberink, Mark; Olofsson, Helena; Carlsson, Jörgen; Lindman, Henrik

doi:10.7150/thno.13502

Cited by 222 publications

(276 citation statements)

References 29 publications

Supporting

Mentioning

258

Contrasting

Unclassified

Order By: Relevance

“…52 Advantage of higher injected protein dose in discrimination between metastases with high and low HER2 expression has been confirmed also in a clinical study. 32 The saturable binding to two HER2-expressing cell lines in vitro demonstrated that binding specificity of the conjugates is preserved. A study using LS174T and SKOV-3 cell lines demonstrated similar cellular processing level and slow internalization of all conjugates (Figures 3 and 4).…”

Section: Comparative In Vivo Studiesmentioning

confidence: 98%

Increasing the Net Negative Charge by Replacement of DOTA Chelator with DOTAGA Improves the Biodistribution of Radiolabeled Second-Generation Synthetic Affibody Molecules

et al. 2016

Self Cite

View full text Add to dashboard Cite

A promising strategy to enable patient stratification for targeted therapies is to monitor the target expression in a tumor by radionuclide molecular imaging. Affibody molecules (7 kDa) are nonimmunoglobulin scaffold proteins with a 25-fold smaller size than intact antibodies. They have shown an apparent potential as molecular imaging probes both in preclinical and clinical studies. Earlier, we found that hepatic uptake can be reduced by the incorporation of negatively charged purification tags at the N-terminus of Affibody molecules. We hypothesized that liver uptake might similarly be reduced by positioning the chelator at the N-terminus, where the chelator-radionuclide complex will provide negative charges. To test this hypothesis, a second generation synthetic anti-HER2 ZHER2:2891 Affibody molecule was synthesized and labeled with (111)In and (68)Ga using DOTAGA and DOTA chelators. The chelators were manually coupled to the N-terminus of ZHER2:2891 forming an amide bond. Labeling DOTAGA-ZHER2:2891 and DOTA-ZHER2:2891 with (68)Ga and (111)In resulted in stable radioconjugates. The tumor-targeting and biodistribution properties of the (111)In- and (68)Ga-labeled conjugates were compared in SKOV-3 tumor-bearing nude mice at 2 h postinjection. The HER2-specific binding of the radioconjugates was verified both in vitro and in vivo. Using the DOTAGA chelator gave significantly lower radioactivity in liver and blood for both radionuclides. The (111)In-labeled conjugates showed more rapid blood clearance than the (68)Ga-labeled conjugates. The most pronounced influence of the chelators was found when they were labeled with (68)Ga. The DOTAGA chelator gave significantly higher tumor-to-blood (61 ± 6 vs 23 ± 5, p < 0.05) and tumor-to-liver (10.4 ± 0.6 vs 4.5 ± 0.5, p < 0.05) ratios than the DOTA chelator. This study demonstrated that chelators may be used to alter the uptake of Affibody molecules, and most likely other scaffold-based imaging probes, for improvement of imaging contrast.

show abstract

Section: Comparative In Vivo Studiesmentioning

confidence: 98%

Increasing the Net Negative Charge by Replacement of DOTA Chelator with DOTAGA Improves the Biodistribution of Radiolabeled Second-Generation Synthetic Affibody Molecules

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…The effective radiation doses were 0.15 6 0.02 mSv/MBq (21 mSv/patient) for 111 In and 0.028 6 0.003 mSv/MBq (5.6 mSv/patient) for 68 Ga (20,22). Injection of 500 mg of 68 Ga-ABY-025 provided better sensitivity and specificity than 100 mg, mainly because of reduced retention in the liver (21). Comparison with immunohistochemical staining of biopsy material demonstrated that the measurement of the maximal uptake value at 2-4 h after injection permits clear discrimination between metastases with 31 and 21 levels of HER2 expression (21).…”

Section: Affibody Molecules In Radionuclide Imagingmentioning

confidence: 99%

“…The second-generation Affibody molecule ABY-025 labeled with 111 In for SPECT imaging and 68 Ga for PET imaging were evaluated in phase I/II clinical studies for assessment of HER2 expression in breast cancer metastases (Fig. 1C) (20,21). ABY-025 was found to be safe in humans, and no anti-Affibody antibodies were found after repeated administration.…”

Section: Affibody Molecules In Radionuclide Imagingmentioning

confidence: 99%

“…Injection of 500 mg of 68 Ga-ABY-025 provided better sensitivity and specificity than 100 mg, mainly because of reduced retention in the liver (21). Comparison with immunohistochemical staining of biopsy material demonstrated that the measurement of the maximal uptake value at 2-4 h after injection permits clear discrimination between metastases with 31 and 21 levels of HER2 expression (21). Furthermore, the spleen can be used as an within-image reference tissue to calculate tumorto-spleen ratios, permitting a simple and robust discrimination between metastases with high and low HER2 expression using both PET and SPECT (23) and thus making the diagnosis independent of external hardware calibrations.…”

Section: Affibody Molecules In Radionuclide Imagingmentioning

confidence: 99%

See 1 more Smart Citation

Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology

Krasniqi¹,

D’Huyvetter²,

Devoogdt³

et al. 2018

J Nucl Med

Self Cite

109

View full text Add to dashboard Cite

Imaging of expression of therapeutic targets may enable stratification of patients for targeted treatments. The use of small radiolabeled probes based on the heavy-chain variable region of heavy-chain-only immunoglobulins or nonimmunoglobulin scaffolds permits rapid localization of radiotracers in tumors and rapid clearance from normal tissues. This makes high-contrast imaging possible on the day of injection. This mini review focuses on small proteins for radionuclide-based imaging that would allow same-day imaging, with the emphasis on clinical applications and promising preclinical developments within the field of oncology.

show abstract

“…68 Ga-ABY-025 and PET have, in a recent study, been shown capable of discriminating HER2-positive metastases, with SUV correlating well with HER2 expression (17). In that study, 2 different amounts of peptides were administered, with the higher peptide dose giving the best results in terms of detectability and discrimination.…”

mentioning

confidence: 99%

Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule ⁶⁸Ga-ABY-025 in Breast Cancer Patients

et al. 2016

Self Cite

View full text Add to dashboard Cite

68 Ga-ABY-025 is a radiolabeled Affibody molecule for in vivo diagnosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer tumors with PET. The aim of the present work was to measure the biodistribution and estimate the radiation dosimetry of 68 Ga-ABY-025 for 2 different peptide mass doses in a single group of patients using dynamic and serial whole-body PET/CT. Methods: Eight patients with metastatic breast cancer were included. Each patient underwent an abdominal 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 4 h after injection of a low peptide dose (LD) and a high peptide dose (HD), with approximately the same amount of radioactivity, in separate investigations 1 wk apart. As input to the absorbed dose calculations, volumes of interest were drawn on all clearly identifiable source organs: liver, kidneys, spleen, descending aorta, and upper large intestine. Absorbed doses were calculated using OLINDA/EXM, version 1.1. Results: Of the major organs, the highest radionuclide uptake at 1, 2, and 4 h after injection was observed in the kidneys and liver. The highest absorbed organ doses were seen in the kidneys, followed by the liver for both LD and HD 68 Ga-ABY-025. Absorbed doses to liver and kidneys were slightly but significantly higher for LD. Total effective dose was 0.030 ± 0.003 mSv/MBq for LD and 0.028 ± 0.002 mSv/MBq for HD. Conclusion: The effective dose for a typical 200-MBq administration of 68 Ga-ABY-025 is 6.0 mSv for LD and 5.6 mSv for HD. Therefore, from a radiation dosimetry point of view, HD is preferred for PET/CT evaluation of HER2-expressing breast cancer tumors. These effective doses are somewhat higher than earlier published values for other 68 Ga-labeled tracers, such as 0.021 ± 0.003 mSv/MBq for 68 Ga-DOTATATE and 68 Ga-DOTATOC, mainly because of higher uptake in liver and kidney. Forwomen,br east cancer is currently the most common cancer.Human epidermal growth factor receptor 2 (HER2) is overexpressed in about 1 of 6 cases (1-3) at initial diagnosis and is associated with poor survival (1,3). Treatments targeted to HER2, such as with the anti-HER2 antibody trastuzumab, have considerably improved overall survival (1,3,4). Today, assessment of HER2 status is based on tumor biopsy. However, HER2 expression can vary between the primary tumor and metastases in up to 40% of cases (2,5,6) and metastatic HER2 expression can change over time, which could necessitate a change of therapy (7,8). Follow-up using biopsies cannot always be performed due to practical reasons or patient discomfort.Molecular imaging using SPECT and PET might be a noninvasive, whole-body-based way to evaluate HER2 expression quantitatively. One such approach is the use of trastuzumab labeled with 111 In (half-time, 2.8 d) (9) or 89 Zr (3.3 d) (10) for use with SPECT and PET, respectively, but the slow kinetics of antibodies require imaging several days after administration. One promising method of fast, safe, and accurate imaging that specifically binds to a site on the receptor not occu...

show abstract

Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [⁶⁸Ga]ABY-025 Affibody PET/CT

Cited by 222 publications

References 29 publications

Increasing the Net Negative Charge by Replacement of DOTA Chelator with DOTAGA Improves the Biodistribution of Radiolabeled Second-Generation Synthetic Affibody Molecules

Increasing the Net Negative Charge by Replacement of DOTA Chelator with DOTAGA Improves the Biodistribution of Radiolabeled Second-Generation Synthetic Affibody Molecules

Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology

Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule ⁶⁸Ga-ABY-025 in Breast Cancer Patients

Contact Info

Product

Resources

About

Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [68Ga]ABY-025 Affibody PET/CT

Cited by 222 publications

References 29 publications

Increasing the Net Negative Charge by Replacement of DOTA Chelator with DOTAGA Improves the Biodistribution of Radiolabeled Second-Generation Synthetic Affibody Molecules

Increasing the Net Negative Charge by Replacement of DOTA Chelator with DOTAGA Improves the Biodistribution of Radiolabeled Second-Generation Synthetic Affibody Molecules

Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology

Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule 68Ga-ABY-025 in Breast Cancer Patients

Contact Info

Product

Resources

About

Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [⁶⁸Ga]ABY-025 Affibody PET/CT

Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule ⁶⁸Ga-ABY-025 in Breast Cancer Patients