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Meeting ReportOral - PhysicianPharm

Targeting Activated Fibroblasts for non-invasive detection of Lung Fibrosis

Carolina Ferreira, Zachary Rosenkrans, Ksenija Bernau, Melissa Moore, Frank Valla, Jeanine Batterton, Christopher Drake, Christopher Massey, Alan McMillan, Nathan Sandbo, Ali Pirasteh and Reinier Hernandez
Journal of Nuclear Medicine May 2021, 62 (supplement 1) 10;
Carolina Ferreira
1University of Wisconsin - Madison Madison WI United States
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Zachary Rosenkrans
1University of Wisconsin - Madison Madison WI United States
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Ksenija Bernau
1University of Wisconsin - Madison Madison WI United States
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Melissa Moore
2Sofie Biosciences Dulles VA United States
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Frank Valla
2Sofie Biosciences Dulles VA United States
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Jeanine Batterton
1University of Wisconsin - Madison Madison WI United States
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Christopher Drake
2Sofie Biosciences Dulles VA United States
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Christopher Massey
1University of Wisconsin - Madison Madison WI United States
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Alan McMillan
1University of Wisconsin - Madison Madison WI United States
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Nathan Sandbo
1University of Wisconsin - Madison Madison WI United States
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Ali Pirasteh
1University of Wisconsin - Madison Madison WI United States
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Reinier Hernandez
1University of Wisconsin - Madison Madison WI United States
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Abstract

10

Objectives: Interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF), are characterized by progressive lung fibrosis and cause significant morbidity and mortality in the U.S., with over 40,000 annual deaths. A major challenge in IPF clinical management is lack of a direct noninvasive biomarker for early detection and monitoring of disease activity. In IPF, activated fibroblasts are a central mediator of extracellular matrix deposition that drives fibrosis and ultimately progressive decline in lung function. The fibroblast activation protein (FAP) is a cell surface serine protease and upregulated in a subset of activated fibroblasts associated with matrix remodeling in IPF and could serve as a target for disease activity assessment. FAP inhibitors (FAPIs) have recently emerged as promising imaging agents in FAP-positive environments, such as cancer. Herein, we utilized a FAPI-based PET/CT radiotracer (68Ga-FAPI-46) for noninvasive early detection and monitoring of pulmonary fibrosis in a mouse model.

Methods: To induce pulmonary fibrosis, a single intratracheal dose of bleomycin (1U/kg) was delivered into the lungs of 13-week-old C57BL/6J mice (n=6). Control mice were given 0.9% normal saline (n=6). FAPI-46 precursor was radiolabeled with 68GaCl3 in sodium acetate buffer (pH = 4.0) containing sodium ascorbate at 95°C for 15 minutes and purified by reversed-phase solid phase extraction. Radiochemical yield and purity were determined by reversed-phase HPLC. For dynamic PET scans, on post-bleomycin days 7 and 14 , subgroups of mice (n=3) were anesthetized and the lateral tail vein was catheterized. Simultaneous with the administration of 1.7 MBq (50 µCi) of 68Ga-FAPI-46 (68Ga-FAPI) as a fast intravenous bolus, dynamic 1 hr PET images were acquired (Inveon microPET/CT; 46 frames) and reconstructed using the OSEM3D/MAP algorithm. CT images (80 kVp, 900 μA, resolution 105 μm) were acquired for anatomical co-registration and to detect fibrosis based on lung CT density in Hounsfield units (HU). Quantification of decay corrected PET/CT images, expressed as percent injected dose (%ID), was performed using Inveon Research Workspace by manually drawing region-of-interest (ROI) over the lungs and other tissues of interest. Following imaging, the mice were sacrificed and major organs were collected and counted in a calibrated gamma counter for confirmatory biodistribution evaluation.

Results: At 7 and 14 days post bleomycin administration, CT images demonstrated radiological evidence of fibrosis with a significantly higher CT density in the lungs of animals injected with bleomycin compared to the control (p < 0.05). Dynamic PET images demonstrated prompt uptake and clearance of radiotracer from the blood, kidneys, and bladder, indicating a predominantly renal radiotracer elimination. Compared to control animals, FAPI uptake in the lungs was markedly higher in the animals given bleomycin starting at 15 minutes after radiotracer injection, at both 7 and 14 days after bleomycin instillation. FAPI uptake in fibrotic lung, 1 hr post-injection, was twice (0.33 ± 0.08 vs 0.16 ± 0.01 %ID/g, p = 0.03) and three-time as high (1.01 ± 0.11 vs 0.36 ± 0.05 %ID/g, p < 0.001) as the control group at days 7 and 14 post-bleomycin, respectively, indicating disease progression. Biodistribution data were in agreement with the lung FAPI uptake, showing bleomycin vs control group %IDs of 0.18 ± 0.05 vs 0.03 ± 0.01 (p = 0.008) and 0.54 ± 0.32 vs 0.11 ± 0.03 (p = 0.002) at 7 and 14 days post-injection, respectively. Conclusion: 68Ga-FAPI-46 PET/CT can be utilized for detection and monitoring of progression of pulmonary fibrosis by directly targeting the fibroblast activation protein expression in a preclinical murine model. Our results suggest the potential of 68Ga-FAPI-46 PET as a noninvasive tool for early diagnosis and monitoring of pulmonary fibrosis and warrant further exploration of this tool in other translationally relevant models of fibrosis.

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Journal of Nuclear Medicine
Vol. 62, Issue supplement 1
May 1, 2021
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Targeting Activated Fibroblasts for non-invasive detection of Lung Fibrosis
Carolina Ferreira, Zachary Rosenkrans, Ksenija Bernau, Melissa Moore, Frank Valla, Jeanine Batterton, Christopher Drake, Christopher Massey, Alan McMillan, Nathan Sandbo, Ali Pirasteh, Reinier Hernandez
Journal of Nuclear Medicine May 2021, 62 (supplement 1) 10;

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Targeting Activated Fibroblasts for non-invasive detection of Lung Fibrosis
Carolina Ferreira, Zachary Rosenkrans, Ksenija Bernau, Melissa Moore, Frank Valla, Jeanine Batterton, Christopher Drake, Christopher Massey, Alan McMillan, Nathan Sandbo, Ali Pirasteh, Reinier Hernandez
Journal of Nuclear Medicine May 2021, 62 (supplement 1) 10;
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