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In Vivo Imaging of the Programmed Death Ligand 1 by F-18 PET
Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
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2017 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 58, no 11, p. 1852-1857Article in journal (Refereed) Published
Abstract [en]

Programmed death ligand 1 (PD-L1) is an immune regulatory ligand that binds to the T-cell immune check point programmed death 1. Tumor expression of PD-L1 is correlated with immune suppression and poor prognosis. It is also correlated with therapeutic efficacy of programmed death 1 and PD-L1 inhibitors. In vivo imaging may enable real-time follow-up of changing PD-L1 expression and heterogeneity evaluation of PD-L1 expression across tumors in the same subject. We have radiolabeled the PD-L1-binding Affibody molecule NOTA-Z(PD-L1_1) with F-18 and evaluated its in vitro and in vivo binding affinity, targeting, and specificity. Methods: The affinity of the PD-L1-binding Affibody ligand Z(PD-L1_1) was evaluated by surface plasmon resonance. Labeling was accomplished by maleimide coupling of NOTA to a unique cysteine residue and chelation of F-18-AlF. In vivo studies were performed in PD-L1-positive, PD-L1-negative, and mixed tumor-bearing severe combined immunodeficiency mice. Tracer was injected via the tail vein, and dynamic PET scans were acquired for 90 min, followed by gamma-counting biodistribution. Immunohistochemical staining with an antibody specific for anti-PD-L1 (22C3) was used to evaluate the tumor distribution of PD-L1. Immunohistochemistry results were then compared with ex vivo autoradiographic images obtained from adjacent tissue sections. Results: NOTA-Z(PD-L1_1) was labeled, with a radiochemical yield of 15.1% +/- 5.6%, radiochemical purity of 96.7% +/- 2.0%, and specific activity of 14.6 +/- 6.5 GBq/mu mol. Surface plasmon resonance showed a NOTA-conjugated ligand binding affinity of 1 nM. PET imaging demonstrated rapid uptake of tracer in the PD-L1-positive tumor, whereas the PD-L1-negative control tumor showed little tracer retention. Tracer clearance from most organs and blood was quick, with biodistribution showing prominent kidney retention, low liver uptake, and a significant difference between PD-L1-positive (percentage injected dose per gram [%ID/g] = 2.56 +/- 0.33) and -negative (% ID/g = 0.32 +/- 0.05) tumors (P = 0.0006). Ex vivo autoradiography showed excellent spatial correlation with immunohistochemistry in mixed tumors. Conclusion: Our results show that Affibody ligands can be effective at targeting tumor PD-L1 in vivo, with good specificity and rapid clearance. Future studies will explore methods to reduce kidney activity retention and further increase tumor uptake.

Place, publisher, year, edition, pages
2017. Vol. 58, no 11, p. 1852-1857
Keywords [en]
programmed death ligand 1, positron emission tomography, immuno-oncology, F-18-AlF-NOTA-Z(PD-L1_1)
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-341354DOI: 10.2967/jnumed.117.191718ISI: 000414241300025PubMedID: 28588151OAI: oai:DiVA.org:uu-341354DiVA, id: diva2:1181975
Available from: 2018-02-12 Created: 2018-02-12 Last updated: 2018-02-12Bibliographically approved

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Frejd, Fredrik Y.

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