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In Vivo Imaging of ...
In Vivo Imaging of the Programmed Death Ligand 1 by F-18 PET
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- Trotter, Dinko E. Gonzalez (författare)
- Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA.
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- Meng, Xiangjun (författare)
- Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA.
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- McQuade, Paul (författare)
- Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA.
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- Rubins, Daniel (författare)
- Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA.
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- Klimas, Michael (författare)
- Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA.
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- Zeng, Zhizhen (författare)
- Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA.
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- Connolly, Brett M. (författare)
- Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA.
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- Miller, Patricia J. (författare)
- Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA.
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- O'Malley, Stacey S. (författare)
- Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA.
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- Lin, Shu-An (författare)
- Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA.
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- Getty, Krista L. (författare)
- Merck & Co Inc, Screening & Prot Sci Dept, West Point, PA 19486 USA.
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- Fayadat-Dilman, Laurence (författare)
- Merck & Co Inc, Biol Discovery, Palo Alto, CA USA.
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- Liang, Linda (författare)
- Merck & Co Inc, Biol Discovery, Palo Alto, CA USA.
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- Wahlberg, Elisabet (författare)
- Affibody AB, Solna, Sweden.
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- Widmark, Olof (författare)
- Affibody AB, Solna, Sweden.
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- Ekblad, Caroline (författare)
- Affibody AB, Solna, Sweden.
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- Frejd, Fredrik Y. (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap,Affibody AB, Solna, Sweden
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- Hostetler, Eric D. (författare)
- Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA.
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- Evelhoch, Jeffrey L. (författare)
- Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA.
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Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA Merck & Co Inc, Screening & Prot Sci Dept, West Point, PA 19486 USA. (creator_code:org_t)
- 2017-06-06
- 2017
- Engelska.
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 58:11, s. 1852-1857
- Relaterad länk:
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http://jnm.snmjourna...
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https://urn.kb.se/re...
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https://doi.org/10.2...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
Nyckelord
- programmed death ligand 1
- positron emission tomography
- immuno-oncology
- F-18-AlF-NOTA-Z(PD-L1_1)
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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- Av författaren/redakt...
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Trotter, Dinko E ...
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Meng, Xiangjun
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McQuade, Paul
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Rubins, Daniel
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Klimas, Michael
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Zeng, Zhizhen
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visa fler...
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Connolly, Brett ...
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Miller, Patricia ...
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O'Malley, Stacey ...
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Lin, Shu-An
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Getty, Krista L.
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Fayadat-Dilman, ...
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Liang, Linda
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Wahlberg, Elisab ...
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Widmark, Olof
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Ekblad, Caroline
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Frejd, Fredrik Y ...
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Hostetler, Eric ...
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Evelhoch, Jeffre ...
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Uppsala universitet